Interests

Teaching

Barnes has taught a senior undergraduate/graduate level interdisciplinary course in Gerontology. The topics include include the biology, psychology and sociology of aging.

Research

The neurobiology of memory change during aging.

Courses

Scholarly Contributions

Chapters

• Barnes, C. A. (2018). The contribution of recollection, familiarity and discrimination to object recognition deficits in advanced age.. In Handbook of Object Novelty Recognition(pp pp: 291-305). Volume 27: London: Academic Press:.
• Burke, S. N., & Barnes, C. A. (2018). The Contribution of Recollection, Familiarity and Discrimination to Object Recognition Deficits in Advanced Age. In Handbook of Behavioral Neuroscience(pp Pages 291-305,). Elsevier B.V. doi:10.1016/b978-0-12-812012-5.00020-3
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  Declines in object recognition are widely reported in older humans and animal models, but the exact nature of these deficits remains a topic of debate. Accumulating data over the past several years have implicated the perirhinal cortex of the medial temporal lobe as a structure that is particularly vulnerable to dysfunction in advancing age. Because the perirhinal cortex is critical for stimulus recognition, these data could explain recognition deficits. Reports of perirhinal cortical dysfunctions, however, stand in contrast to other notions that the perirhinal cortex is unaffected by old age and perhaps compensates for a compromised hippocampus. One source of these discrepant interpretations is the differing views regarding the contributions of perirhinal cortical computations to cognitive function, which span from complex sensory representations to novelty detection. In this chapter we will discuss recent data from humans and animal models regarding age-related declines in object recognition in relation to perirhinal cortical function, and we propose that the perirhinal cortex is critical for stimulus discrimination, a process that is a core feature of recognition.
• Schimanski, L. A., & Barnes, C. A. (2015). Insights into age-related cognitive decline: Coupling neurophysiological and behavioral approaches.. In The Maze Book: Your Guidebook to Theories, Practice, and Protocols for Testing Rodent Cognition(pp 121-142). New York: Springer.
• Siniard, A. A., Corneveaux, J. J., DeBoth, M., Barnes, C. A., & Huentelman, M. J. (2015). RNA sequencing from laser capture microdissected brain tissue to study normal aging and Alzheimer’s disease. In Applied Neurogenomics(pp 111-120). New York: Spring.
• Siniard, A. L., Corneveaux, J. J., Chawla, M. K., Barnes, C. A., Huentelman, M. J., & Both, M. D. (2015).

  RNA Sequencing from Laser Capture Microdissected Brain Tissue to Study Normal Aging and Alzheimer’s Disease

  . In Applied Neurogenomics(pp 111-120). Humana Press, New York, NY. doi:10.1007/978-1-4939-2247-5_4
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  The next-generation sequencing (NGS) of RNA, or RNA-Seq, has significantly changed the way that the transcriptional content of a biological sample is investigated. RNA-Seq is a major advance for the field due to its largely unbiased and digital nature, its ability to empower RNA splice form construction at a genomic level, and its improved dynamic range when compared to a microarray technology. Investigating the healthy or diseased brain presents unique problems from the standpoint of transcriptional analysis as each cell type, and perhaps even each individual cell, is in a unique state of transcription. The organ is a complex mixture of main cell types (neuronal, glial, vascular, etc.), and within each of those types, there are a multitude of subtypes (specific neuronal populations, different classes of glial cells, etc.) that could each be targeted for investigation and could each respond to health and disease in distinct and functionally important ways. Here, we discuss the approach of using laser capture microdissection (LCM) to specifically select cell types of interest for transcriptional dissection. We highlight approaches to couple this with RNA-Seq to generate highly specific transcriptional profiles from the brain. Sample inputs into RNA-Seq protocols continue to be pushed lower, including several reports of single-cell transcriptome profiles; therefore, the combination of cell selection approaches, like LCM, with RNA-Seq is well poised to provide a researcher with the cell-specific digital whole transcriptome information that has been desired since transcriptomic profiling became feasible during the earliest days of the microarray.
• , ., Barnes, C. A., Goertz, M. E., & Massell, D. (2014).

  How State Education Agencies Acquire and Use Research Knowledge for School Improvement

  . In Using Research Evidence in Education. doi:10.1007/978-3-319-04690-7_8
• Barnes, C. A., Erickson, C. A., Erickson, C. A., Davis, S., & Mcnaughton, B. L. (2012).

  Hippocampal Synaptic Enhancement as a Basis for Learning and Memory: A Selected Review of Current Evidence from Behaving Animals

  . In Brain and Memory: Modulation and Mediation of Neuroplasticity(pp 259-276). Oxford University Press. doi:10.1093/ACPROF:OSO/9780195082944.003.0016
• Hoang, L. T., Lister, J. P., & Barnes, C. A. (2012).

  The Ageing Hippocampus

  . In The Clinical Neurobiology of the Hippocampus: An integrative view(pp 152-173). Oxford University Press. doi:10.1093/ACPROF:OSO/9780199592388.003.0009
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  This chapter reviews alterations observed in the hippocampus during normative ageing in the absence of pathology. Topics include discussions of age-related spatial memory deficits across mammalian species, as well as neuroanatomical, biophysical, and electrophysiological changes observed in the aged hippocampus. Further, the impact that these changes might have on plasticity mechanisms and dynamic processes such as gene expression and epigenetic modifications over the lifespan is discussed. Special emphasis is given to the fact that normative ageing is distinct from neuropathological states such as Alzheimer’s disease. Moreover, this overview highlights how the study of normal ageing in the hippocampus has furthered the understanding of the specificity of pathological processes as well as presented possible avenues for the development of interventions, treatments, or therapeutic strategies for optimizing cognition during the normal life course.
• Burke, S. N., & Barnes, C. A. (2008).

  Aging Ensembles: Circuit Contributions to Memory Deficits

  . In Hippocampal Place Fields: Relevance to Learning and Memory(pp 364-384). Oxford University Press. doi:10.1093/ACPROF:OSO/9780195323245.003.0028
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  This chapter reviews current knowledge about aged neural ensembles in the hippocampus and how alterations in the dynamics of these circuits are linked to memory decline. Topics discussed include fundamental properties of place cells in young and old rats, advanced age and the dynamic properties of hippocampal place cells, and memory decline. It is shown that old rats have notable differences in the dynamic properties of CA1 place fields, and several of these differences correspond with observed age-associated behavioral deficits. Aged rats fail to show experience-dependent place field expansion plasticity to the same extent as young rats. Between episodes of experience in a single environment, aged rats are also impaired at maintaining stable spatial representations in the CA1 subregion of the hippocampus. This observation is consistent with the finding that old rats exhibit impaired performance on tasks requiring the solution of an allocentric spatial reference frame.
• Penner, M. R., & Barnes, C. A. (2007).

  Memory Changes with Age. Neurobiological Correlates

  . In Neurobiology of Learning and Memory (Second Edition)(pp 483-518). Academic Press. doi:10.1016/B978-012372540-0/50016-9
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  Publisher Summary This chapter highlights selected domains of cognition that can be studied across mammalian species and that have known age-related neurobiological underpinnings. Research aimed at understanding the aging process, including the change of learning and memory processes with respect to age, provides the basis for the development of better preventative strategies and treatment strategies for successful ageing (particularly older population). In the general field of aging research, the focus has been on the pathological aging that may be associated with diseases such as Alzheimer's disease (AD). Many people do not develop dementing conditions such as AD with age; instead, most people develop mild memory deficits known as age-associated memory impairment (AAMI).There is a large literature that has examined the impact of aging process on learning and memory function. Tasks in which age-related impairments have been found include classical conditioning, such as eyeblink and heart rate conditioning, conditioned taste aversion, fear conditioning, operant tasks such delayed matching-to-sample and delayed nonmatching-to-sample tasks, and instrumental tasks such as active avoidance, passive avoidance, and maze learning tasks. The studies discussed in the chapter focus on the form of learning and memory that involves the ability of an organism to acquire and retain information that is critical for successful navigation through space. The discussion includes the process of learning and memory with respect to both humans and rodents, the involvement of the hippocampus in spatial learning and memory, and normal brain aging outside the hippocampus.
• Naughton, B. L., Naughton, B. L., Barnes, C. A., Battaglia, F. P., Bower, M. R., Cowen, S. L., Ekstrom, A. D., Ekstrom, A. D., Gerrard, J. L., Hofman, K. L., Houston, F. P., Karten, Y., Lipa, P., Pennartz, C. M., Pennartz, C. M., Sutherland, G. R., & Cowen, S. L. (2003).

  Off-line reprocessing of recent memory and its role in memory consolidation: a progress report

  . In Sleep and Brain Plasticity(pp 225-246). Oxford University Press.
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  This chapter reviews the theoretical considerations for why the brain might require an active reprocessing of memories during periods when it is relatively ‘disconnected’ from external input. It summarizes the current understanding of the phenomenon based on neurophysiological investigations in animals.
• Goddard, G. V., Mcnaughton, B. L., Douglas, R. M., & Barnes, C. A. (1978).

  Synaptic Change in the Limbic System; Evidence from Studies Using Electrical Stimulation with and without Seizure Activity

  . In Limbic Mechanisms:The Continuing Evolution of the Limbic System Concept(pp 355-368). Springer, Boston, MA. doi:10.1007/978-1-4757-0716-8_14
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  Agents with the potential to induce seizure-like discharge in the limbic system also have the potential to induce permanent alteration in that system. The most dramatic set of alterations have been called, collectively, the kindling effect (Goddard, McIntyre & Leech, 1969). Kindling is observed when an agent is applied mildly, repeatedly, usually once per day, and the response to that agent progressively changes until it includes a major clinical convulsion. If the treatments are discontinued, the system does not return to normal, but remains in a state of readiness even for a year or more. It will respond with convulsions to unusually low doses or gentle application of a wide range of the known epileptogenic agents (Pinel & Van Oot, 1976). When sufficient time is allowed between treatments, the sensitivity of the convulsive response may continue to increase; and, in some cases after many repetitions, the convulsions may recur spontaneously (Wada, Sato & Corcoran, 1974; Wada, Osawa & Mizoguchi, 1976; Pinel, Mucha & Phillips, 1975).

Journals/Publications

• McDermott, K. E., & Barnes, C. A. (2025). An immunohistochemical protocol for visualizing adrenergic receptor subtypes in the rhesus macaque hippocampus. Journal of Neuroscience Methods, 418(Issue). doi:10.1016/j.jneumeth.2025.110410
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  Background: The noradrenergic system is an important modulatory system in the brain, and dysfunction in this system is implicated in multiple neurodegenerative diseases. The study of this system in neuronal tissues relies on the availability of specific antibodies but to date no protocol exists for immunohistological visualization of α1, α2, and β adrenergic receptors in rhesus macaques. New method: Here, we test the ability of various commercially available antibodies to detect these receptors in the primate brain and develop a protocol for visualization of receptors alongside noradrenergic axons and glial and vascular cells that interact with the noradrenergic system. Results: Of the eleven primary antibodies for adrenergic receptors tested, five did not produce staining at any concentration. The remaining six antibodies underwent a preadsorption protocol to determine specificity of the antibody to its’ immunogen sequence. Two antibodies failed this test, indicating they were binding to other targets in the brain. We then determined optimum concentrations for the remaining four antibodies. Additionally, we develop an immunofluorescence protocol that allows for the visualization of each AR - α1, α2a, or β1 – along with adrenergic axons as well as with glia and vasculature. Comparison with existing methods: While protocols exist for visualizing receptors in rodents, this is the first protocol for use in nonhuman primates. Conclusions: Seven out of the eleven tested antibodies were inaccurate, highlighting the importance of comprehensive testing. The stringent tests conducted here suggest that some commercially available antibodies can reliably detect adrenergic receptor subtypes in nonhuman primate tissue.
• McDermott, K., & Barnes, C. (2025). Stability of locus coeruleus cell counts despite volume loss in cognitively impaired aged rhesus macaques. Neurobiology of Aging, 148. doi:10.1016/j.neurobiolaging.2025.01.007
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  The locus coeruleus (LC) is a brainstem nucleus that provides the primary source of noradrenaline (NA) in the nervous system and optimizes behavioral performance in mammals. In humans, the LC shows Alzheimer's disease (AD)-like pathology at its earliest stages, but little is known about LC integrity in normative, non-pathological aging. The present research addresses these gaps by investigating neuron numbers, densities of glia and vasculature, and volume of the LC itself in cognitively assessed adult and aged rhesus macaques. These primates do not spontaneously exhibit AD, and thus are an excellent model for normative human aging. Immunohistochemical methods were used to quantify noradrenaline-producing cells, total cells, and vascular and glial density in the LC, and use a recently developed alignment protocol to incorporate Nissl- and immunohistochemically stained tissue with previously collected magnetic resonance images to generate precise volumes of the LC and its’ subcompartments. The medial LC subcompartment alone (not the lateral or compact regions) in aged animals showed significantly smaller volume than did the adult monkeys, however, there was no difference in NA-containing cell numbers, vascular or glial densities observed in any compartment between age groups. Additionally, volumes and cell counts were not significantly associated with performance on memory tasks, indicating that cell populations within the locus coeruleus nucleus itself are highly resistant to age-related change.
• Hamza, Y., Yang, Y., Vu, J., Abdelmalek, A., Malekifar, M., Barnes, C., & Zeng, F. (2024). Auditory brainstem responses as a biomarker for cognition. Communications Biology, 7(1). doi:10.1038/s42003-024-07346-4
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  A non-invasive, accessible and effective biomarker is critical to the diagnosis, monitoring and treatment of age-related cognitive decline. Recent work has suggested a strong association between auditory brainstem responses (ABR) and cognitive function in aging macaques. Here we show in 118 human participants (66 females; age range=18-92 years; hearing loss = -5 to 70 dB HL) that cognition is associated with both age and hearing level, but this triad relationship is mainly driven by the age factor. After adjusting for age, cognition is still significantly associated with both the ABR wave V amplitude (B, 0.110, 95% CI, 0.018– 0.202; p = 0.020) and latency (B, -0.101, 95% CI, -0.186– -0.016; p = 0.021). Importantly, this age-adjusted ABR-cognition association is primarily driven by older individuals and language-dependent cognitive functions. We also perform the area under the curve (AUC) of the receiver-operating-characteristic analysis and find that the ABR wave V amplitude is best for detecting good cognitive performers (AUC = 0.96) whereas the wave V latency is best for detecting poor ones (AUC = 0.86). The present result not only confirms the previous animal work in humans but also shows the clinical potential of using auditory brainstem responses to improve diagnosis and treatment of age-related cognitive decline.
• Hill, P., Bermudez, S., McAvan, A., Garren, J., Grilli, M., Barnes, C., & Ekstrom, A. (2024). Age differences in spatial memory are mitigated during naturalistic navigation. Aging, Neuropsychology, and Cognition, 31(6). doi:10.1080/13825585.2024.2326244
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  Spatial navigation deficits are often observed among older adults on tasks that require navigating virtual reality (VR) environments on a computer screen. We investigated whether these age differences are attenuated when tested in more naturalistic and ambulatory virtual environments. In Experiment 1, young and older adults navigated a variant of the Morris Water Maze task in each of two VR conditions: a desktop VR condition which required using a mouse and keyboard to navigate, and an ambulatory VR condition which permitted unrestricted locomotion. In Experiment 2, we examined whether age- and VR-related differences in spatial performance were affected by the inclusion of additional spatial cues. In both experiments, older adults navigated to target locations less precisely than younger individuals in the desktop condition. Age differences were significantly attenuated, however, when tested in the ambulatory VR environment. These findings underscore the importance of developing naturalistic assessments of spatial memory and navigation.
• Sinakevitch, I., McDermott, K., Gray, D., & Barnes, C. (2024). A combined MRI, histological and immunohistochemical rendering of the rhesus macaque locus coeruleus (LC) enables the differentiation of three distinct LC subcompartments. Journal of Chemical Neuroanatomy, 140. doi:10.1016/j.jchemneu.2024.102449
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  Locus coeruleus (LC) neurons send their noradrenergic axons across multiple brain regions, including neocortex, subcortical regions, and spinal cord. Many aspects of cognition are known to be dependent on the noradrenergic system, and it has been suggested that dysfunction in this system may play central roles in cognitive decline associated with both normative aging and neurodegenerative disease. While basic anatomical and biochemical features of the LC have been examined in many species, detailed characterizations of the structure and function of the LC across the lifespan are not currently available. This includes the rhesus macaque, which is an important model of human brain function because of their striking similarities in brain architecture and behavioral capacities. In the present study, we describe a method to combine structural MRI, Nissl, and immunofluorescent histology from individual monkeys to reconstruct, in 3 dimensions, the entire macaque LC nucleus. Using these combined methods, a standardized volume of the LC was determined, and high-resolution confocal images of tyrosine hydroxylase-positive neurons were mapped into this volume. This detailed representation of the LC allows definitions to be proposed for three distinct subnuclei, including a medial region and a lateral region (based on location with respect to the central gray, inside or outside, respectively), and a compact region (defined by densely packed neurons within the medial compartment). This enabled the volume to be estimated and cell density to be calculated independently in each LC subnucleus for the first time. This combination of methods should allow precise characterization of the LC and has the potential to do the same for other nuclei with distinct molecular features.
• Barnes, C. A., Ekstrom, A. D., Garren, J. D., Grilli, M. D., Hill, P. F., & McAvan, A. S. (2023).

  Age differences in spatial memory are mitigated during naturalistic navigation

  . bioRxiv (Cold Spring Harbor Laboratory). doi:10.1101/2023.01.23.525279
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  Abstract Spatial navigation deficits in older adults are well documented. These findings are based on experimental paradigms that require using a joystick or keyboard to navigate a virtual desktop environment. In the present study, cognitively normal young and older adults navigated in each of two virtual reality (VR) conditions: a desktop VR condition which required using a mouse and keyboard to navigate and an immersive and ambulatory VR condition which permitted unrestricted locomotion. Consistent with past studies, older adults navigated to target locations less precisely than did younger individuals in the desktop condition. These age differences were significantly attenuated when tested in the immersive environment. Additional analyses indicated that older adults showed a preference for route-based search strategies compared to young adults, regardless of condition. These findings suggest that certain aspects of navigation performance in older adults are improved in paradigms that offer a fuller range of enriched and naturalistic cues.
• Gray, D. T., Gray, D., Zempare, M. A., Zempare, M., Carey, N., Khattab, S., Sinakevitch, I., Biase, L. M., De Biase, L., Barnes, C. A., & Barnes, C. (2023). Extracellular matrix proteoglycans support aged hippocampus networks: a potential cellular-level mechanism of brain reserve. Neurobiology of Aging, 131. doi:10.1016/j.neurobiolaging.2023.07.010
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  One hallmark of normative brain aging is vast heterogeneity in whether older people succumb to or resist cognitive decline. Resilience describes a brain's capacity to maintain cognition in the face of aging and disease. One factor influencing resilience is brain reserve—the status of neurobiological resources available to support neuronal circuits as dysfunction accumulates. This study uses a cohort of behaviorally characterized adult, middle-aged, and aged rats to test whether neurobiological factors that protect inhibitory neurotransmission and synapse function represent key components of brain reserve. Histochemical analysis of extracellular matrix proteoglycans, which play critical roles in stabilizing synapses and modulating inhibitory neuron excitability, was conducted alongside analyses of lipofuscin-associated autofluorescence. The findings indicate that aging results in lower proteoglycan density and more lipofuscin in CA3. Aged rats with higher proteoglycan density exhibited better performance on the Morris watermaze, whereas lipofuscin abundance was not related to spatial memory. These data suggest that the local environment around neurons may protect against synapse dysfunction or hyperexcitability and could contribute to brain reserve mechanisms.
• Stern, Y., Albert, M., Barnes, C., Cabeza, R., Pascual-Leone, A., & Rapp, P. (2023). A framework for concepts of reserve and resilience in aging. Neurobiology of Aging, 124. doi:10.1016/j.neurobiolaging.2022.10.015
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  The study of factors, across species, that allow some individuals to age more successfully than others has important implications for individual wellbeing as well as health education, policy and intervention. Design of studies and communication across investigators in this area has been hampered by a diversity of terminology. The Collaboratory on Research Definitions for Reserve and Resilience in Cognitive Aging and Dementia was funded by the National Institute on Aging and established in 2019 as a 3-year process of developing consensus definitions and research guidelines. The proposed Framework is based on an iterative process including 3 annual Workshops, focused workgroups, and input from numerous international investigators. It suggests the overarching term: resilience, and presents operational definitions for 3 concepts: cognitive reserve, brain maintenance, and brain reserve. Twelve pilot studies that integrate these definitions are presented. The use of a common vocabulary and operational definitions will facilitate even greater progress in understanding the factors that are associated with successful aging.
• Zheng, L., Gao, Z., Doner, S., Oyao, A., Forloines, M., Grilli, M. D., Barnes, C. A., & Ekstrom, A. D. (2023). Hippocampal contributions to novel spatial learning are both age-related and age-invariant. Proceedings of the National Academy of Sciences, 120(50). doi:10.1073/pnas.2307884120
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  Older adults show declines in spatial memory, although the extent of these alterations is not uniform across the healthy older population. Here, we investigate the stability of neural representations for the same and different spatial environments in a sample of younger and older adults using high-resolution functional MRI of the medial temporal lobes. Older adults showed, on average, lower neural pattern similarity for retrieving the same environment and more variable neural patterns compared to young adults. We also found a positive association between spatial distance discrimination and the distinctiveness of neural patterns between environments. Our analyses suggested that one source for this association was the extent of informational connectivity to CA1 from other subfields, which was dependent on age, while another source was the fidelity of signals within CA1 itself, which was independent of age. Together, our findings suggest both age-dependent and independent neural contributions to spatial memory performance.
• Zheng, L., Gao, Z., Doner, S., Oyao, A., Forloines, M., Grilli, M., Barnes, C., & Ekstrom, A. (2023). Hippocampal contributions to novel spatial learning are both age-related and age-invariant. Proceedings of the National Academy of Sciences of the United States of America, 120(50). doi:10.1073/pnas.2307884120
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  Older adults show declines in spatial memory, although the extent of these alterations is not uniform across the healthy older population. Here, we investigate the stability of neural representations for the same and different spatial environments in a sample of younger and older adults using high-resolution functional MRI of the medial temporal lobes. Older adults showed, on average, lower neural pattern similarity for retrieving the same environment and more variable neural patterns compared to young adults. We also found a positive association between spatial distance discrimination and the distinctiveness of neural patterns between environments. Our analyses suggested that one source for this association was the extent of informational connectivity to CA1 from other subfields, which was dependent on age, while another source was the fidelity of signals within CA1 itself, which was independent of age. Together, our findings suggest both age-dependent and independent neural contributions to spatial memory performance.
• Barnes, C. A., Gray, D. T., Härtig, W., Khattab, S., McDermott, K., Meltzer, J., Schwyhart, R., & Sinakevitch, I. (2022).

  Retrosplenial cortex microglia and perineuronal net densities are associated with memory impairment in aged rhesus macaques

  . Cerebral Cortex, 33(8), 4626-4644. doi:10.1093/cercor/bhac366
• Crown, L., Gray, D., Schimanski, L., Barnes, C., & Cowen, S. (2022). Aged Rats Exhibit Altered Behavior-Induced Oscillatory Activity, Place Cell Firing Rates, and Spatial Information Content in the CA1 Region of the Hippocampus. Journal of Neuroscience, 42(22). doi:10.1523/JNEUROSCI.1855-21.2022
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  Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was greater in older animals. Finally, aged rats had reduced within-field firing rates but greater spatial information per spike within the field. These data support a strong relationship between locomotor behavior and local-field potential activity and suggest that age significantly affects this relationship. Furthermore, observed changes in CA1 place cell firing rates and information content lend support to the hypothesis that age may result in more general and context-invariant hippocampal representations over more detailed information. These results may explain the observation that older adults tend to recall the gist of an experience rather than the details.
• Lester, A., Jordan, G., Blum, C., Philpot, Z., & Barnes, C. (2022). Differential Effects in Young and Aged Rats’ Navigational Accuracy Following Instantaneous Rotation of Environmental Cues. Behavioral Neuroscience, 136(6). doi:10.1037/bne0000536
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  Successful navigation depends critically upon two broad categories of spatial navigation strategies that include allocentric and egocentric reference frames, relying on external or internal spatial information, respectively. As with older adults, aged rats show robust impairments on a number of different spatial navigation tasks. There is some evidence that these navigation impairments are accompanied by a bias toward relying on egocentric over allocentric navigation strategies. To test the degree to which young and aged animals utilize these two navigation approaches, a novel behavioral arena was used in which rats are trained to traverse a circular track and to stop at a learned goal location that is fixed with respect to a panorama of visual cues projected onto the surrounding walls. By instantaneously rotating the cues, allocentric and egocentric reference frames were put in direct and immediate conflict and goal navigation performance was assessed with respect to how accurately young and aged animals were able to utilize the rotated cues. Behavioral data collected from nine young and eight aged animals revealed that both age groups were able to update their navigation performance following cue rotation. Contrary to what was expected, however, aged animals showed more accurate overall goal navigation performance, stronger allocentric strategy use, and more evident changes in behavior in response to cue rotation compared to younger animals. The young rats appeared to mix egocentric and allocentric strategies for ICR task solution.
• Barnes, C. A., Bolla, Y., Both, M. D., Brinton, R. D., Glisky, E. L., Haberg, A. K., Hay, M., Hoscheidt, S. M., Huentelman, M. J., Levin, B. E., Lewis, C. R., Naymik, M. A., Rundek, T., Ryan, L., Schmidt, A. M., & Talboom, J. S. (2021). Smoking is associated with impaired verbal learning and memory performance in women more than men.. Scientific reports, 11(1), 10248. doi:10.1038/s41598-021-88923-z
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  Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.
• Fox, A. S., Holley, D., Klink, P. C., Arbuckle, S. A., Barnes, C. A., Diedrichsen, J., Kwok, S. C., Kyle, C., Pruszynski, J. A., Seidlitz, J., Zhou, X., Poldrack, R. A., & Gorgolewski, K. J. (2021). Sharing voxelwise neuroimaging results from rhesus monkeys and other species with Neurovault. NeuroImage, 225, 117518.
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  Animal neuroimaging studies can provide unique insights into brain structure and function, and can be leveraged to bridge the gap between animal and human neuroscience. In part, this power comes from the ability to combine mechanistic interventions with brain-wide neuroimaging. Due to their phylogenetic proximity to humans, nonhuman primate neuroimaging holds particular promise. Because nonhuman primate neuroimaging studies are often underpowered, there is a great need to share data amongst translational researchers. Data sharing efforts have been limited, however, by the lack of standardized tools and repositories through which nonhuman neuroimaging data can easily be archived and accessed. Here, we provide an extension of the Neurovault framework to enable sharing of statistical maps and related voxelwise neuroimaging data from other species and template-spaces. Neurovault, which was previously limited to human neuroimaging data, now allows researchers to easily upload and share nonhuman primate neuroimaging results. This promises to facilitate open, integrative, cross-species science while affording researchers the increased statistical power provided by data aggregation. In addition, the Neurovault code-base now enables the addition of other species and template-spaces. Together, these advances promise to bring neuroimaging data sharing to research in other species, for supplemental data, location-based atlases, and data that would otherwise be relegated to a "file-drawer". As increasing numbers of researchers share their nonhuman neuroimaging data on Neurovault, this resource will enable novel, large-scale, cross-species comparisons that were previously impossible.
• Talboom, J., De Both, M., Naymik, M., Schmidt, A., Lewis, C., Jepsen, W., Rundek, T., Levin, B., Hoscheidt, S., Bolla, Y., Brinton, R., Schork, N., Hay, M., Barnes, C., Glisky, E., Ryan, L., Huentelman, M., & Håberg, A. (2021). Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance. npj Aging and Mechanisms of Disease, 7(1). doi:10.1038/s41514-021-00067-6
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  To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (ntotal = 75,666, nwomen = 47,700, nmen = 27,966; ages 18–85 years old, mean (M)Age = 46.54, standard deviation (SD)Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (ntotal = 158,249 nwomen = 89,333 nmen = 68,916; ages 40–70 years old, MAge = 55.81, SDAge = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (ntotal = 39,795, nwomen = 29,640, nmen = 10,155; ages 40–70 years old, MAge = 56.59, SDAge = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer’s disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.
• Zhou, Y., Chawla, M., Rios-Monterrosa, J., Wang, L., Zempare, M., Hruby, V., Barnes, C., & Cai, M. (2021). Aged brains express less melanocortin receptors, which correlates with age-related decline of cognitive functions. Molecules, 26(20). doi:10.3390/molecules26206266
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  Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurode-generative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer’s disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex/hypothalamus and the hippocampus regions and the rats’ performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function.
• Alexander, G. E., Lin, L., Yoshimaru, E. S., Bharadwaj, P. K., Bergrield, K. L., Hoang, L. T., Chawla, M. K., Chen, K., Moeller, J. R., Barnes, C. A., & Trouard, T. P. (2020). Age-related regional network covariance of magnetic resonance imaging gray matter in the rat.. Frontiers in Aging Neuroscience. doi:doi: 10.3389/fnagi.2020.00267
• Bai, D., Barnes, C. A., Houston, F. P., Mariathasan, S., Matsumoto, G., Ohashi, P. S., Oliveira-dos-santos, A. J., Penninger, J. M., Roder, J. C., Sasaki, T., Siderovski, D. P., Snow, B. E., Wakeham, A., & Whishaw, I. Q. (2020). Correction for Oliveira-dos-Santos et al., Regulation of T cell activation, anxiety, and male aggression by RGS2.. Proceedings of the National Academy of Sciences of the United States of America, 117(40), 25182. doi:10.1073/pnas.2018014117
• Barnes, C. A., Peterson, M. A., Ryan, L., & Knierim, J. J. (2020). Commemorating the Contributions of Lynn Nadel to the Understanding Hippocampal Function: Issue Editors. Hippocampus, 30(8), 771- 909.
• Barnes, C., Barnes, C., Ryan, L., Ryan, L., Peterson, M., & Peterson, M. (2020). Nadel special issue introduction. Hippocampus, 30(8). doi:10.1002/hipo.23176
• Cowen, S. L., Gray, D. T., Wiegand, J. L., Schimanski, L. A., & Barnes, C. A. (2020). Age-associated changes in waking hippocampal sharp-wave ripples.. Hippocampus, 30, 28-38.
• Gray, D. T., De La Peña, N. M., Umapathy, L., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2020). Auditory and Visual System White Matter Is Differentially Impacted by Normative Aging in Macaques. The Journal of neuroscience : the official journal of the Society for Neuroscience, 40, 8913-8923.
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  Deficits in auditory and visual processing are commonly encountered by older individuals. In addition to the relatively well described age-associated pathologies that reduce sensory processing at the level of the cochlea and eye, multiple changes occur along the ascending auditory and visual pathways that further reduce sensory function in each domain. One fundamental question that remains to be directly addressed is whether the structure and function of the central auditory and visual systems follow similar trajectories across the lifespan or sustain the impacts of brain aging independently. The present study used diffusion magnetic resonance imaging and electrophysiological assessments of auditory and visual system function in adult and aged macaques to better understand how age-related changes in white matter connectivity at multiple levels of each sensory system might impact auditory and visual function. In particular, the fractional anisotropy (FA) of auditory and visual system thalamocortical and interhemispheric corticocortical connections was estimated using probabilistic tractography analyses. Sensory processing and sensory system FA were both reduced in older animals compared with younger adults. Corticocortical FA was significantly reduced only in white matter of the auditory system of aged monkeys, while thalamocortical FA was lower only in visual system white matter of the same animals. Importantly, these structural alterations were significantly associated with sensory function within each domain. Together, these results indicate that age-associated deficits in auditory and visual processing emerge in part from microstructural alterations to specific sensory white matter tracts, and not from general differences in white matter condition across the aging brain. Age-associated deficits in sensory processing arise from structural and functional alterations to both peripheral sensory organs and central brain regions. It remains unclear whether different sensory systems undergo similar or distinct trajectories in function across the lifespan. To provide novel insights into this question, this study combines electrophysiological assessments of auditory and visual function with diffusion MRI in aged macaques. The results suggest that age-related sensory processing deficits in part result from factors that impact the condition of specific white matter tracts, and not from general decreases in connectivity between sensory brain regions. Such anatomic specificity argues for a framework aimed at understanding vulnerabilities with relatively local influence and brain region specificity.
• Gray, D. T., Umapathy, L., De La Peña, N. M., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2020). Auditory Processing Deficits Are Selectively Associated with Medial Temporal Lobe Mnemonic Function and White Matter Integrity in Aging Macaques. Cerebral cortex (New York, N.Y. : 1991), 30(5), 2789-2803.
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  Deficits in auditory function and cognition are hallmarks of normative aging. Recent evidence suggests that hearing-impaired individuals have greater risks of developing cognitive impairment and dementia compared to people with intact auditory function, although the neurobiological bases underlying these associations are poorly understood. Here, a colony of aging macaques completed a battery of behavioral tests designed to probe frontal and temporal lobe-dependent cognition. Auditory brainstem responses (ABRs) and visual evoked potentials were measured to assess auditory and visual system function. Structural and diffusion magnetic resonance imaging were then performed to evaluate the microstructural condition of multiple white matter tracts associated with cognition. Animals showing higher cognitive function had significantly better auditory processing capacities, and these associations were selectively observed with tasks that primarily depend on temporal lobe brain structures. Tractography analyses revealed that the fractional anisotropy (FA) of the fimbria-fornix and hippocampal commissure were associated with temporal lobe-dependent visual discrimination performance and auditory sensory function. Conversely, FA of frontal cortex-associated white matter was not associated with auditory processing. Visual sensory function was not associated with frontal or temporal lobe FA, nor with behavior. This study demonstrates significant and selective relationships between ABRs, white matter connectivity, and higher-order cognitive ability.
• Hay, M., Barnes, C., Huentelman, M., Brinton, R., & Ryan, L. (2020). Hypertension and Age-Related Cognitive Impairment: Common Risk Factors and a Role for Precision Aging. Current hypertension reports, 22(10), 80.
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  Precision Aging® is a novel concept that we have recently employed to describe how the model of precision medicine can be used to understand and define the multivariate risks that drive age-related cognitive impairment (ARCI). Hypertension and cardiovascular disease are key risk factors for both brain function and cognitive aging. In this review, we will discuss the common mechanisms underlying the risk factors for both hypertension and ARCI and how the convergence of these mechanisms may be amplified in an individual to drive changes in brain health and accelerate cognitive decline.
• Huentelman, M. J., Talboom, J. S., Lewis, C. R., Chen, Z., & Barnes, C. A. (2020). Reinventing Neuroaging Research in the Digital Age. Trends in neurosciences, 43(1), 17-23.
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  The worldwide average human lifespan has increased over the past century. These changing demographics demand a reinvention of experimental approaches to study the brain and aging, with the aim of better matching cognitive healthspan with human lifespan. Past studies of cognitive aging included sample sizes that tended to be underpowered, were not sufficiently representative of national population characteristics, and often lacked longitudinal assessments. As a step to address these shortcomings, we propose a framework that encourages interaction between electronic-based and face-to-face study designs. We argue that this will achieve the necessary synergy to accelerate progress in the discovery and application of personalized interventions to optimize brain and cognitive health.
• Lester, A. W., Kapellusch, A. J., & Barnes, C. A. (2020). A novel apparatus for assessing virtual cue-based navigation in rodents.. Journal of Neuroscience Methods. doi:https://doi.org/10.1016/j.jneumeth.2020.10866
• Oliveira-Dos-Santos, A., Oliveira-Dos-Santos, A., Matsumoto, G., Matsumoto, G., Snow, B., Snow, B., Bai, D., Bai, D., Houston, F., Houston, F., Whishaw, I., Whishaw, I., Mariathasan, S., Mariathasan, S., Sasaki, T., Sasaki, T., Wakeham, A., Wakeham, A., Ohashi, P., , Ohashi, P., et al. (2020). Erratum: Regulation of T cell activation, anxiety, and male aggression by RGS2 (Proc. Natl. Acad. Sci. U.S.A. (2000) 97 (12272–12277) DOI: 10.1073/pnas.220414397). Proceedings of the National Academy of Sciences of the United States of America, 117(40). doi:10.1073/pnas.2018014117
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  Correction for "Regulation of T cell activation, anxiety, and male aggression by RGS2," by Antonio J. Oliveira-dos-Santos, Goichi Matsumoto, Bryan E. Snow, Donglin Bai, Frank P. Houston, Ian Q. Whishaw, Sanjeev Mariathasan, Takehiko Sasaki, Andrew Wakeham, Pamela S. Ohashi, John C. Roder, Carol A. Barnes, David P. Siderovski, and Josef M. Penninger, which was first published October 10, 2000; 10.1073/pnas.220414397 (Proc. Natl. Acad. Sci. U.S.A. 97, 12272-12277). The authors note, "Fig. 2 contains a mistake in panel A as the CD4/CD8 scatterplots for rgs2 and rgs2-/- mice were duplicated when preparing the figure for publication. Multiple independent experiments showed and confirmed that there is no difference between the groups in the thymocyte populations. Therefore none of the conclusions of the paper are affected. We have included a new set of graphs for Fig 2A from an independent experiment performed concurrently with that in the published paper. We apologize for the oversight in preparing the original figure." The revised figure and its legend appear below. (figure presented).
• Peterson, M. A., Ryan, L., Knierim, J. J., & Barnes, C. A. (2020). Commemorating the Contributions of Lynn Nadel to the Understanding Hippocampal Function. Hippocampus, 30(8), 771 - 909.
• Alexander, G. E., Barnes, C. A., Biwer, L. A., Chawla, M. K., Coleman, P. D., De Both, M., Fitzhugh, M. C., Hale, T. M., Hoang, L. T., Huentelman, M., Mitchell, K. D., Trouard, T. P., Uprety, A. R., Willeman, M. N., & Zempare, M. A. (2019).

  Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning

  . Physiological Reports, 7(6), e14010. doi:10.14814/phy2.14010
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  Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1-Ren2 xenobiotic-inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15-month-old transgenic rats were fed 0.15% indole-3-carbinol (I3C) chow to slowly induce renin-dependent hypertension over a 6-week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C-treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus-dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular-renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.
• Barnes, C. A., & Gray, D. T. (2019).

  Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function

  . Proceedings of the National Academy of Sciences, 116(52), 26247-26254. doi:10.1073/pnas.1902279116
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  The use of animal models in brain aging research has led to numerous fundamental insights into the neurobiological processes that underlie changes in brain function associated with normative aging. Macaque monkeys have become the predominant nonhuman primate model system in brain aging research due to their striking similarities to humans in their behavioral capacities, sensory processing abilities, and brain architecture. Recent public concern about nonhuman primate research has made it imperative to attempt to clearly articulate the potential benefits to human health that this model enables. The present review will highlight how nonhuman primates provide a critical bridge between experiments conducted in rodents and development of therapeutics for humans. Several studies discussed here exemplify how nonhuman primate research has enriched our understanding of cognitive and sensory decline in the aging brain, as well as how this work has been important for translating mechanistic implications derived from experiments conducted in rodents to human brain aging research.
• Barnes, C. A., Bertinelli, S. F., De Both, M. D., Fritz, M. A., Glisky, E., Hammersland, C., Hay, M., Huentelman, M. J., Håberg, A., Lewis, C. R., Myers, A. J., Naymik, M. A., Ryan, L., Schrauwen, I., & Talboom, J. S. (2019).

  Author response: Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors

  . eLife. doi:10.7554/elife.46179.018
• Barnes, C. A., Bertinelli, S. F., De Both, M. D., Fritz, M. A., Glisky, E., Hammersland, C., Hay, M., Huentelman, M. J., Håberg, A., Lewis, C. R., Myers, A. J., Naymik, M. A., Ryan, L., Schrauwen, I., & Talboom, J. S. (2019).

  Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors

  . eLife, 8. doi:10.7554/elife.46179
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  In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer’s disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18–85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.
• Gray, D. T., & Barnes, C. A. (2019). Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function. Proceedings of the National Academy of Sciences of the United States of America, 116, 26247-26254.
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  The use of animal models in brain aging research has led to numerous fundamental insights into the neurobiological processes that underlie changes in brain function associated with normative aging. Macaque monkeys have become the predominant nonhuman primate model system in brain aging research due to their striking similarities to humans in their behavioral capacities, sensory processing abilities, and brain architecture. Recent public concern about nonhuman primate research has made it imperative to attempt to clearly articulate the potential benefits to human health that this model enables. The present review will highlight how nonhuman primates provide a critical bridge between experiments conducted in rodents and development of therapeutics for humans. Several studies discussed here exemplify how nonhuman primate research has enriched our understanding of cognitive and sensory decline in the aging brain, as well as how this work has been important for translating mechanistic implications derived from experiments conducted in rodents to human brain aging research.
• Kyle, C. T., Kyle, C. T., Kyle, C. T., Kyle, C. T., Stokes, J., Stokes, J., Stokes, J., Stokes, J., Bennett, J., Bennett, J., Bennett, J., Bennett, J., Meltzer, J., Meltzer, J., Meltzer, J., Meltzer, J., Permenter, M. R., Permenter, M. R., Permenter, M. R., , Permenter, M. R., et al. (2019).

  Cover Image, Volume 29, Issue 5

  . Hippocampus, 29(5). doi:10.1002/hipo.22969
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  This cover image is based on the Research Article Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: Preservation of subfi eld volumes in aging by Colin T. Kyle et al., DOI: 10.1002/hipo.22969.
• Kyle, C. T., Permenter, M. R., Vogt, J. A., Rapp, P. R., & Barnes, C. A. (2019). Behavioral Impact of Long-Term Chronic Implantation of Neural Recording Devices in the Rhesus Macaque.. Neuromodulation : journal of the International Neuromodulation Society, 22(4), 435-440. doi:10.1111/ner.12794
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  Ensemble recording methods are pervasive in basic and clinical neuroscience research. Invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or Parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. Studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflammatory response as well as a chronic foreign body response. Despite use of invasive recording methods with animal models and humans, little is known of their effect on behavior in healthy populations..To quantify the effect of chronic electrode implantation targeting the hippocampus on recognition memory performance..Four healthy female rhesus macaques were tested in a delayed nonmatching-to-sample (DNMS) recognition memory task before and after hippocampal implantation with a tetrode array device..Trials to criterion and recognition memory performance were not significantly different before vs. after chronic electrode implantation..Our results suggest that chronic implants did not produce significant impairments on DNMS performance.
• Kyle, C. T., Stokes, J., Bennett, J., Meltzer, J., Permenter, M. R., Vogt, J. A., Ekstrom, A., & Barnes, C. A. (2019). Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: preservation of subfield volumes in aging.. Hippocampus, 29(5), 409-421.
• Pyon, W., Gray, D. T., & Barnes, C. A. (2019). An alternative to dye-based approaches to remove background autofluorescence from primate brain tissue.. Frontiers In Neuroanatomy, 13, 73. doi:doi: 10.3389/fnana.2019.00073
• Ryan, L., Hay, M., Huentelman, M. J., Duarte, A., Rundek, T., Levin, B., Soldan, A., Pettigrew, C., Mehl, M. R., & Barnes, C. A. (2019). Precision Aging: Applying Precision Medicine to the Field of Cognitive Aging. Frontiers in aging neuroscience, 11, 128.
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  The current "one size fits all" approach to our cognitive aging population is not adequate to close the gap between cognitive health span and lifespan. In this review article, we present a novel model for understanding, preventing, and treating age-related cognitive impairment (ARCI) based on concepts borrowed from precision medicine. We will discuss how multiple risk factors can be classified into because of their interrelatedness in real life, the that increase sensitivity to, or ameliorate, risk for ARCI, and the or common mechanisms mediating brain aging. Rather than providing a definitive model of risk for ARCI and cognitive decline, the Precision Aging model is meant as a starting point to guide future research. To that end, after briefly discussing key risk categories, genetic risks, and brain drivers, we conclude with a discussion of steps that must be taken to move the field forward.
• Stern, Y., Barnes, C. A., Grady, C., Jones, R. N., & Raz, N. (2019). Brain reserve, cognitive reserve, compensation, and maintenance: operationalization, validity, and mechanisms of cognitive resilience. Neurobiology of aging, 83, 124-129.
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  Significant individual differences in the trajectories of cognitive aging and in age-related changes of brain structure and function have been reported in the past half-century. In some individuals, significant pathological changes in the brain are observed in conjunction with relatively well-preserved cognitive performance. Multiple constructs have been invoked to explain this paradox of resilience, including brain reserve, cognitive reserve, brain maintenance, and compensation. The aim of this session of the Cognitive Aging Summit III was to examine the overlap and distinctions in definitions and measurement of these constructs, to discuss their neural and behavioral correlates and to propose plausible mechanisms of individual cognitive resilience in the face of typical age-related neural declines.
• Talboom, J. S., Håberg, A. K., DeBoth, M. D., Naymik, M. A., Schrauwen, I., Lewis, D. R., Bertinelli, S. F., Hammersland, C., Fritz, M. A., Myers, A., Hay, M., Barnes, C. A., Glisky, E., Ryan, L., & Huentelman, M. J. (2019). Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors.. eLife, 8, e46179.
• Willeman, M. n., Chawla, M. K., Zempare, M. A., Biwer, L. A., Hoang, l. t., Uprety, A. R., Fitzhugh, M. C., DeBoth, M., Coleman, P. D., Trouard, T. P., Alexander, G. E., Mitchell, K. D., Barnes, C. A., Hale, T. M., & Huentelman, M. (2019). Gradual hypertension induction in middle-aged Cyp1a1-Ren2- transgenic rats produces significant impairments in spatial learning.. Physiological Reports, 7(6), e14010.
• Anandhan, A., Barnes, C. A., Corenblum, M. J., Madhavan, L., Ortiz, F. O., Ray, S., Reed, A., & Zhang, D. D. (2018).

  A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells

  . Cell Transplantation, 27(4), 589-606. doi:10.1177/0963689718774030
• Barnes, C. A., Barnes, C. A., Chawla, M. K., Chawla, M. K., McNaughton, B. L., McNaughton, B. L., Olson, K., Olson, K., Sutherland, V. L., & Sutherland, V. L. (2018).

  Behavior-drivenarcexpression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus

  . Hippocampus, 28(2), 178-185. doi:10.1002/hipo.22820
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  Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal–ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior-driven cells across the dorsal–ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two- to-threefold reduction in spatial behavior-driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self-motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non-spatial information within the hippocampus along its dorso-ventral axis.
• Barnes, C. A., Barnes, C. A., Cowen, S. L., Cowen, S. L., Gray, D. T., Gray, D. T., Schimanski, L. A., Schimanski, L. A., Wiegand, J. L., & Wiegand, J. L. (2018).

  Age‐associated changes in waking hippocampal sharp‐wave ripples

  . Hippocampus, 30(1), 28-38. doi:10.1002/hipo.23005
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  Hippocampal sharp-wave ripples are brief high-frequency (120–250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate-of-occurrence of ripples during sleep that may contribute to age-associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age-dependent changes. Sharp-wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place-dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track-running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task-relevant information and compensate for age-related declines in ripple rate during task performance.
• Burke, S. N., Gaynor, L. S., Barnes, C. A., Bauer, R. M., Bizon, J. L., Roberson, E. D., & Ryan, T. L. (2018). Shared Functions of Perirhinal and Parahippocampal Cortices: Implications for Cognitive Aging. Trends in Neurosciences, 41, 349-359.
• Chawla, M. K., Gray, D. T., Nguyen, C., Dhaliwal, H., Okuno, H., Huentelman, M. J., & Barnes, C. A. (2018). Seizure-induced Arc mRNA expression thresholds in rat hippocampus and perirhinal cortex.. Frontiers in Systems Neuroscience, 12, 53. doi:https://doi.org/10.3389/fnsys.2018.00053
• Chawla, M. K., Sutherland, V. L., Olson, K., McNaughton, B. L., & Barnes, C. A. (2018). Behavior-driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus. Hippocampus, 28(2), 178-185.
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  Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal-ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior-driven cells across the dorsal-ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two- to-threefold reduction in spatial behavior-driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self-motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non-spatial information within the hippocampus along its dorso-ventral axis.
• Comrie, A. E., Gray, D. T., Smith, A. C., & Barnes, C. A. (2018). Different macaque models of cognitive aging exhibit task-dependent behavioral disparities.. Behavioral Brain Research, 344, 110-119. doi:10.1016/j.bbr.2018.02.008
• Cowen, S. L., Gray, D. T., Wiegand, J. L., Schimanski, L. A., & Barnes, C. A. (2018). Age-associated changes in waking hippocampal sharp-wave ripples.. Hippocampus (online). doi:10.1002/hipo.23005
• Gray, D. T., Umapathy, L., Burke, S. N., Trouard, T. P., & Barnes, C. A. (2018). Tract-Specific White Matter Correlates of Age-Related Reward Devaluation Deficits in Macaque Monkeys. Journal of Neuroimaging in Psychiatry & Neurology, 3(2), 13-26.
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  Cognitive aging is known to alter reward-guided behaviors that require interactions between the orbitofrontal cortex (OFC) and amygdala. In macaques, OFC, but not amygdala volumes decline with age and correlate with performance on a reward devaluation (RD) task. The present study used diffusion magnetic resonance imaging (dMRI) methods to investigate whether the condition of the white matter associated with amygdala-OFC connectivity changes with age and relates to reward devaluation.
• Kapellusch, A. J., Lester, A. W., Schwartz, B. A., Smith, A. C., & Barnes, C. A. (2018). Analysis of learning deficits in aged rats on the W-track continuous spatial alternation task.. Behavioral Neuroscience, 132, 512–519.
• Kyle, C. T., Permenter, M. R., Vogt, J. A., Rapp, P. R., & Barnes, C. A. (2018). Behavioral impact of long-term chronic implantation of neural recording devices in the rhesus macaque.. Neuromodulation: Technology at the Neural Interface, 22, 435-440.
• Malem-Shinitski, N., Zhang, Y., Gray, D. T., Burke, S. N., Smith, A., Barnes, C. A., & Ba, D. (2018). A separable two-dimensional random field model of binary response data from multi-day behavioral experiences.. Journal of Neuroscience Methods, 307, 175-187.
• Ray, S., Corenblum, M. J., Anandhan, A., Reed, A., Ortiz, F. O., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2018). A role for Nrf2 expression in defining the aging of hippocampal neural stem cells.. Cell Transplantation, 27(4), 589-606.
• Gray, D. T., Smith, A. C., Burke, S. N., Gazzaley, A., & Barnes, C. A. (2017). Attentional updating and monitoring and affective shifting are impacted independently by aging in macaque monkeys. Behavioural Brain Research, 322(Issue). doi:10.1016/j.bbr.2016.06.056
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  One hallmark of the normal cognitive aging process involves alterations in executive function. Executive function can be divided into at least three separable components, including set shifting, attentional updating and monitoring, and inhibition of prepotent responses. The ability to study the neural basis of cognitive aging has been enriched by the use of animal models such as the macaque monkey. In aged macaques, changes in attentional updating and monitoring systems are poorly understood compared to changes in shifting and inhibition. A partial explanation for this is the fact that the tasks designed to study executive function in aged monkeys, to date, primarily have probed shifting and inhibition processes. Here we examine how aging impacts attentional updating and monitoring processes in monkeys using an interference task designed after a paradigm used to examine multi-tasking in older humans. Young and aged macaque monkeys were tested on this interference task as well as on an object reversal learning task to study these processes in the same animals. Relative to the young monkeys, aged animals were impaired on both tasks. Proactive and retroactive interference did not differ between age groups on an array of 40 object pairs presented each day in the object reversal learning task. The levels of performance on the interference task were not correlated with levels of performance in the object reversal task. These results suggest that attentional updating and monitoring and affective shifting are separable functions in the macaque, and that normal aging affects these mental operations independently.
• Gray, D. T., Smith, A. C., Burke, S. N., Gazzaley, A., & Barnes, C. A. (2017). Attentional updating and monitoring and affective shifting are impacted independently by aging in the macaque monkeys. Behavioral Brain Research, 322, 329-338.
• Gray, D. T., Smith, A. C., Burke, S. N., Gazzaley, A., & Barnes, C. A. (2017). Attentional updating and monitoring and affective shifting are impacted independently by aging in the macaque monkeys.. Behavioral Brain Research, 322, 329-338.
• Han, P., Nielsen, M., Song, M., Yin, J., Permenter, M. R., Vogt, J. A., Engle, j. R., Dugger, B. N., Beach, T. G., Barnes, C. A., & Shi, J. (2017). The impact of aging on brain pituitary adenylate cyclase activating polypeptide pathology and cognition in mice and rhesus macaque.. Frontiers in Aging Neuroscience,, 9(180). doi:doi:10.3389/fnagi.2017.00180
• Han, P., Nielson, M., Song, M., Yin, J., Permenter, M. R., Vogt, J. A., Engle, J. R., Dugger, B. N., Beach, T. G., Barnes, C. A., & Shi, J. (2017). The impact of aging on brain pituitary adenylate cylse activating polypeptide, pathology and cognition in APP transgenic mice and nonhuman primates. Frontiers in Aging Neuroscience, 9, 80. doi:10.3389/fnagi.2017.00180..
• Hay, M., Vanderah, T. W., Samareh-Jahani, F., Constantopoulos, E., Uprety, A. J., & Barnes, C. A. (2017). Cognitive impairment in heart failure: A protective role for Angiotensin-(1-7). Behavioral Neuroscience, 131, 99-114.
• Hay, M., Vanderah, T. W., Samereh-Jahani, F., Constantopoulos, E., Uprety, A. R., Barnes, C. A., & Konhilas, J. (2017). Cognitive impairment in heart failure: A protective role for Angiotensin-(1-7).. Behavioral Neuroscience, 131, 99-114.
• Ianov, L., Barnes, C. A., DeBoth, M., Chawla, M. K., Rani, A., Kennedy, A. J., Piras, I., Day, J. J., Siniard, A., Kumar, A., Sweatt, J. D., Barnes, C. A., Huentelman, M., & Foster, T. C. (2017). Hippocampal transcriptomic profiles: Subregional vulnerability to age and cognitive impairment.. Frontiers in Aging Neuroscience.
• Kyle, C. T., Stokes, J., Bennett, J., Meltzer, J., Permenter, M. R., Vogt, J. A., Ekstrom, A., & Barnes, C. A. (2017). Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: preservation of subfield volumes in aging.. Hippocampus. doi:10.1002/hipo.22809
• Lester, A. W., Moffat, S. D., Barnes, C. A., & Wolbers, T. (2017). The aging navigational system. Neuron, 9, 1019-1035.
• Maurer, A. P., Burke, S. N., Diba, K., & Barnes, C. A. (2017). Attenuated activity across multiple cell types and reduced monosynaptic connectivity in the aged perirhinal cortex.. Journal of Neuroscience, 37(8965-8974).
• Maurer, A. P., Burke, S. N., Diba, K., & Barnes, C. A. (2017). Attenuated activity across multiple cell types and reduced monosynaptic connectivity in the aged perirhinal cortx. The Journal of Neuroscience, 37, 8965-8974.
• Pacheco, S., Wang, C., Chawla, M. K., Nguyen, M., Baggett, B. K., Utzinger, U., Barnes, C. A., & Liang, R. (2017). High resolution, high speed, long working distance, large field of view confocal fluorescence microscope. Scientific Reports, 7, 13349.
• Pacheco, S., Wang, C., Chawla, M. K., Nguyen, M., Baggett, B. K., Utzinger, U., Barnes, C. A., & Liang, R. (2017). High resolution, high speed, long working distance, large field of view confocal fluorescence microscope.. Scientific Reports, 7, 13349.
• Samson, R. D., Lester, A. W., Duarte, L., Venkatesh, A., & Barnes, C. A. (2017). Emergence of beta band oscillations in the aged rat amygdala during discrimination learning and decision making tasks. ENeuro, 4(5) e0245-17.2017.
• Samson, R. D., Lester, A. W., Duarte, L., Venkatesh, A., & Barnes, C. A. (2017). Emergence of beta band oscillations in the aged rat amygdala during discrimination learning and decision making tasks.. ENeuro, 4(5), e0245-17.2017.
• Thome, A., Marrone, D. F., Chawla, N. K., Lipa, P., Ramirez-Amaya, V., Lisanby, S. H., McNaughton, B. L., & Barnes, C. A. (2017). Evidence for an evolutionarily conserved memory coding scheme in the mammalian hippocampus.. Journal of Neuroscience, 37, 2795-2801.
• Thome, A., Marrone, D. F., Ellmore, T. M., Chawla, M. K., Lipa, P., Ramirez-Amaya, V., Lisanby, S. H., McNaughton, B. L., & Barnes, C. A. (2017). Evidence for an evolutionarily conserved memory coding scheme in the mammalian hippocampus.. Journal of Neuroscience, 37, 2795–2801.
• Alme, C., Alme, C., Barnes, C., Barnes, C., Cardiff, J., Cardiff, J., Chawla, M., Chawla, M., Demchuk, A., Demchuk, A., Eckert, M., Eckert, M., Guzowski, J., Guzowski, J., Lapointe, V., Lapointe, V., Maurer, A., Maurer, A., McNaughton, B., , McNaughton, B., et al. (2016).

  Nonuniform allocation of hippocampal neurons to place fields across all hippocampal subfields: HIPPOCAMPAL SUBFIELDS

  . Hippocampus, 26(10), 1328-1344. doi:10.1002/hipo.22609
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  The mechanisms governing how the hippocampus selects neurons to exhibit place fields are not well understood. A default assumption in some previous studies was the uniform random draw with replacement (URDWR) model, which, theoretically, maximizes spatial "pattern separation", and predicts a Poisson distribution of the numbers of place fields expressed by a given cell per unit area. The actual distribution of mean firing rates exhibited by a population of hippocampal neurons, however, is approximately exponential or log-normal in a given environment and these rates are somewhat correlated across multiple places, at least under some conditions. The advantage of neural activity-dependent immediate-early gene (IEG) analysis, as a proxy for electrophysiological recording, is the ability to obtain much larger samples of cells, even those whose activity is so sparse that they are overlooked in recording studies. Thus, a more accurate representation of the activation statistics can potentially be achieved. Some previous IEG studies that examined behavior-driven IEG expression in CA1 appear to support URDWR. There was, however, in some of the same studies, an under-recruitment of dentate gyrus granule cells, indicating a highly skewed excitability distribution, which is inconsistent with URDWR. Although it was suggested that this skewness might be related to increased excitability of recently generated granule cells, we show here that CA1, CA3, and subiculum also exhibit cumulative under-recruitment of neurons. Thus, a highly skewed excitability distribution is a general principle common to all major hippocampal subfields. Finally, a more detailed analysis of the frequency distributions of IEG intranuclear transcription foci suggests that a large fraction of hippocampal neurons is virtually silent, even during sleep. Whether the skewing of the excitability distribution is cell-intrinsic or a network phenomenon, and the degree to which this excitability is fixed or possibly time-varying are open questions for future studies.
• Barnes, C. A., Baggett, B. K., Chawla, M. K., Gray, D. T., Liang, R., Pacheco, S., Utzinger, U., & Wang, C. (2016). Whole brain imaging with a scalable microscope. Cancer. doi:10.1364/cancer.2016.jw3a.30
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  A high speed, high resolution, long working distance, large field of view scalable confocal fluorescence microscope is developed to image the large field of view of a rat brain with subcellular resolution.
• Barnes, C. A., Corenblum, M. J., Harder, B., Long, M., Madhavan, L., Ray, S., Remley, Q. W., & Zhang, D. D. (2016).

  Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle‐age period

  . Aging Cell, 15(4), 725-736. doi:10.1111/acel.12482
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  Although it is known that the regenerative function of neural stem/progenitor cells (NSPCs) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone (SVZ) NSPCs, in various groups of rats across the aging spectrum, using in vitro and in vivo histological and behavioral techniques. These studies indicate that although NSPC function continuously declines with advancing age, there is a critical time period during middle age (13–15 months) when a striking reduction in NSPC survival and regeneration (proliferation and neuronal differentiation) occurs. The studies also indicate that this specific temporal pattern of NSPC deterioration is functionally relevant at a behavioral level and correlates with the decreasing expression of the redox-sensitive transcription factor, Nrf2, in the NSPCs. When Nrf2 expression was suppressed in ‘young’ NSPCs, using short interfering RNAs, the survival and regeneration of the NSPCs was significantly compromised and mirrored ‘old’ NSPCs. Conversely, Nrf2 overexpression in ‘old’ NSPCs rendered them similar to ‘young’ NSPCs, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2 −/−) mice revealed a lower number of SVZ NSPCs in these animals, when compared to wild-type controls. In addition, the proliferative and neurogenic potential of the NSPCs was also compromised in the Nrf2−/− mice. These results identify a novel regulatory role for Nrf2 in NSPC function during aging and have important implications for developing NSPC-based strategies to support healthy aging and to treat age-related neurodegenerative disorders.
• Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2016). Reduced NrF2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell.
• Engle, J. R., Machada, C. J., Permenter, M. R., Vogt, J. A., Maurer, A. P., Bulleri, A. M., & Barnes, C. A. (2016). Network patterns associated with navigation behavior are altered in aged nonhuman primates. Journal of Neuroscience, 36, 12217-12227.
• Penner, M. R., Parrish, R. R., Hoang, L. T., Roth, T. L., Lubin, F. D., & Barnes, C. A. (2016). Age-related changes in Egr1 transcription and DNA methylation within the hippocampus. Hippocampus, 26, 1008-1020.
• Thome, A., Gray, D. T., Erickson, C. A., Lipa, P., & Barnes, C. A. (2016). Memory impairment in aged primates is associated with region-specific network dysfunction. Molecular Psychiatry, 21, 1257-1262.
• Wiegand, J. -., Gray, D. T., Schimanski, L. A., Lipa, P., Barnes, C. A., & Cowen, S. L. (2016). Age is associated with reduced sharp-wave ripple frequency and altered patterns of neuronal variability. The Journal of Neuroscience.
• Witharana, W. K., Cardiff, J., Chawla, M. K., Xie, J. Y., Alme, C., Eckert, M., Lapointe, V., Witharana, A., Maurer, A. P., Trivedi, V., Sutherland, R. J., Guzowski, J. F., Barnes, C. A., & McNaughton, B. L. (2016). Nonuniform allocation of hippocampal neurons to place fields across all hippocampal subfields. Hippocampus, 26, 1382-1344.
• Barnes, C. A. (2015). Engaging Practitioners in State School Improvement Initiatives. Peabody Journal of Education. doi:10.1080/0161956x.2015.988540
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  For most of U.S. history, local communities were the primary arbiters of school quality. Beginning in the mid-twentieth century, states began assuming more and more control over school standards and outcomes. The question we seek to answer is whether and the extent to which a particular kind of local voice—the voice of education practitioners—is represented in states' current, significant initiatives to improve low-performing schools. In the article, we focus on the role that practitioner knowledge played in the development of school improvement policies across three state education agencies. We draw on interviews, surveys, and document analyses collected for a larger exploratory study of knowledge utilization. Contrary to earlier research showing weak or uneven connections between state agencies and practitioners, we found that practitioner advice networks were generally stronger than states' research advice networks. We found ample illustration of staff using this advice to make sense of research for th...
• Burke, S. N., & Barnes, C. A. (2015). The neural representation of 3-dimensional objects in rodent memory circuits. Behavioral Brain Research, 138-148, 120.
• Cohen, C. H., Neumann, J. T., Dave, K. R., Alekseyenko, A., Binkert, M., Stransky, K., Lin, L. W., Barnes, C. A., Wright, C. B., & Perez-Pinzon, M. A. (2015). Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS. doi:10:e0124918
• Gray, D. T., & Barnes, C. A. (2015). Distinguishing adaptive plasticity from vulnerability in the aging hippocampus. Neuroscience, 309, 17-28.
• Insel, N. N., & Barnes, C. A. (2015). Differential activation of fast-spiking and regular-firing neuron populations during movement and reward in the dorsal medial frontal cortex. Cerebral Cortex, 25, 2631-2647.
• Samson, R. D., Venkatesh, A., Lester, A. W., Weinstein, A. T., Lipa, P., & Barnes, C. A. (2015). Age differences in strategy selection and risk preference during risk-based decision making. Behavioral Neuroscience, 129, 138-148.
• Schimanski, L. A., & Barnes, C. A. (2015). Insights into age-related cognitive decline: Coupling neurophysiological and behavioral approaches. Neuromethods. doi:10.1007/978-1-4939-2159-1_5
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  A major goal of research in systems and behavioral neuroscience today is to understand how our brains produce the complex and diverse behaviors that reflect what we refer to as cognition. Tremendous gains have been made over the past century in understanding the neural bases of behavior. These include insights into the basic cellular mechanisms of information processing and storage, and the identification of brain circuits critical to specific behaviors. Some studies have focused on how such neuronal networks develop in early life, reach full functional maturity, and change during aging. Defining the factors that determine successful versus pathological cognitive aging is a particularly important goal because, in most developed countries, the fastest growing segment of the population is those over 85 years of age. Although there has been significant improvement in the precision of the cognitive test batteries developed for humans across the life span, as well as improvements in the resolution and specificity of brain imaging methods, animal models of cognitive aging continue to play a critical role in revealing the brain mechanisms responsible for normal behavioral function. The use of such animal models is most productive when the cognitive operations studied depend on brain structures whose function is conserved across evolution. The circular platform spatial memory task (“Barnes Maze”) was developed to be sensitive to the function of specific brain circuits within the temporal lobe hypothesized to be important for memory in both humans and rodents, and likely to change with age. This chapter provides a personal account of the development of the circular platform task and a historical perspective regarding the overall goal for the design to develop an effective task for aged animals that minimizes task demand stress and ensures sensitivity to even small changes in the cognitive domain investigated. Detailed discussion in this chapter includes how past and newer research have converged, and have uncovered relations between memory and place cell functioning in the hippocampus by coupling neurophysiological and behavioral methodologies. This approach has allowed great insight into the processes underlying learning and memory, and has been particularly fruitful in elucidating the underpinnings of age-related cognitive decline.
• Barnes, C. A. (2014). Biography - Carol A. Barnes, Ph.D. (Biography for APA Award for Distinguished Scientific Contributions. American Psychologist, 69, 730-732.
• Burke, S. N., Maurer, A. P., Nematollahi, S., Uprety, A., Wallace, J. L., & Barnes, C. A. (2014). Advanced age dissociates dual functions of the perirhinal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(2), 467-80.
• Burke, S. N., Thome, A., Plange, K., Engle, J. R., Trouard, T. P., Gothard, K. M., & Barnes, C. A. (2014). Orbitofrontal cortex volume in area 11/13 predicts reward devaluation, but not reversal learning performance, in young and aged monkeys. Journal of Neuroscience, 34(30), 9905-9916.
• Insel, N., & Barnes, C. A. (2014). Neuron population activity in the medial prefrontal cortex suggests superimposed codes for situation and situation value. BMC Neuroscience, 15(1). doi:10.1186/1471-2202-15-s1-p220
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  The medial prefrontal cortex (mPFC) may be necessary for an animal to use contextual information to generate appropriate behaviors[1]. Consistent with this, neuron activity in the mPFC is sensitive to an animal’s behavioral and environmental context[2,3]. The mPFC also appears to be important for determining a situation’ sv alue: it projects strongly to other value-coding regions such as the ventral striatum, ventral tegmental area, and amygdale[4], and functional neuroimaging studies often show increased blood oxygenation in the region during high-valued situations[5]. In the present study we find evidence that the output of the mPFC includes both a high-dimensional code for an animal’s behavioral situation and, superimposed on this, a single-dimensional code for value. Neuron ensembles and local field potentials were recorded while rats performed a novel, 3-choice, 2-cue decision task, as well as during rest epochs before and after the task. 2433 single neurons were subdivided into classes according to waveform shape and firing patterns. The majority of neurons were found to be regular-firing, putative excitatory projection neurons. Activity of individual neurons in this group carried high levels of information about behavioral context (e.g., session epoch, trial phases, space, and movement), while the population as a whole was most active near reward sites. In contrast, fast-spiking, putative inhibitory interneurons carried less information about behavioral context and fired most during rats’ acceleration or in response to task cues. The dissociations between fast-spiking and regular-firing neurons were observed even between adjacent cells with apparently reciprocal, inhibitory-excitatory connections. Notably, movement-related activity in both neuron groups was reduced in more ventral regions of the mPFC. Another, smaller population of projection neurons with burst-firing characteristics did not show clustered firing fields around rewards. This group, although heterogeneous, was also less selective for behavioral context than regular-firing cells. Based on these results, we propose that the mPFC repre
• Maurer, A. P., Lester, A. W., Burke, S. N., Ferng, J. J., & Barnes, C. A. (2014). Back to the future: preserved hippocampal network activity during reverse ambulation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(45), 15022-31. doi:10.1523/JNEUROSCI.1129-14.2014
• Samson, R. D., Venkatesh, A., Patel, D. H., Lipa, P., & Barnes, C. A. (2014). Enhanced performance of aged rats in contingency degradation and instrumental extinction tasks. Behavioral neuroscience, 128(2), 122-33. doi:10.1037/a0035986
• Zelikowsky, M., Hersman, S., Chawla, M. K., Barnes, C. A., & Fanselow, M. S. (2014). Neuronal ensembles in amygdala, hippocampus, and prefrontal cortex track differential components of contextual fear. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(25), 8462-6. doi:10.1523/JNEUROSCI.3624-13.2014
• Chawla, M. K., Penner, M. R., Olson, K. M., Sutherland, V. L., Mittleman-Smith, M. A., & Barnes, C. A. (2013). Spatial behavior and seizure-included changes in c-fos mRNA expression in young and old rats. Neurobiology of Aging, 34, 1184-1198.
• Hartzell, A. L., Burke, S. N., Hoang, L. T., Lister, J. P., Rodriquez, C. N., & Barnes, C. A. (2013). Transcription of the immediate-early gene Arc in CA1 of the hippocampus reveals activity differences along the proximodistal axis that are attenuated by advanced age. Journal of Neuroscience, 33, 3424-3433.
• Lu, L., Leutgeb, J. K., Tsao, A., Henriksen, E. J., Leutgeb, S., Barnes, C. A., Witter, M. P., Moser, M. -., & Moser, E. I. (2013). Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex, 16, 1085-1093.
• Ramirez-Amaya, V., Angelo-Perkins, A., Chawla, M. K., Barnes, C. A., & Rosi, S. (2013). Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration. Journal of Neuroscience, 33, 1631-1639.
• Samson, R. D., & Barnes, C. A. (2013). Impact of Aging Brain Circuits on Cognition. European Journal of Neuroscience, 37, 1903-1915.
• Schimanski, L. A., Lipa, P., & Barnes, C. A. (2013). Tracking the course of hippocampal representations during learning: When is the map required?. Journal of Neuroscience, 33, 3094-3106.
• Takehara-Nishiuchi, K., Insel, N., Hoang, L. T., Wagner, Z., Olson, K., Chawla, M. K., Burke, S. N., & Barnes, C. A. (2013). Activation patterns in superficial layers of neocortex change between experiences independent of behavior, environment, or the hippocampus. Cerebral Cortex, 23, 2225-2234.
• Burke, S., Burke, S., Maurer, A., Maurer, A., Hartzell, A., Hartzell, A., Nematollahi, S., Nematollahi, S., Uprety, A., Uprety, A., Wallace, J., Wallace, J., Barnes, C., & Barnes, C. (2012). Representation of three-dimensional objects by the rat perirhinal cortex. Hippocampus, 22(10). doi:10.1002/hipo.22060
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  The perirhinal cortex (PRC) is known to play an important role in object recognition. Little is known, however, regarding the activity of PRC neurons during the presentation of stimuli that are commonly used for recognition memory tasks in rodents, that is, three-dimensional objects. Rats in the present study were exposed to three-dimensional objects while they traversed a circular track for food reward. Under some behavioral conditions, the track contained novel objects, familiar objects, or no objects. Approximately 38% of PRC neurons demonstrated "object fields" (a selective increase in firing at the location of one or more objects). Although the rats spent more time exploring the objects when they were novel compared to familiar, indicating successful recognition memory, the proportion of object fields and the firing rates of PRC neurons were not affected by the rats' previous experience with the objects. Together, these data indicate that the activity of PRC cells is powerfully affected by the presence of objects while animals navigate through an environment; but under these conditions, the firing patterns are not altered by the relative novelty of objects during successful object recognition. © 2012 Wiley Periodicals, Inc.
• Burke, S., Ryan, L., & Barnes, C. (2012). Characterizing cognitive aging of recognition memory and related processes in animal models and in humans. Frontiers in Aging Neuroscience, 4. doi:10.3389/fnagi.2012.00015
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  Analyses of complex behaviors across the lifespan of animals can reveal the brain regions that are impacted by the normal aging process, thereby, elucidating potential therapeutic targets. Recent data from rats, monkeys, and humans converge, all indicating that recognition memory and complex visual perception are impaired in advanced age. These cognitive processes are also disrupted in animals with lesions of the perirhinal cortex, indicating that the the functional integrity of this structure is disrupted in old age. This current review summarizes these data, and highlights current methodologies for assessing perirhinal cortex-dependent behaviors across the lifespan. © 2012 Burke, Ryan and Barnes.
• Engle, J., & Barnes, C. (2012). Characterizing cognitive aging of associative memory in animal models. Frontiers in Aging Neuroscience, 4. doi:10.3389/fnagi.2012.00010
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  An overview is provided of the simple single-cue delay and trace eyeblink conditioning paradigms as techniques to assess associative learning and memory in the aged. We highlight and focus this review on the optimization of the parameter space of eyeblink conditioning designs in the aged to avoid and control for potential confounds that may arise when studying aged mammals. The need to examine the contribution of non-associative factors that can contribute to performance outcomes is emphasized, and how age-related changes in the central nervous system as well as peripheral sensory factors can potentially bias the interpretation of the data in the aged is discussed. The way in which slight alterations of the parameter space in the delay and trace eyeblink conditioning paradigms can lead to delayed but intact conditioning, rather than impaired performance in aged animals is also discussed. Overall, the eyeblink conditioning paradigm, when optimized for the age of the animal in the study, is an elegantly simple technique for assessment of associative learning and memory. When design caveats described above are taken into account, this important type of memory, with its well-defined neural substrates, should definitely be included in cognitive assessment batteries for the aged. © 2012 Engle and Barnes.
• Insel, N., Patron, L., Hoang, L., Nematollahi, S., Schimanski, L., Lipa, P., & Barnes, C. (2012). Reduced gamma frequency in the medial frontal cortex of aged rats during behavior and rest: Implications for age-related behavioral slowing. Journal of Neuroscience, 32(46). doi:10.1523/JNEUROSCI.1577-12.2012
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  Age-related cognitive and behavioral slowing may be caused by changes in the speed of neural signaling or by changes in the number of signaling steps necessary to achieve a given function. In the mammalian cortex, neural communication is organized by a 30-100 Hz "gamma" oscillation. There is a putative link between the gamma frequency and the speed of processing in a neural network: the dynamics of pyramidal neuron membrane time constants suggest that synaptic integration is framed by the gamma cycle, and pharmacological slowing of gamma also slows reaction times on behavioral tasks. The present experiments identify reductions in a robust 40-70 Hz gamma oscillation in the aged rat medial frontal cortex. The reductions were observed in the form of local field potentials, later peaks in fast-spiking neuron autocorrelations, and delays in the spiking of inhibitory neurons following local excitatory signals. Gamma frequency did not vary with movement speed, but rats with slower gamma also moved more slowly. Gamma frequency age differences were not observed in hippocampus. Hippocampal CA1 fast-spiking neurons exhibited interspike intervals consistent with a fast (70-100 Hz) gamma frequency, a pattern maintained across theta phases and theta frequencies independent of fluctuations in the average firing rates of the neurons. We propose that an average lengthening of the cortical 15-25 ms gamma cycle is one factor contributing to age-related slowing and that future attempts to offset cognitive declines will find a target in the response of fast-spiking inhibitory neurons to excitatory inputs. © 2012 the authors.
• Marrone, D., Marrone, D., Ramirez-Amaya, V., Ramirez-Amaya, V., Barnes, C., & Barnes, C. (2012). Neurons generated in senescence maintain capacity for functional integration. Hippocampus, 22(5). doi:10.1002/hipo.20959
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  Adult-born neurons in the dentate gyrus (DG) can survive for long periods, are capable of integrating into neuronal networks, and are important for hippocampus-dependent learning. Neurogenesis is dramatically reduced during senescence, and it remains unknown whether those few neurons that are produced remain capable of network integration. The expression of Arc, a protein coupled to neuronal activity, was used to measure activity among granule cells that were labeled with BrdU 4 months earlier in young (9 months) and aged (25 months) Fischer344 rats. The results indicate that while fewer cells are generated in the senescent DG, those that survive are (a) more likely to respond to spatial processing by expressing Arc relative to the remainder of the granule cell population and (b) equally responsive to spatial exploration as granule cells of the same age from young animals. These findings provide compelling evidence that newborn granule cells in the aged DG retain the capacity for participation in functional hippocampal networks. © 2011 Wiley Periodicals, Inc.
• Marrone, D., Satvat, E., Shaner, M., Worley, P., & Barnes, C. (2012). Attenuated long-term Arc expression in the aged fascia dentata. Neurobiology of Aging, 33(5). doi:10.1016/j.neurobiolaging.2010.07.022
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  One prominent component of aging is a defect in memory stabilization. To understand how the formation of enduring memories is altered in the aged brain, long-term markers of the biological events that may mediate memory consolidation were used to examine the activity dynamics of hippocampal circuits over extended intervals. The immediate early gene Arc, which is implicated in both durable memory and synaptic plasticity, is expressed in the fascia dentata (FD) for long periods following behavioral experience. To test the hypothesis that aging alters long-term Arc transcription in the FD, a region critical for spatial memory and impaired with progressive age, young and aged rats explored a novel environment twice, separated by an 8-hour interval, and FD Arc transcription was assessed. Relative to young rats, (a) fewer granule cells in the aged FD transcribe arc 8 hours after spatial exploration, and (b) this decrease is correlated with impaired spatial memory. These findings are consistent with behavioral evidence of age-related decline in hippocampal-dependent memory processing long after an event is to be remembered, and reaffirm the integral role of the FD in the neural circuits supporting durable memory. © 2012 Elsevier Inc.
• Maurer, A. P., Maurer, A. P., Burke, S. N., Burke, S. N., Lipa, P., Lipa, P., Skaggs, W. E., Skaggs, W. E., Barnes, C. A., & Barnes, C. A. (2012). Greater running speeds result in altered hippocampal phase sequence dynamics.. Hippocampus, 22(4), 737-47. doi:10.1002/hipo.20936
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  Hebb (1949) described a "phase sequence" to be the sequential activation of sets of cell assemblies. Within the hippocampus, cell assemblies have been described as groups of coactive neurons whose place fields overlap. Membership of assemblies in a phase sequence changes systematically as a rat travels through an environment, serving to accelerate the temporal order that place fields are encountered during a single theta cycle. This sweeping forward of network activity ("look ahead"), results in locations in front of the animal being transiently represented. In this experiment, a population vector-based reconstruction method was used to capture the look ahead and reveals that the composition of the phase sequence changes with velocity, such that more cell assemblies are active within a theta cycle at higher running speeds. These results are consistent with hypotheses suggesting that hippocampal networks generate short time scale predictions of future events to optimize behavior.
• Roberson, E., DeFazio, R., Barnes, C., Alexander, G., Bizon, J., Bowers, D., Foster, T., Glisky, E., Levin, B., Ryan, L., Wright, C., & Geldmacher, D. (2012). Challenges and opportunities for characterizing cognitive aging across species. Frontiers in Aging Neuroscience, 4. doi:10.3389/fnagi.2012.00006
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  The gradual decline of cognitive ability with age, even in the absence of overt brain disease, is a growing problem. Although cognitive aging is a common and feared accompaniment of the aging process, its underlying mechanisms are not well understood and there are no highly effective means to prevent it. Additional research on cognitive aging is sorely needed, and methods that enable ready translation between human subjects and animal models stand to provide the most benefit. Here and in the six companion pieces in this special issue, we discuss a variety of challenges and opportunities for studying cognitive aging across species. We identify tests of associative memory, recognition memory, spatial and contextual memory, and working memory and executive function as cognitive domains that are age-sensitive and amenable to testing with parallel means in both humans and animal models. We summarize some of the important challenges in using animal models to test cognition. We describe unique opportunities to study cognitive aging in human subjects, such as those provided by recent large-scale initiatives to characterize cognition in large groups of subjects across the lifespan. Finally, we highlight some of the challenges of studying cognitive aging in human subjects. © 2012 Roberson, DeFazio, Barnes, Alexander, Bizon, Bowers, Foster, Glisky, Levin, Ryan, Wright and Geldmacher.
• Rogalski, E., Stebbins, G. T., Barnes, C. A., Murphy, C. M., Stoub, T. R., George, S., Ferrari, C., Shah, R. C., & Detoledo-morrell, L. (2012). Age-related changes in parahippocampal white matter integrity: a diffusion tensor imaging study.. Neuropsychologia, 50(8), 1759-65. doi:10.1016/j.neuropsychologia.2012.03.033
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  The axons in the parahippocampal white matter (PWM) region that includes the perforant pathway relay multimodal sensory information, important for memory function, from the entorhinal cortex to the hippocampus. Previous work suggests that the integrity of the PWM shows changes in individuals with amnestic mild cognitive impairment and is further compromised as Alzheimer's disease progresses. The present study was undertaken to determine the effects of healthy aging on macro- and micro-structural alterations in the PWM. The study characterized in vivo white matter changes in the parahippocampal region that includes the perforant pathway in cognitively healthy young (YNG, n=21) compared to cognitively healthy older (OLD, n=21) individuals using volumetry, diffusion tensor imaging (DTI) and tractography. Results demonstrated a significant reduction in PWM volume in old participants, with further indications of reduced integrity of remaining white matter fibers. In logistic regressions, PWM volume, memory performance and DTI indices of PWM integrity were significant indicator variables for differentiating the young and old participants. Taken together, these findings suggest that age-related alterations do occur in the PWM region and may contribute to the normal decline in memory function seen in healthy aging by degrading information flow to the hippocampus.
• Stoub, T., Barnes, C., Shah, R., Stebbins, G., Ferrari, C., & deToledo-Morrell, L. (2012). Age-related changes in the mesial temporal lobe: The parahippocampal white matter region. Neurobiology of Aging, 33(7). doi:10.1016/j.neurobiolaging.2011.02.010
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  The perforant pathway originates from cells in the entorhinal cortex and relays sensory information from the neocortex to the hippocampus, a region critical for memory function. Imaging studies have demonstrated structural alterations in the parahippocampal white matter in the region of the perforant pathway in people at risk for developing Alzheimer's disease. It is not clear, however, if changes noted in this region are indicative of pathological aging or are a function of the normal aging process. We compared magnetic resonance imaging (MRI)-derived mesial temporal lobe volumes in 51 healthy older individuals and 40 young participants, with an emphasis on the parahippocampal white matter. Yearly clinical evaluations showed that 9 of the older cohort declined in cognitive function. Parahippocampal white matter, hippocampal, and entorhinal cortex volumes were significantly reduced in healthy older people who remained stable over time compared with young participants. These findings suggest that volume differences in mesial temporal lobe gray and white matter structures may take place as a result of the normative aging process. © 2012 Elsevier Inc.
• Thome, A., Thome, A., Erickson, C., Erickson, C., Lipa, P., Lipa, P., Barnes, C., & Barnes, C. (2012). Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task. Hippocampus, 22(10). doi:10.1002/hipo.22070
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  The structures of the medial temporal lobe (MTL) have been shown to be causally involved in episodic and recognition memory. However, recent work in a number of species has demonstrated that impairments in recognition memory seen following lesions of the perirhinal cortex (PRh) can be accounted for by deficits in perceptual discrimination. These findings suggest that object representation, rather than explicit recognition memory signals, may be crucial to the mnemonic process. Given the large amount of visual information encountered by primates, there must be a reconsideration of the mechanisms by which the brain efficiently stores visually presented information. Previous neurophysiological recordings from MTL structures in primates have largely focused on tasks that implicitly define object familiarity (i.e., novel vs. familiar) or contain significant mnemonic demands (e.g., conditional associations between two stimuli), limiting their utility in understanding the mechanisms underlying visual object recognition and information storage. To clarify how different regions in the MTL may contribute to visual recognition, we recorded from three rhesus macaques performing a passive viewing task. The task design systematically varies the relative familiarity of different stimuli enabling an examination of how neural activity changes as a function of experience. The data collected during this passive viewing task revealed that neurons in the MTL are generally not sensitive to the relative familiarity of a stimulus. In addition, when the specificity (i.e., which images a neuron was selective for) of individual neurons was analyzed, there was a significant dissociation between different medial temporal regions, with only neurons in TF, but not CA3 or the PRh, altering their activity as stimuli became familiar. The implications of these findings are discussed in the context of how MTL structures process information during a passive viewing paradigm. © 2012 Wiley Periodicals, Inc.
• Barnes, C. A. (2011).
  ecrets of aging: What does a normally aging brain look like?

   

   

  . The Scientist, 25(9). doi:22003369/3186042
• Barnes, C. A. (2011).

  Faculty Opinions recommendation of Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade.

  . Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. doi:10.3410/F.13284977.14644077
• Barnes, C. A. (2011).

  Faculty Opinions recommendation of The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat.

  . Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. doi:10.3410/F.13284975.14644075
• Barnes, C. A. (2011). Faculty Opinions recommendation of Age-related alterations in potentiation in the CA1 region in F344 rats.. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. doi:10.3410/F.13284972.14644072
• Barnes, C. A., Buxton, R. B., Schobel, S. A., Small, S. A., & Witter, M. P. (2011). A pathophysiological framework of hippocampal dysfunction in ageing and disease.. Nature reviews. Neuroscience, 12(10), 585-601. doi:10.1038/nrn3085
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  The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.
• Burke, S. N., Burke, S. N., Maurer, A. P., Maurer, A. P., Nematollahi, S., Nematollahi, S., Uprety, A. R., Uprety, A. R., Wallace, J. L., Wallace, J. L., Barnes, C. A., & Barnes, C. A. (2011). The influence of objects on place field expression and size in distal hippocampal CA1.. Hippocampus, 21(7), 783-801. doi:10.1002/hipo.20929
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  The perirhinal and lateral entorhinal cortices send prominent projections to the portion of the hippocampal CA1 subfield closest to the subiculum, but relatively little is known regarding the contributions of these cortical areas to hippocampal activity patterns. The anatomical connections of the lateral entorhinal and perirhinal cortices, as well as lesion data, suggest that these brain regions may contribute to the perception of complex stimuli such as objects. The current experiments investigated the degree to which three-dimensional objects affect place field size and activity within the distal region (closest to the subiculum) of CA1. The activity of CA1 pyramidal cells was monitored as rats traversed a circular track that contained no objects in some conditions and three-dimensional objects in other conditions. In the area of CA1 that receives direct lateral entorhinal input, three factors differentiated the objects-on-track conditions from the no-object conditions: more pyramidal cells expressed place fields when objects were present, adding or removing objects from the environment led to partial remapping in CA1, and the size of place fields decreased when objects were present. In addition, a proportion of place fields remapped under conditions in which the object locations were shuffled, which suggests that at least some of the CA1 neurons' firing patterns were sensitive to a particular object in a particular location. Together, these data suggest that the activity characteristics of neurons in the areas of CA1 receiving direct input from the perirhinal and lateral entorhinal cortices are modulated by non-spatial sensory input such as three-dimensional objects. © 2011 Wiley-Liss, Inc.
• Burke, S. N., Wallace, J. L., Hartzell, A. L., Nematollahi, S., Plange, K., & Barnes, C. A. (2011). Age-associated deficits in pattern separation functions of the perirhinal cortex: a cross-species consensus.. Behavioral neuroscience, 125(6), 836-47. doi:10.1037/a0026238
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  Normal aging causes a decline in object recognition. Importantly, lesions of the perirhinal cortex produce similar deficits and also lead to object discrimination impairments when the test objects share common features, suggesting that the perirhinal cortex participates in perceptual discrimination. The current experiments investigated the ability of young and aged animals to distinguish between objects that shared features with tasks with limited mnemonic demands. In the first experiment, young and old rats performed a variant of the spontaneous object recognition task in which there was a minimal delay between the sample and the test phase. When the test objects did not share any features ("Easy" perceptual discrimination) both young and aged rats correctly identified the novel object. When the test objects contained overlapping features, however, only the young rats showed an exploratory preference for the novel object. In Experiment 2, young and aged monkeys were tested on an object discrimination task. When the object pairs were dissimilar, both the young and aged monkeys learned to select the rewarded object quickly. In contrast, when LEGOs® were used to create object pairs with overlapping features, the aged monkeys took significantly longer than did the young animals to learn to discriminate between the rewarded and the unrewarded object. Together, these data indicate that behaviors requiring the perirhinal cortex are disrupted in advanced age, and suggest that at least some of these impairments may be explained by changes in high-level perceptual processing in advanced age.
• Lister, J. P., Bjornsson, C. S., Shain, W., Barnes, C. A., Roysam, B., Smith, K. L., & Tsai, C. L. (2011). Robust, globally consistent and fully automatic multi-image registration and montage synthesis for 3-D multi-channel images.. Journal of microscopy, 243(2), 154-71. doi:10.1111/j.1365-2818.2011.03489.x
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  The need to map regions of brain tissue that are much wider than the field of view of the microscope arises frequently. One common approach is to collect a series of overlapping partial views, and align them to synthesize a montage covering the entire region of interest. We present a method that advances this approach in multiple ways. Our method (1) produces a globally consistent joint registration of an unorganized collection of three-dimensional (3-D) multi-channel images with or without stage micrometer data; (2) produces accurate registrations withstanding changes in scale, rotation, translation and shear by using a 3-D affine transformation model; (3) achieves complete automation, and does not require any parameter settings; (4) handles low and variable overlaps (5-15%) between adjacent images, minimizing the number of images required to cover a tissue region; (5) has the self-diagnostic ability to recognize registration failures instead of delivering incorrect results; (6) can handle a broad range of biological images by exploiting generic alignment cues from multiple fluorescence channels without requiring segmentation and (7) is computationally efficient enough to run on desktop computers regardless of the number of images. The algorithm was tested with several tissue samples of at least 50 image tiles, involving over 5000 image pairs. It correctly registered all image pairs with an overlap greater than 7%, correctly recognized all failures, and successfully joint-registered all images for all tissue samples studied. This algorithm is disseminated freely to the community as included with the Fluorescence Association Rules for Multi-Dimensional Insight toolkit for microscopy (http://www.farsight-toolkit.org).
• Penner, M. R., Roth, T. L., Chawla, M. K., Hoang, L. T., Roth, E. D., Lubin, F. D., Sweatt, J. D., Worley, P. F., & Barnes, C. A. (2011). Age-related changes in Arc transcription and DNA methylation within the hippocampus.. Neurobiology of aging, 32(12), 2198-210. doi:10.1016/j.neurobiolaging.2010.01.009
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  The transcription of genes that support memory processes are likely to be impacted by the normal aging process. Because Arc is necessary for memory consolidation and enduring synaptic plasticity, we examined Arc transcription within the aged hippocampus. Here, we report that Arc transcription is reduced within the aged hippocampus compared to the adult hippocampus during both "off line" periods of rest, and following spatial behavior. This reduction is observed within ensembles of CA1 "place cells", which make less mRNA per cell, and in the dentate gyrus (DG) where fewer granule cells are activated by behavior. In addition, we present data suggesting that aberrant changes in methylation of the Arc gene may be responsible for age-related decreases in Arc transcription within CA1 and the DG. Given that Arc is necessary for normal memory function, these subregion-specific epigenetic and transcriptional changes may result in less efficient memory storage and retrieval during aging.
• Shamy, J. L., Hof, P. R., Amaral, D. G., Fong, S. G., Buonocore, M. H., Stern, Y., Barnes, C. A., Rapp, P. R., & Habeck, C. G. (2011). Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys.. Cerebral cortex (New York, N.Y. : 1991), 21(7), 1559-73. doi:10.1093/cercor/bhq210
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  Spatiotemporal and recognition memory are affected by aging in humans and macaque monkeys. To investigate whether these deficits are coupled with atrophy of memory-related brain regions, T(1)-weighted magnetic resonance images were acquired and volumes of the cerebrum, ventricles, prefrontal cortex (PFC), calcarine cortex, hippocampus, and striatum were quantified in young and aged rhesus monkeys. Subjects were tested on a spatiotemporal memory procedure (delayed response [DR]) that requires the integrity of the PFC and a medial temporal lobe-dependent recognition memory task (delayed nonmatching to sample [DNMS]). Region of interest analyses revealed that age inversely correlated with striatal, dorsolateral prefrontal cortex (dlPFC), and anterior cingulate cortex volumes. Hippocampal volume predicted acquisition of the DR task. Striatal volume correlated with DNMS acquisition, whereas total prefrontal gray matter, prefrontal white matter, and dlPFC volumes each predicted DNMS accuracy. A regional covariance analysis revealed that age-related volumetric changes could be captured in a distributed network that was coupled with declining performance across delays on the DNMS task. This volumetric analysis adds to growing evidence that cognitive aging in primates arises from region-specific morphometric alterations distributed across multiple memory-related brain systems, including subdivisions of the PFC.
• Barnes, C. A. (2010). Developing Instructional Leaders: Using Mixed Methods to Explore the Black Box of Planned Change in Principals’ Professional Practice. Educational Administration Quarterly. doi:10.1177/1094670510361748
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  Purpose: This study examines learning, and both cognitive and behavioral change among a sample of randomly assigned urban principals, half of whom participated in a sustained, district-based professional development program (DPD). Research Methods: Latent class analyses of daily log data, qualitative typology development, and case studies of change provide a rich portrait of the learning and change process. Findings: Few dramatic transformations of practice. Instead, principals attributed to the DPD a gradual refinement of existing practice through a process that allowed them to “break down” declarative knowledge to better understand its consequences for their work, but also provided knowledge structures, tools, and routines for reintegrating ideas from the program into strategically valuable procedural knowledge. Implications: Results suggest potential for developing principals’ competencies within continuing practice communities, but expectation of incremental rather than a dramatic “turn around” in principals’ leadership through program interventions.
• Barnes, C. A. (2010). Mixing methods in randomized controlled trials (RCTs): Validation, contextualization, triangulation, and control. Educational assessment, evaluation and accountability, 22, 5-28. doi:10.1007/s11092-009-9089-8
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  In this paper we described how we mixed research approaches in a Randomized Control Trial (RCT) of a school principal professional development program. Using examples from our study we illustrate how combining qualitative and quantitative data can address some key challenges from validating instruments and measures of mediator variables to examining how contextual factors interact with the treatment. Describing how we transformed our qualitative and quantitative data, we consider how mixing methods enabled us to deal with the two core RCT challenges of random assignment and treatment control critical. Our account offers insights into ways of maximizing the potential of mixing research methods in RCTs.
• Burke, S. N., & Barnes, C. A. (2010). Senescent synapses and hippocampal circuit dynamics.. Trends in neurosciences, 33(3), 153-61. doi:10.1016/j.tins.2009.12.003
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  Excitatory synaptic transmission is altered during aging in hippocampal granule cells, and in CA3 and CA1 pyramidal cells. These functional changes contribute to age-associated impairments in experimentally-induced plasticity in each of these primary hippocampal subregions. In CA1, plasticity evoked by stimulation shares common mechanisms with the synaptic modification observed following natural behavior. Aging results in deficits in both artificially- and behaviorally-induced plasticity, and this could in part reflect age-related changes in Ca2+ homeostasis. Other observations, however, suggest that increased intracellular Ca2+ levels are beneficial under some circumstances. This review focuses on age-associated changes in synaptic function, how these alterations might contribute to cognitive decline, and the extent to which altered hippocampal circuit properties are detrimental or reflect compensatory processes.
• Burke, S. N., Wallace, J. L., Nematollahi, S., Uprety, A. R., & Barnes, C. A. (2010). Pattern separation deficits may contribute to age-associated recognition impairments.. Behavioral neuroscience, 124(5), 559-73. doi:10.1037/a0020893
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  Normal aging is associated with impairments in stimulus recognition. In the current investigation, object recognition was tested in adult and aged rats with the standard spontaneous object recognition (SOR) task or two variants of this task. On the standard SOR task, adult rats showed an exploratory preference for the novel object over delays up to 24 h, whereas the aged rats only showed significant novelty discrimination at the 2-min delay. This age difference appeared to be because of the old rats behaving as if the novel object was familiar. To test this hypothesis directly, rats participated in a variant of the SOR task that allowed the exploration times between the object familiarization and the test phases to be compared, and this experiment confirmed that aged rats falsely "recognize" the novel object. A final control examined whether or not aged rats exhibited reduced motivation to explore objects. In this experiment, when the environmental context changed between familiarization and test, young and old rats failed to show an exploratory preference because both age groups spent more time exploring the familiar object. Together these findings support the view that age-related impairments in object recognition arise from old animals behaving as if novel objects are familiar, which is reminiscent of behavioral impairments in young rats with perirhinal cortical lesions. The current experiments thus suggest that alterations in the perirhinal cortex may be responsible for reducing aged animals' ability to distinguish new stimuli from ones that have been encountered previously.
• Henriksen, E. J., Colgin, L. L., Barnes, C. A., Witter, M. P., Moser, M., & Moser, E. I. (2010). Spatial representation along the proximodistal axis of CA1.. Neuron, 68(1), 127-37. doi:10.1016/j.neuron.2010.08.042
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  CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part.
• Penner, M. R., Roth, T. L., Barnes, C. A., & Sweatt, J. D. (2010). An epigenetic hypothesis of aging-related cognitive dysfunction.. Frontiers in aging neuroscience, 2, 9. doi:10.3389/fnagi.2010.00009
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  This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be "plastic". The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic "marks" drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.
• Schimanski, L. A., & Barnes, C. A. (2010). Neural Protein Synthesis during Aging: Effects on Plasticity and Memory.. Frontiers in aging neuroscience, 2. doi:10.3389/fnagi.2010.00026
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  During aging, many experience a decline in cognitive function that includes memory loss. The encoding of long-term memories depends on new protein synthesis, and this is also reduced during aging. Thus, it is possible that changes in the regulation of protein synthesis contribute to the memory impairments observed in older animals. Several lines of evidence support this hypothesis. For instance, protein synthesis is required for a longer period following learning to establish long-term memory in aged rodents. Also, under some conditions, synaptic activity or pharmacological activation can induce de novo protein synthesis and lasting changes in synaptic transmission in aged, but not young, rodents; the opposite results can be observed in other conditions. These changes in plasticity likely play a role in manifesting the altered place field properties observed in awake and behaving aged rats. The collective evidence suggests a link between memory loss and the regulation of protein synthesis in senescence. In fact, pharmaceuticals that target the signaling pathways required for induction of protein synthesis have improved memory, synaptic plasticity, and place cell properties in aged animals. We suggest that a better understanding of the mechanisms that lead to different protein expression patterns in the neural circuits that change as a function of age will enable the development of more effective therapeutic treatments for memory loss.
• Barnes, C. A. (2009). Weakening of replay of temporal patterns may result in memory consolidation failures in older animals. Neuroscience Research, 65, S6. doi:10.1016/j.neures.2009.09.1500
• Huentelman, M., Stephan, D., Talboom, J., Corneveaux, J., Reiman, D., Gerber, J., Barnes, C., Alexander, G., Reiman, E., & Bimonte-Nelson, H. (2009). Peripheral Delivery of a ROCK Inhibitor Improves Learning and Working Memory. Behavioral Neuroscience, 123(1). doi:10.1037/a0014260
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  Previously, utilizing a series of genome-wide association, brain imaging, and gene expression studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model. This study supports the action of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the promotion of cognition in humans, and highlights the powerful potential of unbiased genome-wide association studies to inform potential novel uses for existing pharmaceuticals. © 2009 American Psychological Association.
• Jenstad, M., Quazi, A. Z., Zilberter, M., Haglerød, C., Berghuis, P., Saddique, N., Goiny, M., Buntup, D., Davanger, S., Haug, F. S., Barnes, C. A., Mcnaughton, B. L., Ottersen, O. P., Storm-mathisen, J., Harkany, T., & Chaudhry, F. A. (2009). System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate.. Cerebral cortex (New York, N.Y. : 1991), 19(5), 1092-106. doi:10.1093/cercor/bhn151
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  Glutamate mediates several modes of neurotransmission in the central nervous system including recently discovered retrograde signaling from neuronal dendrites. We have previously identified the system N transporter SN1 as being responsible for glutamine efflux from astroglia and proposed a system A transporter (SAT) in subsequent transport of glutamine into neurons for neurotransmitter regeneration. Here, we demonstrate that SAT2 expression is primarily confined to glutamatergic neurons in many brain regions with SAT2 being predominantly targeted to the somatodendritic compartments in these neurons. SAT2 containing dendrites accumulate high levels of glutamine. Upon electrical stimulation in vivo and depolarization in vitro, glutamine is readily converted to glutamate in activated dendritic subsegments, suggesting that glutamine sustains release of the excitatory neurotransmitter via exocytosis from dendrites. The system A inhibitor MeAIB (alpha-methylamino-iso-butyric acid) reduces neuronal uptake of glutamine with concomitant reduction in intracellular glutamate concentrations, indicating that SAT2-mediated glutamine uptake can be a prerequisite for the formation of glutamate. Furthermore, MeAIB inhibited retrograde signaling from pyramidal cells in layer 2/3 of the neocortex by suppressing inhibitory inputs from fast-spiking interneurons. In summary, we demonstrate that SAT2 maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate.
• Lister, J. P., & Barnes, C. A. (2009). Neurobiological changes in the hippocampus during normative aging.. Archives of neurology, 66(7), 829-33. doi:10.1001/archneurol.2009.125
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  The number of individuals older than 65 years is projected to exceed 71.5 million in the year 2030, which is twice the number alive during the year 2000. While this dramatic increase in the number of individuals at risk for Alzheimer and vascular disease will pose a significant challenge to the health care industry, many older individuals will not actually die of these age-related dementias. Instead, a significant proportion of those older than 65 years will have to cope with alterations in memory function that are associated with normative aging. A clear understanding of the neurobiological mechanisms underlying normal age-related changes will be essential in helping elderly populations maintain cognitive performance with increasing age. This review covers the major age-related alterations in the hippocampus, a critical structure for learning and memory.
• Rosi, S., Ramirez-Amaya, V., Vazdarjanova, A., Esparza, E., Larkin, P., Fike, J., Wenk, G., & Barnes, C. (2009). Accuracy of hippocampal network activity is disrupted by neuroinflammation: Rescue by memantine. Brain, 132(9). doi:10.1093/brain/awp148
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  Understanding how the hippocampus processes episodic memory information during neuropathological conditions is important for treatment and prevention applications. Previous data have shown that during chronic neuroinflammation the expression of the plasticity related behaviourally-induced immediate early gene Arc is altered within the CA3 and the dentate gyrus; both of these hippocampal regions show a pronounced increase in activated microglia. Low doses of memantine, a low to moderate affinity open channel uncompetitive N-Methyl-d-aspartate receptor antagonist, reduce neuroinflammation, return Arc expression to control levels and attenuate cognitive deficits induced by lipopolysaccharide. Here we investigate whether neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions and if this is modified by memantine treatment. Using the immediate early gene-based brain-imaging method called cellular analysis of temporal activity by fluorescence in situ hybridization, it is possible to detect primary transcripts at the genomic alleles; this provides exceptional temporal and cellular resolution and facilitates the mapping of neuronal activity. Here, we use this method to compare the neuronal populations activated by two separate experiences in CA1 and CA3 and evaluate the accuracy of information processing during chronic neuroinflammation. Our results show that the CA3 pyramidal neuron activity is not stable between two exposures to the same environment context or two different contexts. CA1 networks, however, do not differ from control conditions. These data suggest that during chronic neuroinflammation, the CA3 networks show a disrupted ability to encode spatial information, and that CA1 neurons can work independently of CA3. Importantly, memantine treatment is able to partially normalize information processing in the hippocampus, suggesting that when given early during the development of the pathology memantine confers neuronal and cognitive protection while indirectly prevents pathological microglial activation.
• Rosi, S., Ramirez-amaya, V., Vazdarjanova, A., Esparza, E. E., Larkin, P. B., Fike, J. R., Wenk, G. L., & Barnes, C. A. (2009). Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine.. Brain : a journal of neurology, 132(Pt 9), 2464-77. doi:10.1093/brain/awp148
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  Understanding how the hippocampus processes episodic memory information during neuropathological conditions is important for treatment and prevention applications. Previous data have shown that during chronic neuroinflammation the expression of the plasticity related behaviourally-induced immediate early gene Arc is altered within the CA3 and the dentate gyrus; both of these hippocampal regions show a pronounced increase in activated microglia. Low doses of memantine, a low to moderate affinity open channel uncompetitive N-Methyl-d-aspartate receptor antagonist, reduce neuroinflammation, return Arc expression to control levels and attenuate cognitive deficits induced by lipopolysaccharide. Here we investigate whether neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions and if this is modified by memantine treatment. Using the immediate early gene-based brain-imaging method called cellular analysis of temporal activity by fluorescence in situ hybridization, it is possible to detect primary transcripts at the genomic alleles; this provides exceptional temporal and cellular resolution and facilitates the mapping of neuronal activity. Here, we use this method to compare the neuronal populations activated by two separate experiences in CA1 and CA3 and evaluate the accuracy of information processing during chronic neuroinflammation. Our results show that the CA3 pyramidal neuron activity is not stable between two exposures to the same environment context or two different contexts. CA1 networks, however, do not differ from control conditions. These data suggest that during chronic neuroinflammation, the CA3 networks show a disrupted ability to encode spatial information, and that CA1 neurons can work independently of CA3. Importantly, memantine treatment is able to partially normalize information processing in the hippocampus, suggesting that when given early during the development of the pathology memantine confers neuronal and cognitive protection while indirectly prevents pathological microglial activation.
• Barnes, C. A., Alexander, G. E., Aschenbrenner, M., Buonocore, M. H., Chen, K., Merkley, T. L., Rapp, P. R., Santerre-lemmon, L. E., Shamy, J. L., & Skaggs, W. E. (2008). Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28(11), 2710-8. doi:10.1523/jneurosci.1852-07.2008
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  Human structural neuroimaging studies have supported the preferential effects of healthy aging on frontal cortex, but reductions in other brain regions have also been observed. We investigated the regional network pattern of gray matter using magnetic resonance imaging (MRI) in young adult and old rhesus macaques (RMs) to evaluate age effects throughout the brain in a nonhuman primate model of healthy aging in which the full complement of Alzheimer's disease (AD) pathology does not occur. Volumetric T1 MRI scans were spatially normalized and segmented for gray matter using statistical parametric mapping (SPM2) voxel-based morphometry. Multivariate network analysis using the scaled subprofile model identified a linear combination of two gray matter patterns that distinguished the young from old RMs. The combined pattern included reductions in bilateral dorsolateral and ventrolateral prefrontal and orbitofrontal and superior temporal sulcal regions with areas of relative preservation in vicinities of the cerebellum, globus pallidus, visual cortex, and parietal cortex in old compared with young RMs. Higher expression of this age-related gray matter pattern was associated with poorer performance in working memory. In the RM model of healthy aging, the major regionally distributed effects of advanced age on the brain involve reductions in prefrontal regions and in the vicinity of the superior temporal sulcus. The age-related differences in gray matter reflect the effects of healthy aging that cannot be attributed to AD pathology, providing support for the targeted effects of aging on the integrity of frontal lobe regions and selective temporal lobe areas and their associated cognitive functions.
• Barnes, C. A., Erickson, C. A., Insel, N., Permenter, M., Ruiz-luna, M. L., & Vogt, J. (2008). Aging in rhesus macaques is associated with changes in novelty preference and altered saccade dynamics.. Behavioral neuroscience, 122(6), 1328-42. doi:10.1037/a0012928
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  Studies demonstrating recognition deficits with aging often use tasks in which subjects have an incentive to correctly encode or retrieve the experimental stimuli. In contrast to these tasks, which may engage strategic encoding and retrieval processes, the visual paired comparison (VPC) task measures spontaneous eye movements made toward a novel as compared with familiar stimulus. In the present study, seven rhesus macaques aged 6 to 30 years exhibited a dramatic age-dependent decline in preference for a novel image compared with one presented seconds earlier. The age effect could not be accounted for by memory deficits alone, because it was present even when familiarization preceded test by 1 second. It also could not be explained by an encoding deficit, because the effect persisted with increased familiarity of the sample stimulus. Reduced novelty preference did correlate with eye movement variables, including reaction time distributions and saccade frequency. At long delay intervals (24 or 48 hours) aging was paradoxically associated with increased novelty preference. Several explanations for the age effect are considered, including the possible role of dopamine.
• Burke, S. N., Maurer, A. P., Yang, Z., Navratilova, Z., & Barnes, C. A. (2008). Glutamate receptor-mediated restoration of experience-dependent place field expansion plasticity in aged rats.. Behavioral neuroscience, 122(3), 535-48. doi:10.1037/0735-7044.122.3.535
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  Place fields of hippocampal pyramidal cells expand asymmetrically when adult rats repeatedly follow the same route. This behaviorally induced expression of neuronal plasticity uses an NMDAR-dependent, LTP-like mechanism and could be used by hippocampal networks to store information. Aged spatial memory-impaired rats exhibit defective experience-dependent place field expansion plasticity. One possible explanation for this aged-associated deficit is alterations in glutamatergic function. In fact, both NMDAR- and AMPAR-mediated field excitatory postsynaptic potentials in CA1 decrease with aging. The current study investigated whether modulation of either AMPA or NDMA receptor activity could restore this experience-dependent plasticity by prolonging AMPAR activity with the ampakine CX516 and modulating the NMDAR with the noncompetitive antagonist memantine. The spatial firing characteristics of multiple CA1 pyramidal cells were monitored under both treatment conditions as aged rats repeatedly traversed a circular track. Compared to the saline baseline condition, acute administration of memantine, but not CX516, reinstated experience-dependent place field expansion. Taken together, these data suggest that pharmacological manipulation of the NMDAR can improve the function of hippocampal networks critical to optimal cognition in aging.
• Burke, S., Maurer, A., Yang, Z., Navratilova, Z., & Barnes, C. (2008). Glutamate Receptor-Mediated Restoration of Experience-Dependent Place Field Expansion Plasticity in Aged Rats. Behavioral Neuroscience, 122(3). doi:10.1037/0735-7044.122.3.535
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  Place fields of hippocampal pyramidal cells expand asymmetrically when adult rats repeatedly follow the same route. This behaviorally induced expression of neuronal plasticity uses an NMDAR-dependent, LTP-like mechanism and could be used by hippocampal networks to store information. Aged spatial memory-impaired rats exhibit defective experience-dependent place field expansion plasticity. One possible explanation for this aged-associated deficit is alterations in glutamatergic function. In fact, both NMDAR- and AMPAR-mediated field excitatory postsynaptic potentials in CA1 decrease with aging. The current study investigated whether modulation of either AMPA or NDMA receptor activity could restore this experience-dependent plasticity by prolonging AMPAR activity with the ampakine CX516 and modulating the NMDAR with the noncompetitive antagonist memantine. The spatial firing characteristics of multiple CA1 pyramidal cells were monitored under both treatment conditions as aged rats repeatedly traversed a circular track. Compared to the saline baseline condition, acute administration of memantine, but not CX516, reinstated experience-dependent place field expansion. Taken together, these data suggest that pharmacological manipulation of the NMDAR can improve the function of hippocampal networks critical to optimal cognition in aging. © 2008 American Psychological Association.
• Gerrard, J., Burke, S., McNaughton, B., & Barnes, C. (2008). Sequence reactivation in the hippocampus is impaired in aged rats. Journal of Neuroscience, 28(31). doi:10.1523/JNEUROSCI.1265-08.2008
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  The hippocampus is thought to coordinate memory consolidation by reactivating traces from behavioral experience when the brain is not actively processing new input. In fact, during slow-wave sleep, the patterns of CA1 pyramidal cell ensemble activity correlations are reactivated in both young and aged rats. In addition to correlated activity patterns, repetitive track running also creates a recurring sequence of pyramidal cell activity. The present study compared CA1 sequence activity pattern replay in young and old animals during rest periods after behavior. Whereas the young rats exhibited significant sequence reactivation, it was markedly impaired in the aged animals. When the spatial memory scores of all animals were compared with the degree of sequence reactivation, there was a significant correlation. The novel finding that weak replay of temporal patterns has behavioral consequences, strengthens the idea that reactivation processes are integral to memory consolidation. Copyright © 2008 Society for Neuroscience.
• Krause, M., Yang, Z., Rao, G., Houston, F., & Barnes, C. (2008). Altered dendritic integration in hippocampal granule cells of spatial learning-impaired aged rats. Journal of Neurophysiology, 99(6). doi:10.1152/jn.01278.2007
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  Glutamatergic transmission at central synapses undergoes activity-dependent and developmental changes. In the hippocampal dentate gyrus, the non-N-methyl D-aspartate (NMDA) receptor component of field excitatory postsynaptic potentials (fEPSPs) increases with age in Fischer-344 rats. This effect may not depend on the animal's activity or experience but could be part of the developmental process. Age-dependent differences in synaptic transmission at the perforant path-granule cell synapse may be caused by changes in non-NMDA and NMDA receptor-mediated currents. To test this hypothesis, we compared whole cell excitatory postsynaptic currents (EPSCs) in dentate granule cells evoked by perforant path stimulation in young (3-4 mo) and aged (22-27 mo) Fischer-344 rats using a Cs+-based intracellular solution. Aged animals as a group showed spatial learning and memory deficits in the Morris water maze. Using whole cell recordings, slope conductances of both non-NMDA and NMDA EPSCs at holding potentials -10 to +50 mV were significantly reduced in aged animals and the non-NMDA/NMDA ratio in aged animals was found to be significantly smaller than in young animals. In contrast, we detected no differences in basic electrophysiological parameters, or absolute amplitudes of non-NMDA and NMDA EPSCs. Extracellular Cs+ increased the fEPSP in young slices to a greater degree than was found in the aged slices, while it increased population spikes to a greater degree in the aged rats. Our results not only provide evidence for reduced glutamatergic synaptic responses in Fischer-344 rats but also point to differential changes in Cs+-sensitive dendritic conductances, such as Ih or inwardly rectifying potassium currents, during aging. Copyright © 2008 The American Physiological Society.
• Wu, W., Brickman, A., Luchsinger, J., Brown, T., Decarli, C., Barnes, C., Vannucci, S., Small, S., Barnes, C. A., Brickman, A. M., Brown, T. R., Ferrazzano, P., Luchsinger, J. A., Mayeux, R., Pichiule, P., Small, S. A., Vannucci, S. J., Wu, W. E., & Yoshita, M. (2008). The brain in the age of old: The hippocampal formation is targeted differentially by diseases of late life. Annals of Neurology, 64(6). doi:10.1002/ana.21557
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  Objective: To rely on the anatomical organization of the hippocampal formation in understanding whether and how late-life diseases such as diabetes and stroke contribute to age-related cognitive decline. Methods: Magnetic resonance imaging (MRI) was used to document brain infarcts and to generate high-resolution functional maps of the hippocampal formation in 240 community-based nondemented elders (mean age, 79.7 years) who received a comprehensive medical evaluation. Sixty participants had type 2 diabetes mellitus, whereas 74 had MRI-documented brain infarcts, and the first analysis was designed to pinpoint hippocampal subregions differentially linked to each disorder. Then, guided by the results, additional functional MRI studies in aging rhesus monkeys and mice were used to test proposed mechanisms of dysfunction. Results: Although both diabetes and brain infarcts were associated with hippocampal dysfunction, each was linked to separate hippocampal subregions, suggesting distinct underlying mechanisms. The hippocampal subregion linked to diabetes implicated blood glucose as a pathogenic mechanism, a hypothesis confirmed by imaging aging rhesus monkeys and a mouse model of diabetes. The hippocampal subregion linked to infarcts suggested transient hypoperfusion as a pathogenic mechanism, a hypothesis provisionally confirmed by comparing anatomical patterns across subjects with infarcts in different vascular territories. Interpretation: Taken together with previous findings, these results clarify how diseases of late life differentially target the hippocampal formation, identify elevations in blood glucose as a contributing cause of age-related memory decline, and suggest specific interventions that can preserve cognitive health. © 2008 American Neurological Association. Published by Wiley-Liss, Inc., through Wiley Subscription Services.
• Yang, Z., Krause, M., Rao, G., McNaughton, B., & Barnes, C. (2008). Synaptic commitment: Developmentally regulated reciprocal changes in hippocampal granule cell NMDA and AMPA receptors over the lifespan. Journal of Neurophysiology, 99(6). doi:10.1152/jn.01276.2007
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  Synaptic transmission in hippocampal field CA1 is largely N-methyl-D-aspartate receptor (NMDAR) dependent during the early postnatal period. It becomes increasingly mediated by α-amino-3-hydroxy-5- methylisoxazole-4-proprionate (AMPA) receptors until an adult ratio of AMPA to NMDA receptors is achieved. It is shown here that increases in the AMPA receptor (AMPAR)-mediated field potential response continue over the life span of the F-344 rat at the perforant path- granule cell synapse in the dentate gyrus. In contrast, the NMDAR-dependent component of the response decreases with age between 1 and 27 mo, leading to an increase of AMPA R/NMDAR ratio with age. One possible explanation of this age difference is that the AMPAR/NMDAR ratio can be modified by experience. To test the idea that the changed ratio is caused by the old rats' longer lives, an intensive 10-mo period of enrichment treatment was given to a group of animals, beginning at 3 mo of age. Compared with animals housed in standard cages, the enrichment treatment did not alter the glutamatergic response ratio measured with field potential recording methods. These data provide support for the conclusion that the observed change with age is developmentally regulated rather than experience dependent. Given the role of the NMDAR in synaptic plasticity, these changes suggest a progressive commitment of perforant path synapses to particular weights over the life span. One possible implication of this effect includes preservation of selected memories, ultimately at the expense of a reduced capacity to store new information. Copyright © 2008 The American Physiological Society.
• Lin, G., Chawla, M., Olson, K., Barnes, C., Guzowski, J., Bjornsson, C., Shain, W., & Roysam, B. (2007). A multi-model approach to simultaneous segmentation and classification of heterogeneous populations of cell nuclei in 3D confocal microscope images. Cytometry Part A, 71(9). doi:10.1002/cyto.a.20430
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  Automated segmentation and morphometry of fluorescently labeled cell nuclei in batches of 3D confocal stacks is essential for quantitative studies. Model-based segmentation algorithms are attractive due to their robustness. Previous methods incorporated a single nuclear model. This is a limitation for tissues containing multiple cell types with different nuclear features. Improved segmentation for such tissues requires algorithms that permit multiple models to be used simultaneously. This requires a tight integration of classification and segmentation algorithms. Two or more nuclear models are constructed semiautomatically from user-provided training examples. Starting with an initial over-segmentation produced by a gradient-weighted watershed algorithm, a hierarchical fragment merging tree rooted at each object is built. Linear discriminant analysis is used to classify each candidate using multiple object models. On the basis of the selected class, a Bayesian score is computed. Fragment merging decisions are made by comparing the score with that of other candidates, and the scores of constituent fragments of each candidate. The overall segmentation accuracy was 93.7% and classification accuracy was 93.5%, respectively, on a diverse collection of images drawn from five different regions of the rat brain. The multi-model method was found to achieve high accuracy on nuclear segmentation and classification by correctly resolving ambiguities in clustered regions containing heterogeneous cell populations. © 2007 International Society for Analytical Cytology.
• Rosi, S., Milliken, H. L., Ramirez-amaya, V., Varzdarjanova, A., Barnes, C. A., & Worley, P. F. (2007).

  AbstractPosterP-107: Neuroinflammation and neuronal networks activation involved in learning and memory

  . Alzheimers & Dementia, 3(3). doi:10.1016/j.jalz.2007.04.171
• Skaggs, W., McNaughton, B., Permenter, M., Archibeque, M., Vogt, J., Amaral, D., & Barnes, C. (2007). EEG sharp waves and sparse ensemble unit activity in the macaque hippocampus. Journal of Neurophysiology, 98(2). doi:10.1152/jn.00401.2007
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  Neural unit activity and EEGs were recorded from inferior temporal regions of three rhesus macaques chronically implanted with "hyperdrives" holding 12 individually movable tetrodes. Recordings were made from each monkey over a period of ∼3 mo, while the electrodes were moved by small increments through the hippocampus and neighboring structures. After recording, the monkeys were necropsied, and the brains were sectioned and Nissl-stained, permitting identification of individual electrode tracks. The results establish that hippocampal pyramidal cells are "complex spike cells," firing at overall average rates of ∼0.3 Hz, with spike trains consisting of long periods of silence interspersed with bursts of activity. The results also establish that the monkey hippocampal EEG shows "sharp wave" events consisting of a high-frequency "ripple" oscillation (∼110 Hz) together with a large slow-wave EEG deflection lasting several hundred milliseconds. The evidence suggests that monkey sharp waves are probably generated mainly in the CA1 region and that sharp waves are associated with an inactive/drowsy-or-sleeping behavioral state, which is also associated with increased hippocampal pyramidal cell activity and increased hippocampal EEG amplitude. The results of this initial study of ensembles of primate hippocampal neurons are consistent with previous studies in rodents and consistent with the hypothesis that theories and models of hippocampal memory function developed on the basis of rat data may be applicable to a wide range of mammalian species. Copyright © 2007 The American Physiological Society.
• Sutherland, V., Timlin, J., Nieman, L., Guzowski, J., Chawla, M., Worley, P., Roysam, B., McNaughton, B., Sinclair, M., & Barnes, C. (2007). Advanced imaging of multiple mRNAs in brain tissue using a custom hyperspectral imager and multivariate curve resolution. Journal of Neuroscience Methods, 160(1). doi:10.1016/j.jneumeth.2006.08.018
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  Simultaneous imaging of multiple cellular components is of tremendous importance in the study of complex biological systems, but the inability to use probes with similar emission spectra and the time consuming nature of collecting images on a confocal microscope are prohibitive. Hyperspectral imaging technology, originally developed for remote sensing applications, has been adapted to measure multiple genes in complex biological tissues. A spectral imaging microscope was used to acquire overlapping fluorescence emissions from specific mRNAs in brain tissue by scanning the samples using a single fluorescence excitation wavelength. The underlying component spectra obtained from the samples are then separated into their respective spectral signatures using multivariate analyses, enabling the simultaneous quantitative measurement of multiple genes either at regional or cellular levels. © 2006 Elsevier B.V. All rights reserved.
• Barnes, C. A., Barnes, C. A., Burke, S. N., Burke, S. N., Cowen, S. L., Cowen, S. L., Maurer, A. P., Maurer, A. P., Mcnaughton, B. L., & Mcnaughton, B. L. (2006). Organization of hippocampal cell assemblies based on theta phase precession.. Hippocampus, 16(9), 785-94. doi:10.1002/hipo.20202
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  The factors that control the spatial tuning of hippocampal neurons are incompletely understood, and there is no generally agreed upon definition of what constitutes a "place field". One factor that must be considered is the phenomenon of "phase precession". As a rat passes through the place field of a particular hippocampal neuron, its spikes shift to earlier phases of the theta rhythm. Except for the special cases discussed herein, the phase shift never exceeds 360 degrees. Moreover, under conditions in which place field sizes change dynamically, precession rate is tightly coupled with the place field size, suggesting that a single cycle of theta phase precession could be used to define unitary place field boundaries. Theta phase precession implies that the "cell assembly" of active hippocampal neurons changes systematically over the course of a single theta cycle. A given cell can exhibit more than one place field in a given environment, each field showing the same pattern of 360 degrees of phase precession. The existence of multiple fields implies that one cell can participate in multiple cell assemblies within the same environment. We show here that place fields, defined as a single cycle of phase precession, can overlap spatially, with the result that the cell fires with spikes clustered at two different phases over the theta cycles in which the fields overlap. Thus, the same neuron can participate in different cell assemblies within a single theta cycle.
• Barnes, C. A., Burke, S. N., Cowen, S. L., Maurer, A. P., & Mcnaughton, B. L. (2006). Phase precession in hippocampal interneurons showing strong functional coupling to individual pyramidal cells.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 26(52), 13485-92. doi:10.1523/jneurosci.2882-06.2006
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  Although hippocampal interneurons typically do not show discrete regions of elevated firing in an environment, such as seen in pyramidal cell place fields, they do exhibit significant spatial modulation (McNaughton et al., 1983a). Strong monosynaptic coupling between pyramidal neurons and nearby interneurons in the CA1 stratum pyramidale has been strongly implicated on the basis of significant, short-latency peaks in cross-correlogram plots (Csicsvari et al., 1998). Furthermore, interneurons receiving a putative monosynaptic connection from a simultaneously recorded pyramidal cell appear to inherit the spatial modulation of the latter (Marshall et al., 2002). Buzsaki and colleagues hypothesize that interneurons may also adopt the firing phase dynamics of their afferent place cells, which show a phase shift relative to the hippocampal theta rhythm as a rat passes through the place field ("phase precession"). This study confirms and extends the previous reports by showing that interneurons in the dorsal and middle hippocampus with putative monosynaptic connections with place cells recorded on the same tetrode share other properties with their pyramidal cell afferents, including the spatial scale of the place field of pyramidal cell, a characteristic of the septotemporal level of the hippocampus from which the cells are recorded, and the rate of phase precession, which is slower in middle regions. Furthermore, variations in pyramidal cell place field scale within each septotemporal level attributable to task variations are similarly associated with variations in interneuron place field scale. The available data strongly suggest that spatial selectivity of CA1 stratum pyramidale interneurons is inherited from a small cluster of local pyramidal cells and is not a consequence of spatially selective synaptic input from CA3 or other sources.
• Burke, S. N., & Barnes, C. A. (2006). Neural plasticity in the ageing brain.. Nature reviews. Neuroscience, 7(1), 30-40. doi:10.1038/nrn1809
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  The mechanisms involved in plasticity in the nervous system are thought to support cognition, and some of these processes are affected during normal ageing. Notably, cognitive functions that rely on the medial temporal lobe and prefrontal cortex, such as learning, memory and executive function, show considerable age-related decline. It is therefore not surprising that several neural mechanisms in these brain areas also seem to be particularly vulnerable during the ageing process. In this review, we discuss major advances in our understanding of age-related changes in the medial temporal lobe and prefrontal cortex and how these changes in functional plasticity contribute to behavioural impairments in the absence of significant pathology.
• Guzowski, J., Miyashita, T., Chawla, M., Sanderson, J., Maes, L., Houston, F., Lipa, P., McNaughton, B., Worley, P., & Barnes, C. (2006). Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons. Proceedings of the National Academy of Sciences of the United States of America, 103(4). doi:10.1073/pnas.0505519103
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  The ability of neurons to alter their transcriptional programs in response to synaptic input is of fundamental importance to the neuroplastic mechanisms underlying learning and memory. Because of technical limitations of conventional gene detection methods, the current view of activity-dependent neural transcription derives from experiments in which neurons are assumed quiescent until a signaling stimulus is given. The present study was designed to move beyond this static model by examining how earlier episodes of neural activity influence transcription of the immediate-early gene Arc. Using a sensitive FISH method that detects primary transcript at genomic alleles, the proportion of hippocampal CA1 neurons that activate transcription of Arc RNA was constant at ≈40% in response to both a single novel exploration session and daily sessions repeated over 9 days. This proportion is similar to the percentage of active neurons defined electrophysiologically. However, this close correspondence was disrupted in rats exposed briefly, but repeatedly, to the same environment within a single day. Arc transcription in CA1 neurons declined dramatically after as few as four 5-min sessions, despite stable electrophysiological activity during all sessions. Additional experiments indicate that the decrement in Arc transcription occurred at the cellular, rather than synaptic level, and was not simply linked to habituation to novelty. Thus, the neural genomic response is governed by recent, but not remote, cell firing history in the behaving animal. This state-dependence of neuronal transcriptional coupling provides a mechanism of metaplasticity and may regulate capacity for synaptic modification in neural networks. © 2006 by The National Academy of Sciences of the USA.
• Kelly, K. M., Nadon, N. L., Morrison, J. H., Thibault, O., Barnes, C. A., & Blalock, E. M. (2006). The neurobiology of aging.. Epilepsy research, 68 Suppl 1, S5-20. doi:10.1016/j.eplepsyres.2005.07.015
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  Basic principles of the neurobiology of aging were reviewed within selected topic areas chosen for their potential relevance to epileptogenesis in the aging brain. The availability of National Institute on Aging-supported aged mouse and rat strains and other biological resources for studies of aging and age-associated diseases was presented, and general principles of animal use in gerontological research were discussed. Neurobiological changes during normal brain aging were compared and contrasted with neuropathological events of Alzheimer's disease (AD) and age-associated memory impairment (AAMI). Major themes addressed were the loss of synaptic connections as vulnerable neurons die and circuits deteriorate in AD, the absence of significant neuron loss but potential synaptic alteration in the same circuits in AAMI, and the effects of decreased estrogen on normal aging. The "calcium hypothesis of brain aging" was examined by a review of calcium dyshomeostasis and synaptic communication in aged hippocampus, with particular emphasis on the role of L-type voltage-gated calcium channels during normal aging. Established and potential mechanisms of hippocampal plasticity during aging were discussed, including long-term potentiation, changes in functional connectivity, and increased gap junctions, the latter possibly being related to enhanced network excitability. Lastly, application of microarray gene chip technology to aging brain studies was presented and use of the hippocampal "zipper slice" preparation to study aged neurons was described.
• Rosi, S., Vazdarjanova, A., Ramirez-Amaya, V., Worley, P., Barnes, C., & Wenk, G. (2006). Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience, 142(4). doi:10.1016/j.neuroscience.2006.08.017
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  Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of the rat resulting in region-selective microglia activation and impaired hippocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the immediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to increased glutamate release, and in enhanced N-methyl-d-aspartate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activation during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antagonist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The results reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluorescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neuroinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeutically relevant doses of memantine delivered early in the development of neuroinflammation-influenced diseases may confer neural and cognitive protection. © 2006 IBRO.
• Abi-dargham, A., Allgulander, C., Gureje, O., Jenkins, R., Kalaria, R. N., Njenga, F., Pinder, R. M., Siever, L. J., Svensson, T. H., Robbins, T. W., Horn, G., Gustafsson, J., Connor, J. R., Zatta, P. Z., Khamis, T. M., Ongecha, F. A., Ndetei, D. M., Khasakhala, L. K., Obeijide, O. A., , Omigbodun, O., et al. (2005). CINP 2005 Regional Meeting, 20-22 April 2005. South African Medical Journal, 11(1), 10. doi:10.4102/sajpsychiatry.v11i1.92
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  List of abstract titles and authors:1. Antipsychotics across the spectrum: An overview of their mechanisms of actionAnissa Abi-Dargham2. Recent advances in the treatment of common anxiety disordersChrister Allgulander3. Psychiatry in Africa: The myths, the realities and the exoticO Gureje4. Mental Health policy developmet in Kenya and Tanznia - A DFID funded projectRachel Jenkins, David Kima, Joseph Mbatia, Frank Njenga5. Vascular factors in Alzheimer's diseaseR N Kalaria6. Depression as an immunologically based Neurodegenerative disorderBrian Leonard7. Eight years of progress in Arican PsychiatryF Njenga8. Treatment of Depression: Present and futureDr R.M. Pinder9. Imaging the Serotinergic system in impulsive aggressive personality disorder patientsLarry J Siever, Antonia S. New, Mari Goodman, Monte Buchsbaum, Erin Hazlett, Karen O'Flynn, Anissa Abi-argham, Marc Lauelle10. Mode of action of Atypical antipsychotic rugs: Focus on A2 AdrnoceptorsT.H. SvenssonNeuroscience: Selected Abstracts11. Chemical odulato of Fronto-execuitive functions: Neropsychiatric implicationsTrevor W Robbins12. Neural mechanisms of recognition memory and of social atacntProf. G Horn13. Estrogen signling after estrogen receptor ß (ERß)Jan-Ake Gustafsson14. Getting Lost: Hippocampal contributions to agerelated memory dysfunctionCarol BarnesMetals and the brain: Selected abstracts15. Modeling the contributin of iron mismanagement to Neurological disordersProf. J R C Connor16. Aluminium-triggered fibrillogenesis of B-AmyloidsProf. PZ Zatta, Dr D Drago, Mr G Tognon, Dr F RicchelliPsychiatry in Africa:17. Psychosocal aspects of Khat use among the youth of NairobiMs T M Khamis18. PTSD among motor vehicle accident survivors, KenyaDr F A Ongecha19. Psychiatric relities within African context - The Kenyan case StudyProf. D M N Ndetei20. Adolescent-parenta interactions from infancy, Nairobi KenyaDr L K Ksakhala, Prof. D M N Ndetei21. Alcohol use ong young persons: A focus group study in Southwest NigeriaO A Obeijide22. Personality disorders and personality traits among tyoe 2 Diabetic patientsProf. O El Rufaie, Dr M Sabosy, Dr M S Abuzeid23. Association of traumatic experiences with depression among Nigerian adolescentsDr O Omigbodun, Dr K BakareMs O B Yusuf, Dr O Esan24. Prevalence of depression among women attending outpatient clinics in MalawiDr M Tugumisirize, Prof. Agn, Dr Musisi25. Non-fatal suicidalbehaviour at the Johannesburg General HospitalDr M Y H Moosa, Prof. F Y Jeenah, Dr A Pillay, Pof. M Vorstere, Dr R Liebenberg26. Integrating mental health into general primary health care - Uganda's experienceDr N Kigozi27. Depression among Nigerian survivors of stroke:Prevalance and associated factorsDr F.O Fatoye Dr M A Komolafe, Dr A. O Adewuya, Dr B.A. Eegunranti Prof. M.A. Lawal28. NGO Involvement mental health care -The way forwardDr Basangwa29. Prevalen of Attenton Deficit Hyperactivity sorder among African school childrenDr E KashalaProf. T Tylleskar, Dr I Elgen, Dr K Sommerfelt30. Barriers to effective mental health care in NigeriaMs L. Kola31. Quay of life evaluation in patients with HIV-I infection with respect to the impact of Phyttherapy (Traditional Herb in Zimbabwe)M B Sebit, S K Chandiwaa, A S Latif, E Gomo, S W Acuda, F Makoni, J Vushe
• Barnes, C. A., Gothard, K. M., Krause, M., Lipa, P., Mcnaughton, B. L., & Terrazas, A. (2005). Self-motion and the hippocampal spatial metric.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 25(35), 8085-96. doi:10.1523/jneurosci.0693-05.2005
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  Self-motion signals are sufficient for animal navigation ("path integration") and for updating hippocampal location-specific firing. The contributions of ambulatory, vestibular, and optic self-motion signals to CA1 unit activity and EEG were studied while rats either walked or drove a car between locations on a circular track (referred to as WALK and CAR, respectively) or experienced pseudomotion, in which the animal was stationary and the environment was rotated (WORLD). Fewer pyramidal cells expressed place fields during CAR and those that did exhibited substantially larger place fields. The number of theta cycles required to traverse a place field increased, whereas the slope of the theta phase of firing versus position function was reduced. The presence and/or location of place fields were not well correlated between conditions. These effects were even more accentuated during WORLD. These results are not explainable by a simple "smearing out" of place fields but, in terms of size of place fields relative to the track size, are comparable with what would be observed if the track circumference was reduced and the animal moved around it at a correspondingly slower speed. Theta (and its 14-18 Hz harmonic) power were dependent on velocity, but the gain of this function was substantially reduced during CAR and WORLD, again as if the rat were moving more slowly. The spatial scale over which the hippocampal population vector is updated appears to be derived primarily from the gain of a self-motion velocity signal with approximately equal components derived from ambulation, vestibular, and optic-flow signals.
• Burke, S. N., Chawla, M. K., Penner, M. R., Crowell, B. E., Worley, P. F., Barnes, C. A., & Mcnaughton, B. L. (2005). Differential encoding of behavior and spatial context in deep and superficial layers of the neocortex.. Neuron, 45(5), 667-74. doi:10.1016/j.neuron.2005.01.042
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  Rodent hippocampal activity is correlated with spatial and behavioral context, but how context affects coding in association neocortex is not well understood. The cellular distribution of the neural activity-regulated immediate-early gene Arc was used to monitor the activity history of cells in CA1, and in deep and superficial layers of posterior parietal and gustatory cortices (which encode movement and taste, respectively), during two behavioral epochs in which spatial and behavioral context were independently manipulated while gustatory input was held constant. Under conditions in which the hippocampus strongly differentiated behavioral and spatial contexts, deep parietal and gustatory layers did not discriminate between spatial contexts, whereas superficial layers in both neocortical regions discriminated well. Deep parietal cells discriminated behavioral context, whereas deep gustatory cortex neurons encoded the two conditions identically. Increased context sensitivity of superficial neocortical layers, which receive more hippocampal outflow, may reflect a general principle of neocortical organization for memory retrieval.
• Chawla, M. K., Chawla, M. K., Guzowski, J. F., Guzowski, J. F., Ramirez-amaya, V., Ramirez-amaya, V., Lipa, P., Lipa, P., Hoffman, K. L., Hoffman, K. L., Marriott, L. K., Marriott, L. K., Worley, P. F., Worley, P. F., Mcnaughton, B. L., Mcnaughton, B. L., Barnes, C. A., & Barnes, C. A. (2005). Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience.. Hippocampus, 15(5), 579-86. doi:10.1002/hipo.20091
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  After a spatial behavioral experience, hippocampal CA1 pyramidal cells express the activity-regulated, immediate early gene Arc in an environment-specific manner, and in similar proportions ( 40%) to cells exhibiting electrophysiologically recorded place fields under similar conditions. Theoretical accounts of the function of the fascia dentata suggest that it plays a role in pattern separation during encoding. The hypothesis that the dentate gyrus (DG) uses a sparse, and thus more orthogonal, coding scheme has been supported by the observation that, while granule cells do exhibit place fields, most are silent in a given environment. To quantify the degree of sparsity of DG coding and its corresponding ability to generate distinct environmental representations, behaviorally induced Arc expression was assessed using in situ hybridization coupled with confocal microscopy. The proportion of Arc(+) cells in the "upper blade" of the fascia dentata (i.e., the portion that abuts CA1) increased in an environment-specific fashion, approximately 4-fold above cage-control activity, after behavioral exploration. Surprisingly, cells in the lower blade of the fascia dentata, which are capable of expressing Arc following electrical stimulation, exhibited virtually no behaviorally-induced Arc expression. This difference was confirmed using "line scan" analyses, which also revealed no patterns or gradients of activity along the upper blade of the DG. The expression of Arc in the upper blade was quantitatively similar after exploring familiar or novel environments. When animals explored two different environments, separated by 20 min, a new group of cells responded to the second environment, whereas two separated experiences in the same environment did not activate a new set of granular cells. Thus, granule cells generate distinct codes for different environments. These findings suggest differential contribution of upper and lower blade neurons to plastic networks and confirm the hypothesis that the DG uses sparse coding that may facilitate orthogonalization of information.
• Guzowski, J. F., Timlin, J. A., Roysam, B., Mcnaughton, B. L., Worley, P. F., & Barnes, C. A. (2005). Mapping behaviorally relevant neural circuits with immediate-early gene expression.. Current opinion in neurobiology, 15(5), 599-606. doi:10.1016/j.conb.2005.08.018
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  Immediate-early genes have gained widespread popularity as activity markers for mapping neuronal circuits involved in specific behaviors in many different species. In situ immediate early gene detection methods provide cellular level resolution, a major benefit for mapping neuronal networks. Recent advances using fluorescence in situ hybridization also afford temporal resolution, enabling within-animal activity maps for two distinct behaviors. Moreover, use of transgenic mice with fluorescent reporter proteins driven by immediate early gene promoters is enabling repeated measurements, over long time scales, of cortical activity within the same animal. These methodological innovations, coupled with recent advances in fluorescence imaging and probe development, will enable large scale mapping of behaviorally relevant circuits with temporal and three-dimensional spatial resolution in experimental animals.
• Leutgeb, J., Leutgeb, S., Treves, A., Meyer, R., Barnes, C., McNaughton, B., Moser, M., & Moser, E. (2005). Progressive transformation of hippocampal neuronal representations in "morphed" environments. Neuron, 48(2). doi:10.1016/j.neuron.2005.09.007
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  Hippocampal neural codes for different, familiar environments are thought to reflect distinct attractor states, possibly implemented in the recurrent CA3 network. A defining property of an attractor network is its ability to undergo sharp and coherent transitions between pre-established (learned) representations when the inputs to the network are changed. To determine whether hippocampal neuronal ensembles exhibit such discontinuities, we recorded in CA3 and CA1 when a familiar square recording enclosure was morphed in quantifiable steps into a familiar circular enclosure while leaving other inputs constant. We observed a gradual noncoherent progression from the initial to the final network state. In CA3, the transformation was accompanied by significant hysteresis, resulting in more similar end states than when only square and circle were presented. These observations suggest that hippocampal cell assemblies are capable of incremental plastic deformation, with incongruous information being incorporated into pre-existing representations. Copyright ©2005 by Elsevier Inc.
• Leutgeb, S., Leutgeb, J., Barnes, C., Moser, E., McNaughton, B., & Moser, M. (2005). Neuroscience: Independent codes for spatial and episodic memory in hippocampal neuronal ensembles. Science, 309(5734). doi:10.1126/science.1114037
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  Hippocampal neurons were recorded under conditions in which the recording chamber was varied but its location remained unchanged versus conditions in which an identical chamber was encountered in different places. Two forms of neuronal pattern separation occurred. In the variable cue-constant place condition, the firing rates of active cells varied, often over more than an order of magnitude, whereas the location of firing remained constant. In the variable place-constant cue condition, both location and rates changed, so that population vectors for a given location in the chamber were statistically independent. These independent encoding schemes may enable simultaneous representation of spatial and episodic memory information.
• Lin, G., Chawla, M., Olson, K., Guzowski, J., Barnes, C., & Roysam, B. (2005). Hierarchical, model-based merging of multiple fragments for improved three-dimensional segmentation of nuclei. Cytometry Part A, 63(1). doi:10.1002/cyto.a.20099
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  Background: Automated segmentation of fluorescently labeled cell nuclei in three-dimensional confocal images is essential for numerous studies, e.g., spatiotemporal fluorescence in situ hybridization quantification of immediate early gene transcription. High accuracy and automation levels are required in high-throughput and large-scale studies. Common sources of segmentation error include tight clustering and fragmentation of nuclei. Previous region-based methods are limited because they perform merging of two nuclear fragments at a time. To achieve higher accuracy without sacrificing scale, more sophisticated yet computationally efficient algorithms are needed. Methods: A recursive tree-based algorithm that can consider multiple object fragments simultaneously is described. Starting with oversegmented data, it searches efficiently for the optimal merging pattern guided by a quantitative scoring criterion based on object modeling. Computation is bounded by limiting the depth of the merging tree. Results: The proposed method was found to perform consistently better, achieving merging accuracy in the range of 92% to 100% compared with our previous algorithm, which varied in the range of 75% to 97%, even with a modest merging tree depth of 3. The overall average accuracy improved from 90% to 96%, with roughly the same computational cost for a set of representative images drawn from the CA1, CA3, and parietal cortex regions of the rat hippocampus. Conclusion: Hierarchical tree model-based algorithms significantly improve the accuracy of automated nuclear segmentation without sacrificing speed. © 2004 Wiley-Liss, Inc.
• Moser, E., Moser, M., Lipa, P., Newton, M., Houston, F., Barnes, C., & Mcnaughton, B. (2005). A test of the reverberatory activity hypothesis for hippocampal 'place' cells. Neuroscience, 130(2). doi:10.1016/j.neuroscience.2004.09.044
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  One of several tenable hypotheses that can be proposed to explain the complex dynamics of spatially selective hippocampal neural activity postulates that the region of space over which a given cell receives its external input is actually much smaller than the classical 'place field.' According to this notion, the later portions of the field reflect some form of network hysteresis resulting from 'reverberatory' activity within reentrant, synaptically coupled cell assemblies within the hippocampus. This hypothesis predicts that transient, global inhibition, induced after the onset of firing, might truncate the remainder of the place field. To test this hypothesis, principal afferents to the hippocampus were stimulated bilaterally in rats running on a circular track, evoking widespread inhibition throughout the hippocampus, and abolishing all spike activity from simultaneously recorded populations of CA1 pyramidal cells for periods of 150-300 ms. Stimulation at any point within the place field of a given cell suppressed firing only for such brief intervals, followed by an immediate resumption for the remainder of the field. These results suggest that without additional cellular and/or synaptic mechanisms, reverberatory activity alone within the hippocampus does not account for the shape and spatial extent of place fields. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved.
• Rosi, S., Ramirez-Amaya, V., Vazdarjanova, A., Worley, P., Barnes, C., & Wenk, G. (2005). Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression. Journal of Neuroscience, 25(3). doi:10.1523/JNEUROSCI.4469-04.2005
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  Neuroinflammation is associated with a variety of neurological and pathological diseases, such as Alzheimer's disease (AD), and is reliably detected by the presence of activated microglia. In early AD, the highest degree of activated microglia is observed in brain regions involved in learning and memory. To investigate whether neuroinflammation alters the pattern of rapid de novo gene expression associated with learning and memory, we studied the expression of the activity-induced immediate early gene Arc in the hippocampus of rats with experimental neuroinflammation. Rats were chronically infused with lipopolysaccharide (LPS) (0.25 μg/h) into the fourth ventricle for 28 d. On day 29, the rats explored twice a novel environment for 5 min, separated by 45 or 90 min. In the dentate gyrus and CA3 regions of LPS-infused rats, Arc and OX-6 (specific for major histocompatibility complex class II antigens) immunolabeling and Arc fluorescence in situ hybridization revealed both activated microglia (OX-6 immunoreactivity) and elevated exploration-induced Arc expression compared with control-infused rats. In contrast, in the CA1 of LPS-infused rats, where there was no OX-6 immunostaining, exploration-induced Arc mRNA and protein remained similar in both LPS- and control-infused rats. LPS-induced neuroinflammation did not affect basal levels of Arc expression. Behaviorally induced Arc expression was altered only within the regions showing activated microglia (OX-6 immunoreactivity), suggesting that neuroinflammation may alter the coupling of neural activity with macromolecular synthesis implicated in learning and plasticity. This activity-related alteration in Arc expression induced by neuroinflammation may contribute to the cognitive deficits found in diseases associated with inflammation, such as AD.
• Vazdarjanova, A., Mikhael, D., Rosi, S., Worley, P., Barnes, C., & Ramírez-Amaya, V. (2005). Spatial exploration-induced Arc mRNA and protein expression: Evidence for selective, network-specific reactivation. Journal of Neuroscience, 25(7). doi:10.1523/JNEUROSCI.4342-04.2005
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  The immediate-early gene Arc is transcribed in neurons that are part of stable neural networks activated during spatial exploratory behaviors. Arc protein has been demonstrated to regulate AMPA-type glutamate receptor trafficking by recruiting endosomal pathways, suggesting a direct role in synaptic plasticity. The purpose of the present study is to examine the fidelity of Arc mRNA translation and the temporal dynamics of behaviorally induced Arc protein expression after rats explore a novel environment. These experiments reveal two waves of Arc protein expression after a single exploration session. In the initial wave, virtually all cells that express Arc mRNA in the hippocampus and parietal cortex also express Arc protein, indicating, at a cellular level, that mRNA transcription and translation are closely correlated from 30 min to 2 h in hippocampal CA and parietal neurons. A second wave of protein expression spans the interval from 8 to 24 h and is also remarkably specific to cells active in the original behavior-induced network. This second wave is detected in a subset of the original active network and displays the novel property that the proportions of Arc-positive neurons become correlated among regions at 24 h. This suggests that the second expression wave is driven by network activity, and the stabilization of circuits reflecting behavioral experience may occur in temporally discrete phases, as memories become consolidated. This is the first demonstration of network-selective translational events consequent to spatial behavior and suggests a role for immediate-early genes in circuit-specific, late-phase synaptic biology.
• Chawla, M. K., Lin, G., Olson, K., Vazdarjanova, A., Burke, S. N., Mcnaughton, B. L., Worley, P. F., Guzowski, J. F., Roysam, B., & Barnes, C. A. (2004). 3D-catFISH: a system for automated quantitative three-dimensional compartmental analysis of temporal gene transcription activity imaged by fluorescence in situ hybridization.. Journal of neuroscience methods, 139(1), 13-24. doi:10.1016/j.jneumeth.2004.04.017
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  Fluorescence in situ hybridization (FISH) of neural activity-regulated, immediate-early gene (IEG) expression provides a method of functional brain imaging with cellular resolution. This enables the identification, in one brain, of which specific principal neurons were active during each of two distinct behavioral epochs. The unprecedented potential of this differential method for large-scale analysis of functional neural circuits is limited, however, by the time-intensive nature of manual image analysis. A comprehensive software tool for processing three-dimensional, multi-spectral confocal image stacks is described which supports the automation of this analysis. Nuclei counterstained with conventional DNA dyes and FISH signals indicating the sub-cellular distribution of specific, IEG RNA species are imaged using different spectral channels. The DNA channel data are segmented into individual nuclei by a three-dimensional multi-step algorithm that corrects for depth-dependent attenuation, non-isotropic voxels, and imaging noise. Intra-nuclear and cytoplasmic FISH signals are associated spatially with the nuclear segmentation results to generate a detailed tabular/database and graphic representation. Here we present a comprehensive validation of data generated by the automated software against manual quantification by human experts on hippocampal and parietal cortical regions (96.5% concordance with multi-expert consensus). The high degree of reliability and accuracy suggests that the software will generalize well to multiple brain areas and eventually to large-scale brain analysis.
• Chawla, M., Lin, G., Olson, K., Vazdarjanova, A., Burke, S., McNaughton, B., Worley, P., Guzowski, J., Roysam, B., & Barnes, C. (2004). 3D-catFISH: A system for automated quantitative three-dimensional compartmental analysis of temporal gene transcription activity imaged by fluorescence in situ hybridization. Journal of Neuroscience Methods, 139(1). doi:10.1016/j.jneumeth.2004.04.017
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  Fluorescence in situ hybridization (FISH) of neural activity-regulated, immediate-early gene (IEG) expression provides a method of functional brain imaging with cellular resolution. This enables the identification, in one brain, of which specific principal neurons were active during each of two distinct behavioral epochs. The unprecedented potential of this differential method for large-scale analysis of functional neural circuits is limited, however, by the time-intensive nature of manual image analysis. A comprehensive software tool for processing three-dimensional, multi-spectral confocal image stacks is described which supports the automation of this analysis. Nuclei counterstained with conventional DNA dyes and FISH signals indicating the sub-cellular distribution of specific, IEG RNA species are imaged using different spectral channels. The DNA channel data are segmented into individual nuclei by a three-dimensional multi-step algorithm that corrects for depth-dependent attenuation, non-isotropic voxels, and imaging noise. Intra-nuclear and cytoplasmic FISH signals are associated spatially with the nuclear segmentation results to generate a detailed tabular/database and graphic representation. Here we present a comprehensive validation of data generated by the automated software against manual quantification by human experts on hippocampal and parietal cortical regions (96.5% concordance with multi-expert consensus). The high degree of reliability and accuracy suggests that the software will generalize well to multiple brain areas and eventually to large-scale brain analysis. © 2004 Elsevier B.V. All rights reserved.
• Pennartz, C., Lee, E., Verheul, J., Lipa, P., Barnes, C., & McNaughton, B. (2004). The ventral striatum in off-line processing: Ensemble reactivation during sleep and modulation by hippocampal ripples. Journal of Neuroscience, 24(29). doi:10.1523/JNEUROSCI.0575-04.2004
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  Previously it has been shown that the hippocampus and neocortex can spontaneously reactivate ensemble activity patterns during post-behavioral sleep and rest periods. Here we examined whether such reactivation also occurs in a subcortical structure, the ventral striatum, which receives a direct input from the hippocampal formation and has been implicated in guidance of consummatory and conditioned behaviors. During a reward-searching task on a T-maze, flanked by sleep and rest periods, parallel recordings were made from ventral striatal ensembles while EEG signals were derived from the hippocampus. Statistical measures indicated a significant amount of reactivation in the ventral striatum. In line with hippocampal data, reactivation was especially prominent during post-behavioral slow-wave sleep, but unlike the hippocampus, no decay in pattern recurrence was visible in the ventral striatum striaturn across the first 40 min of post-behavioral rest. We next studied the relationship between ensemble firing patterns in ventral striatum and hippocampal ripples-sharp waves, which have been implicated in pattern replay. Firing rates were significantly modulated in close temporal association with hippocampal ripples in 25% of the units, showing a marked transient enhancement in the average response profile. Strikingly, ripple-modulated neurons in ventral striatum showed a clear reactivation, whereas nonmodulated cells did not. These data suggest, first, the occurrence of pattern replay in a subcortical structure implied in the processing and prediction of reward and, second, a functional linkage between ventral striatal reactivation and a specific type of high-frequency population activity associated with hippocampal replay.
• Regard, J., Scheek, S., Borbiev, T., Lanahan, A., Schneider, A., Demetriades, A., Hiemisch, H., Barnes, C., Verin, A., & Worley, P. (2004). Verge: A Novel Vascular Early Response Gene. Journal of Neuroscience, 24(16). doi:10.1523/JNEUROSCI.4252-03.2004
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  Vascular endothelium forms a continuous, semipermeable barrier that regulates the transvascular movement of hormones, macromolecules, and other solutes. Here, we describe a novel immediate early gene that is expressed selectively in vascular endothelial cells, verge (vascular early response gene). Verge protein includes an N-terminal region of ∼70 amino acids with modest homology (∼30% identity) to Apolipoprotein L but is otherwise unique. Verge mRNA and protein are induced selectively in the endothelium of adult vasculature by electrical or chemical seizures. Verge expression appears to be responsive to local tissue conditions, because it is induced in the hemisphere ipsilateral to transient focal cerebral ischemia. In contrast to the transient expression in adult, Verge mRNA and protein are constitutively expressed at high levels in the endothelium of developing tissues (particularly heart) in association with angiogenesis. Verge mRNA is induced in cultured endothelial cells by defined growth factors and hypoxia. Verge protein is dramatically increased by cysteine proteinase inhibitors, suggesting rapid turnover, and is localized to focal regions near the periphery of the cells. Endothelial cell lines that stably express Verge form monolayers that show enhanced permeability in response to activation of protein kinase C by phorbol esters. This response is accompanied by reorganization of the actin cytoskeleton and the formation of paracellular gaps. These studies suggest that Verge functions as a dynamic regulator of endothelial cell signaling and vascular function.
• Barnes, C. A., & Erickson, C. A. (2003). The neurobiology of memory changes in normal aging.. Experimental gerontology, 38(1-2), 61-9. doi:10.1016/s0531-5565(02)00160-2
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  Cognitive alterations occur over the lifespan of every species studied and have been quantified carefully in humans, other primates and rodents. Correspondingly, changes in hippocampal function have been associated with a number of observed memory impairments across species. It appears that humans, alone, show Alzheimer's disease-like cognitive and neural pathology spontaneously. Thus, a comparison of normal age-related changes in cognition in other animals can help disambiguate the boundary between normal and pathological states of aging in humans. Another important contribution made from studying aging in non-human species is the ability to examine, in more detail, the basic neural mechanisms that may be responsible for brain aging in these species. So far, most of the functional neurobiological studies have been conducted in the aged rat. We propose that the link between rodent and human work can be made much stronger by combining neurophysiological and behavioral investigation of normal aging in the non-human primate.
• Lin, G., Adiga, U., Olson, K., Guzowski, J. F., Barnes, C. A., & Roysam, B. (2003). A hybrid 3D watershed algorithm incorporating gradient cues and object models for automatic segmentation of nuclei in confocal image stacks.. Cytometry. Part A : the journal of the International Society for Analytical Cytology, 56(1), 23-36. doi:10.1002/cyto.a.10079
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  Automated segmentation of fluorescently-labeled cell nuclei in 3D confocal microscope images is essential to many studies involving morphological and functional analysis. A common source of segmentation error is tight clustering of nuclei. There is a compelling need to minimize these errors for constructing highly automated scoring systems..A combination of two approaches is presented. First, an improved distance transform combining intensity gradients and geometric distance is used for the watershed step. Second, an explicit mathematical model for the anatomic characteristics of cell nuclei such as size and shape measures is incorporated. This model is constructed automatically from the data. Deliberate initial over-segmentation of the image data is performed, followed by statistical model-based merging. A confidence score is computed for each detected nucleus, measuring how well the nucleus fits the model. This is used in combination with the intensity gradient to control the merge decisions..Experimental validation on a set of rodent brain cell images showed 97% concordance with the human observer and significant improvement over prior methods..Combining a gradient-weighted distance transform with a richer morphometric model significantly improves the accuracy of automated segmentation and FISH analysis.
• Barnes, C. A., Mcnaughton, B. L., & Rosenzweig, E. S. (2002). Making room for new memories.. Nature neuroscience, 5(1), 6-8. doi:10.1038/nn0102-6
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  A new finding suggests that memory removal may be an active process, as blocking NMDA receptors after induction of long-term potentiation prolongs LTP and memory retention.
• Pennartz, C. M., Uylings, H. B., Barnes, C. A., & Mcnaughton, B. L. (2002). Memory reactivation and consolidation during sleep: from cellular mechanisms to human performance.. Progress in brain research, 138, 143-66. doi:10.1016/s0079-6123(02)38076-2
• Vazdarjanova, A., McNaughton, B., Barnes, C., Worley, P., & Guzowski, J. (2002). Experience-dependent coincident expression of the effector immediate-early genes Arc and Homer 1a in hippocampal and neocortical neuronal networks. Journal of Neuroscience, 22(23). doi:10.1523/jneurosci.22-23-10067.2002
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  The transcription of the immediate-early genes Arc and Homer 1a (H1a) is dynamically regulated in response to synaptic activity; their protein products function at the postsynaptic sites of excitatory synapses. Previous studies demonstrate a role for Arc in the maintenance of long-term potentiation and in memory consolidation processes and indicate a role for H1a in modifying glutamatergic signaling pathways. Using doublelabel fluorescence in situ hybridization, we demonstrate that Arc and H1a RNA expression is induced strongly in the same neurons of rat hippocampus and neocortex after exploration of a novel environment. These findings support the view that novel experience activates a cell-specific genomic program and that Arc and H1a may function in concert in the structural and functional modifications of dendrites that lead to long-term changes in synaptic efficacy.
• Baldwin, C., Houston, F., Podgornik, M., Young, R., Barnes, C., & Witten, M. (2001). Effects of aerosol-vapor JP-8 jet fuel on the Functional Observational Battery, and learning and memory in the rat. Archives of Environmental Health, 56(3). doi:10.1080/00039890109604445
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  To determine whether JP-8 jet fuel affects parameters of the Functional Observational Battery (FOB), visual discrimination, or spatial learning and memory, the authors exposed groups of male Fischer Brown Norway hybrid rats for 28 d to aerosol/vapor-delivered JP-8, or to JP-8 followed by 15 min of aerosolized substance P analogue, or to sham-confined fresh room air. Behavioral testing was accomplished with the U.S. Environmental Protection Agency's Functional Observational Battery. The authors used the Morris swim task to test visual and spatial learning and memory testing. The spatial test included examination of memory for the original target location following 15 d of JP-8 exposure, as well as a 3-d new target location learning paradigm implemented the day that followed the final day of exposure. Only JP-8 exposed animals had significant weight loss by the 2nd week of exposure compared with JP-8 with substance P and control rats; this finding compares with those of prior studies of JP-8 jet fuel. Rats exposed to JP-8 with or without substance P exhibited significantly greater rearing and less grooming behavior over time than did controls during Functional Observational Battery open-field testing. Exposed rats also swam significantly faster than controls during the new target location training and testing, thus supporting the increased activity noted during Functional Observational Battery testing. There were no significant differences between the exposed and control groups' performances during acquisition, retention, or learning of the new platform location in either the visual discrimination or spatial version of the Morris swim task. The data suggest that although visual discrimination and spatial learning and memory were not disrupted by JP-8 exposure, arousal indices and activity measures were distinctly different in these animals.
• Barnes, C. A. (2001). Plasticity in the aging central nervous system.. International review of neurobiology, 45, 339-54. doi:10.1016/s0074-7742(01)45018-5
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  Publisher Summary The majority of data are consistent with the idea that plasticity mechanisms in the hippocampus are altered, as is spatial cognition, during aging. A number of studies, including several to which Frank Morrell contributed, show that the age-related changes in these neural and behavioral variables are significantly correlated and that they can be manipulated in a way such that older animals show more effective brain plasticity and more accurate spatial behavior. Frank Morrell was very interested in how plasticity mechanisms are altered during aging and how these changes may affect cognition. This chapter summarizes the progress to date in the understanding of how long-term potentiation (LTP) and other plasticity characteristics of the hippocampus are altered by the aging process and how this may relate to learning and memory alterations during aging, which includes the experimental work that Frank Morrell contributed to this area of scientific inquiry. Challenge now is to move these basic research facts into clinical application.
• Barnes, C. A., Ekstrom, A. D., Mcnaughton, B. L., & Meltzer, J. (2001). NMDA receptor antagonism blocks experience-dependent expansion of hippocampal "place fields".. Neuron, 31(4), 631-8. doi:10.1016/s0896-6273(01)00401-9
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  In agreement with theories of sequence learning, hippocampal place representations expand asymmetrically during repeated route following. This behaviorally induced, experience-dependent expression of neuronal plasticity was blocked by the NMDA(R) antagonist CPP, suggesting that it may result from the temporal asymmetry and associative properties of LTP. NMDA(R) antagonism, however, had no effect on the range of the progressive shift of firing phase of hippocampal cells, relative to the theta rhythm, as the rat traverses the cell's "place field." Thus, when place fields normally expand with experience, the relationship between firing phase and position is altered, as predicted by models that account for "phase precession" on the basis of asymmetry of synaptic connection strengths. These effects of CPP mimic changes that occur during normal aging, suggesting mechanisms by which sequence learning deficits may arise in aged animals.
• Barnes, C. A., Gerrard, J. L., Kudrimoti, H. S., & Mcnaughton, B. L. (2001). Reactivation of hippocampal ensemble activity patterns in the aging rat.. Behavioral Neuroscience, 115(6), 1180-1192. doi:10.1037/0735-7044.115.6.1180
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  In young rats, the pattern of neuronal ensemble activity correlations expressed among hippocampal pyramidal cells during behavior persists during subsequent quiet wakefulness and slow-wave sleep, a process that may facilitate the consolidation of episodic memories. The present study explored the hypothesis that age-related changes in this process might contribute to memory impairments observed during normal aging. Neuronal activity was recorded from CA1 pyramidal cells, and in both young and old rats, there was a strong similarity between the resting epoch activity patterns and those from the preceding behavior epoch. This similarity was strongest during sharp-wave events. There were no detectable differences in the reactivation process or the decay rate between the young and old age groups. Thus, age differences in spatial memory do not appear to be explainable by differences in the spontaneous reactivation of familiar patterns within the hippocampus during the immediate postbehavior period.
• Barnes, C. A., Bohanick, J. D., Mcnaughton, B. L., Redish, A. D., & Rosenzweig, E. S. (2000). Dynamics of Hippocampal Ensemble Activity Realignment: Time versus Space. The Journal of Neuroscience, 20(24), 9298-9309. doi:10.1523/jneurosci.20-24-09298.2000
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  Whether hippocampal map realignment is coupled more strongly to position or time was studied in rats trained to shuttle on a linear track. The rats were required to run from a start box and to pause at a goal location at a fixed location relative to stable distal cues (room-aligned coordinate frame). The origin of each lap was varied by shifting the start box and track as a unit (box-aligned coordinate frame) along the direction of travel. As observed by Gothard et al. (1996a), on each lap the hippocampal activity realigned from a representation that was box-aligned to one that was room-aligned. We studied the dynamics of this transition using a measure of how well the moment-by-moment ensemble activity matched the expected activity given the location of the animal in each coordinate frame. The coherency ratio, defined as the ratio of the matches for the two coordinate systems, provides a quantitative measure of the ensemble activity alignment and was used to compare four possible descriptions of the realignment process. The elapsed time since leaving the box provided a better predictor of the occurrence of the transition than any of the three spatial parameters investigated, suggesting that the shift between coordinate systems is at least partially governed by a stochastic, time-dependent process.
• Barnes, C., Meltzer, J., Houston, F., Orr, G., McGann, K., & Wenk, G. (2000). Chronic treatment of old rats with donepezil or galantamine: Effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience, 99(1). doi:10.1016/S0306-4522(00)00180-9
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  The function of the cholinergic system is known to change during normal aging and in pathological conditions such as Alzheimer’s disease. The present study was designed to assess, within the same group of old animals, the behavioral, electrophysiological and neurochemical effects of chronic treatment with agents that increase the function of the cholinergic system through both muscarinic and nicotinic mechanisms. Doses were determined that produced 60% cholinesterase inhibition by donepezil and galantamine for the old rats. This was chosen to be analogous to therapeutic levels achieved for treatment of human Alzheimer’s disease patients with these agents. Because of the well-known age-related changes in spatial memory and hippocampal synaptic plasticity, spatial working memory in the radial eight-arm maze and hippocampal long-term potentiation induction and decay, as well as nicotinic receptor density and affinity, were measured in old rats implanted with minipumps that delivered donepezil, galantamine or saline. There was no effect of drug treatment on baseline synaptic transmission or on the threshold or magnitude of long-term potentiation induction. Both drug treatment groups, however, showed significantly extended long-term potentiation decay times at the perforant path-granule cell synapse over the saline control animals, as measured during the week following induction. Both drugs also elevated the number of nicotinic receptors within the hippocampus and neocortex. This is the first demonstration of cholinergic modulation of synaptic plasticity over the time-course of days. Furthermore, the durability of long-term potentiation was significantly, positively correlated with nicotinic receptor binding in the hippocampus. Chronic treatment with donepezil or galantamine had no significant effect on a well-learned spatial working memory task on the radial maze.These data suggest that the therapeutic doses of cholinesterase inhibitors used to treat patients with Alzheimer’s disease may have effects on neurophysiology and neurochemistry that are close to the threshold for producing detectable behavioral improvements. © 2000 IBRO. Published by Elsevier Science Ltd.
• Barnes, C., Rao, G., & Orr, G. (2000). Age-related decrease in the schaffer collateral-evoked EPSP in awake, freely behaving rats. Neural Plasticity, 7(3). doi:10.1155/NP.2000.167
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  Synaptic response size in the CA1 region of the hippocampus in aged rats is reduced for a given stimulus intensity, compared with that elicited in young rats. Consistent with the in vitro findings of reduced Schaffer collateral-evoked CA1 EPSPs in old rats, the population currents evoked to iontophoretically applied AMPA are also smaller relative to the presynaptic fiber potential amplitude. On the other hand, the size of the presynaptic fiber potential and amplitude of unitary intra-cellularly recorded EPSP responses do not change across age in the CA1 region. These electrophysiological findings are consistent with the hypothesis that old rats have fewer functional synaptic contacts per Schaffer collateral axon than do young rats. The possibility that this age change arises as a result of a differential tissue recovery response to in vitro preparation was examined in the present study. CA1 presynaptic fiber potential and EPSP amplitudes evoked by the stimulation of Schaffer collateral afferents were studied in intact, freely behaving young and old rats. We confirmed in vivo the pattern of electrophysiophysiological results previously reported in vitro and found significant correlations between the synaptic response amplitudes and the accuracy of spatial behavior in the Morris swim task. The data suggest that changes in functional connectivity of old rats may be a significant contributor to cognitive changes during aging.
• Oliveira-dos-Santos, A., Matsumoto, G., Snow, B., Bai, D., Houston, F., Whishaw, I., Mariathasan, S., Sasaki, T., Wakeham, A., Ohashi, P., Roder, J., Barnes, C., Siderovski, D., & Penninger, J. (2000). Regulation of T cell activation, anxiety, and male aggression by RGS2. Proceedings of the National Academy of Sciences of the United States of America, 97(22). doi:10.1073/pnas.220414397
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  Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα protein subunits in vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family member rgs2 was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2 in vivo, we generated rgs2-deficient mice. We show that targeted mutation of rgs2 in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunity in vivo. Interestingly, rgs2(-/-) mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.
• Poe, G. R., Barnes, C. A., Mcnaughton, B. L., & Nitz, D. A. (2000). Experience-dependent phase-reversal of hippocampal neuron firing during REM sleep.. Brain research, 855(1), 176-80. doi:10.1016/s0006-8993(99)02310-0
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  The idea that sleep could serve a cognitive function has remained popular since Freud stated that dreams were "not nonsense" but a time to sort out experiences [S. Freud, Letter to Wilhelm Fliess, May 1897, in The Origins of Psychoanalysis - Personal Letters of Sigmund Freud, M. Bonaparte, A. Freud, E. Kris (Eds.), Translated by E. Mosbacher, J. Strachey, Basic Books and Imago Publishing, 1954]. Rapid eye movement (REM) sleep, which is associated with dream reports, is now known to be is important for acquisition of some tasks [A. Karni, D. Tanne, B.S. Rubenstein, J.J.M. Askenasy, D. Sagi, Dependence on REM sleep of overnight improvement of a perceptual skill, Science 265 (1994) 679-682; C. Smith, Sleep states and learning: a review of the animal literature, Biobehav. Rev. 9 (1985) 157-168]; although why this is so remains obscure. It has been proposed that memories may be consolidated during REM sleep or that forgetting of unnecessary material occurs in this state [F. Crick, G. Mitchison, The function of dream sleep, Nature 304 (1983) 111-114; D. Marr, Simple memory: a theory for archicortex, Philos. Trans. R. Soc. B. 262 (1971) 23-81]. We studied the firing of multiple single neurons in the hippocampus, a structure that is important for episodic memory, during familiar and novel experiences and in subsequent REM sleep. Cells active in familiar places during waking exhibited a reversal of firing phase relative to local theta oscillations in REM sleep. Because firing-phase can influence whether synapses are strengthened or weakened [C. Holscher, R. Anwyl, M.J. Rowan, Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can be depotentiated by stimulation on the negative phase in area CA1 in vivo, J. Neurosci. 15 (1977) 6470-6477; P.T. Huerta, J.E. Lisman, Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro, Neuron 15 (1995) 1053-1063; C. Pavlides, Y.J. Greenstein, M. Grudman, J. Winson, Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm, Brain Res. 439 (1988) 383-387] this experience-dependent phase shift, which developed progressively over multiple sessions in the environment, is consistent with the hypothesis that circuits may be restructured during REM sleep by selectively strengthening recently acquired memories and weakening older ones.
• Poe, G. R., Teed, R. G., Insel, N., White, R., Mcnaughton, B. L., & Barnes, C. A. (2000). Partial hippocampal inactivation: effects on spatial memory performance in aged and young rats.. Behavioral neuroscience, 114(5), 940-9. doi:10.1037//0735-7044.114.5.940
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  Changes in anatomical or functional connectivity during normal aging are thought to contribute to cognitive alterations over the lifespan. Neural network theories predict that synaptic loss in an aging brain could place the organism near the point of dysfunction in the nonlinear curve defining neural compromise versus performance. The present experiments examined whether aged rats are closer to this point of behavioral dysfunction by reversibly inactivating one or both hippocampal hemispheres. As expected, bilateral tetracaine inactivation of the hippocampus disrupted spatial memory in both age groups. Unilateral left hippocampal inactivation significantly increased errors only in aged rats; however, unilateral inactivation of the right hippocampus had no effect. The present outcome could reflect more extensive synaptic dysfunction in the aged right hippocampus or a greater involvement of the left hippocampus in spatial working memory problems.
• Redish, A., McNaughton, B., & Barnes, C. (2000). Place cell firing shows an inertia-like process. Neurocomputing, 32-33. doi:10.1016/S0925-2312(00)00169-7
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  Place cells were recorded from five animals performing a shuttle task on a linear track in which reward was only available at one end of the journey. Although place fields during the journey itself were directional, place fields at the turn-around point were bidirectional. Place fields that were directional on full-length journeys became locally bidirectional when the animal turned around in the middle of the place field. This suggests that place cells show an inertia-like process in which, once they begin firing, they continue firing whatever trajectory the animal takes. This process would be useful for storing routes and sequences. (C) 2000 Elsevier Science B.V. All rights reserved. Place cells were recorded from five animals performing a shuttle task on a linear track in which reward was only available at one end of the journey. Although place fields during the journey itself were directional, place fields at the turn-around point were bidirectional. Place fields that were directional on full-length journeys became locally bidirectional when the animal turned around in the middle of the place field. This suggests that place cells show an inertia-like process in which, once they begin firing, they continue firing whatever trajectory the animal takes. This process would be useful for storing routes and sequences.
• Smith, A. C., Gerrard, J. L., Barnes, C. A., & Mcnaughton, B. L. (2000). Effect of age on burst firing characteristics of rat hippocampal pyramidal cells.. Neuroreport, 11(17), 3865-71. doi:10.1097/00001756-200011270-00052
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  During behavior, hippocampal pyramidal cells emit high frequency bursts, modulated by the animal's location and the 7 Hz theta rhythm. During rest, CA1 EEG exhibits large irregular activity (LIA), containing sharp-wave/ripple complexes, during which pyramidal cells exhibit burst discharge. Aging results in altered intracellular calcium homeostasis, increased electrical coupling and reduced cholinergic modulation within CA1, all of which might affect burst discharge characteristics. During LIA, old rats exhibited more short (3-7 ms) inter-spike intervals, with no change in mean firing rate. During behavior induced theta rhythm, however, interval distributions were not affected by age. Thus, different mechanisms must underlie burst discharge in theta and LIA states. Moreover, age related changes in the cholinergic system appear not to play a major role in shaping the temporal discharge characteristics of CA1 pyramidal cells. The mechanism and significance of the higher frequency bursting in old rats during LIA remains to be determined.
• Wenk, G. L., & Barnes, C. A. (2000). Regional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat.. Brain research, 885(1), 1-5. doi:10.1016/s0006-8993(00)02792-x
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  The current study dissected the fascia dentata (FD) and hilar region from the CA and subicular cell fields of the rat and conducted in vitro determinations of the number of binding sites for N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) glutamate receptors across the lifespan. We determined the density of binding of [3H]-glutamate or [3H]-AMPA to NMDA or AMPA receptor sites, respectively. The changes reported might be due to either a change in receptor number or an alteration in the binding characteristics of the receptor site with aging. We found an age-related decline in the number of NMDA receptors in the CA1, CA3 and subicular cell regions of the hippocampus, but not in the FD/hilar region, and an age-related decline in the number of AMPA receptors in the FD/hilar region, but not in the CA fields. The decline in the number of NMDA or AMPA receptors that occurs with aging was not a continuous or homogeneous process. These changes in receptor number might underlie selected age-associated changes in sensitivity to drugs that influence hippocampal function as well as to changes in NMDA-dependent long-term potentiation. A thorough understanding of the mechanisms underlying changes in glutamate receptor function in discrete brain regions, using combined neurochemical and electrophysiological methods, may ultimately provide insight into the fundamental substrates of age-associated memory disorders related to hippocampal dysfunction.
• Barnes, C. A. (1999). Do synaptic markers provide a window on synaptic effectiveness in the aged hippocampus?. Neurobiology of aging, 20(3), 349-51; discussion 359-60. doi:10.1016/s0197-4580(99)00074-3
• Barnes, C. A., Houston, F. P., Mcnaughton, B. L., & Stevenson, G. D. (1999). Effects of age on the generalization and incubation of memory in the F344 rat.. Learning & Memory, 6(2), 111-119. doi:10.1101/lm.6.2.111
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  Freezing (immobility) in the presence of aversive stimuli is a species-specific behavior that is used as an operational measure of fear. Conditioning of this response to discrete sensory stimuli and environmental context cues has been used as a tool to study the neuropsychology of memory dynamics and their development over the lifespan. Three age groups of F344 rats (3, 9, and 27 month) received tone-foot shock pairing (or tone only) in a distinctive chamber on two consecutive days. Separate subgroups of rats from each age group were then tested, at retention intervals of 1, 20, 40, or 60 days, for context-mediated fear in the environment in which they were trained, for generalization of the fear response to a novel chamber, and for fear of the tone. Beginning at day 20, the 27-month-old rats exhibited less freezing behavior than did younger rats when tested in the conditioning context. This age difference was a result of freezing behavior becoming progressively stronger with time in the two younger age groups, a phenomenon that has been referred to as memory incubation. Incubation of the contextual fear response was not detected in the old rats. In a novel context, all age groups exhibited significantly more freezing than did control animals. There was also pronounced incubation of this generalized freezing response, and the extent of incubation declined significantly with age. In the novel context, the freezing response to the tone was robust in all age groups and increased over time, in constant proportion to the degree of freezing elicited by the novel context itself, prior to tone onset. The fact that old animals are known to be relatively selectively impaired in forms of memory that depend on a functional hippocampus suggests a possible explanation for the reduced incubation effects seen in old rats; however, whether the increased expression of fear over time is mediated by a hippocampal-dependent memory consolidation process or whether it reflects a generalized increase in the gain of the circuitry mediating the fear response itself, remains to be determined.
• Guzowski, J. F., Mcnaughton, B. L., Barnes, C. A., & Worley, P. F. (1999). Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles.. Nature neuroscience, 2(12), 1120-4. doi:10.1038/16046
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  We used fluorescent in-situ hybridization and confocal microscopy to monitor the subcellular distribution of the immediate-early gene Arc. Arc RNA appeared in discrete intranuclear foci within minutes of neuronal activation and subsequently disappeared from the nucleus and accumulated in the cytoplasm by 30 minutes. The time course of nuclear versus cytoplasmic Arc RNA accumulation was distinct, and could therefore be used to infer the activity history of individual neurons at two times. Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles. Arc gene induction is thus specifically linked to neural encoding processes.
• Kudrimoti, H. S., Barnes, C. A., & Mcnaughton, B. L. (1999). Reactivation of Hippocampal Cell Assemblies: Effects of Behavioral State, Experience, and EEG Dynamics. The Journal of Neuroscience, 19(10), 4090-4101. doi:10.1523/jneurosci.19-10-04090.1999
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  During slow wave sleep (SWS), traces of neuronal activity patterns from preceding behavior can be observed in rat hippocampus and neocortex. The spontaneous reactivation of these patterns is manifested as the reinstatement of the distribution of pairwise firing-rate correlations within a population of simultaneously recorded neurons. The effects of behavioral state [quiet wakefulness, SWS, and rapid eye movement (REM)], interactions between two successive spatial experiences, and global modulation during 200 Hz electroencephalographic (EEG) "ripples" on pattern reinstatement were studied in CA1 pyramidal cell population recordings. Pairwise firing-rate correlations during often repeated experiences accounted for a significant proportion of the variance in these interactions in subsequent SWS or quiet wakefulness and, to a lesser degree, during SWS before the experience on a given day. The latter effect was absent for novel experiences, suggesting that a persistent memory trace develops with experience. Pattern reinstatement was strongest during sharp wave-ripple oscillations, suggesting that these events may reflect system convergence onto attractor states corresponding to previous experiences. When two different experiences occurred in succession, the statistically independent effects of both were evident in subsequent SWS. Thus, the patterns of neural activity reemerge spontaneously, and in an interleaved manner, and do not necessarily reflect persistence of an active memory (i.e., reverberation). Firing-rate correlations during REM sleep were not related to the preceding familiar experience, possibly as a consequence of trace decay during the intervening SWS. REM episodes also did not detectably influence the correlation structure in subsequent SWS, suggesting a lack of strengthening of memory traces during REM sleep, at least in the case of familiar experiences.
• Barnes, C. A. (1998). Memory Changes during Normal Aging: Neurobiological Correlates. Neurobiology of Learning and Memory, 247-287. doi:10.1016/b978-012475655-7/50008-3
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  Publisher Summary An approach to the study of learning and memory has as its focus the attempt to understand memory's “normal” operations in enough detail to allow abnormal conditions to be identified and properly diagnosed. This chapter discusses that a major difficulty in distinguishing normal from pathological mnemonic function arises from the fact that learning and memory processes are continually changing throughout the course of development. It also underlines that the interest in memory and old age can be traced at least as far back as the first Greek and Roman memory theorists. Aging is a natural process that must be studied intensively, for it remains one of the most agonizing problems in all biology. Landfield and his colleagues demonstrate that the anatomical appearance of brains of animals that were adrenalectomized at 12 months of age and examined at 24 months resembled younger brains when compared with old animals that had intact adrenal glands. One of the major aims of gerontology is to provide society and individuals with advice on the formulation of societal and individual choices.
• Ingi, T., Krumins, A. M., Chidiac, P., Brothers, G. M., Chung, S., Snow, B. E., Barnes, C. A., Lanahan, A. A., Siderovski, D. P., Ross, E. M., Gilman, A. G., & Worley, P. F. (1998). Dynamic Regulation of RGS2 Suggests a Novel Mechanism in G-Protein Signaling and Neuronal Plasticity. The Journal of Neuroscience, 18(18), 7178-7188. doi:10.1523/jneurosci.18-18-07178.1998
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  Long-term neuronal plasticity is known to be dependent on rapidde novo synthesis of mRNA and protein, and recent studies provide insight into the molecules involved in this response. Here, we demonstrate that mRNA encoding a member of the regulator of G-protein signaling (RGS) family, RGS2, is rapidly induced in neurons of the hippocampus, cortex, and striatum in response to stimuli that evoke plasticity. Although several members of the RGS family are expressed in brain with discrete neuronal localizations, RGS2 appears unique in that its expression is dynamically responsive to neuronal activity. In biochemical assays, RGS2 stimulates the GTPase activity of the α subunit of Gq and Gi1. The effect on Gi1 was observed only after reconstitution of the protein in phospholipid vesicles containing M2 muscarinic acetylcholine receptors. RGS2 also inhibits both Gq- and Gi-dependent responses in transfected cells. These studies suggest a novel mechanism linking neuronal activity and signal transduction.
• Jung, M. W., Mcnaughton, B. L., Barnes, C. A., & Qin, Y. (1998). Firing characteristics of deep layer neurons in prefrontal cortex in rats performing spatial working memory tasks.. Cerebral cortex (New York, N.Y. : 1991), 8(5), 437-50. doi:10.1093/cercor/8.5.437
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  Single cells were recorded with 'tetrodes' in regions of the rat medial prefrontal cortex, including those which are targets of hippocampal afferents, while rats were performing three different behavioral tasks: (i) an eight-arm radial maze, spatial working memory task, (ii) a figure-eight track, delayed spatial alternation task, and (iii) a random food search task in a square chamber. Among 187 recorded units, very few exhibited any evidence of place-specific firing on any of the behavioral tasks, except to the extent that different spatial locations were related to distinct phases of the task. Furthermore, no prefrontal unit showed unambiguous spatially dependent delay activity that might mediate working memory for spatial locations. Rather, the cells exhibited diverse correlates that were generally associated with the behavioral requirements of performing the task. This included firing related to intertrial intervals, onset or end of trials, selection of specific arms on the eight-arm radial maze, delay periods, approach to or departure from goals, and selection of paths on the figure-eight track. Although a small number of cells showed similar behavioral correlates across tasks, the majority of cells showed no consistent correlate when recorded across multiple tasks. Furthermore, some units did not exhibit altered firing patterns in any of the three tasks, while others showed changes in firing that were not consistently related to specific behaviors or task components. These results are in agreement with previous lesion and behavioral studies in rats that suggest a prefrontal cortical role in encoding 'rules' (i.e. structural features) or behavioral sequences within a task but not in encoding allocentric spatial information. Given that the hippocampal projection to this cortical region is capable of undergoing LTP, our data lead to the hypothesis that the role of this projection is not to impose spatial representations upon prefrontal activity, but to provide a mechanism for learning the spatial context in which particular behaviors are appropriate.
• Jung, M., Qin, Y., McNaughton, B., & Barnes, C. (1998). Firing characteristics of deep layer neurons in prefrontal cortex in rats performing spatial working memory tasks. Cerebral Cortex, 8(5). doi:10.1093/cercor/8.5.437
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  Single cells were recorded with 'tetrodes' in regions of the rat medial prefrontal cortex, including those which are targets of hippocampal afferents, while rats were performing three different behavioral tasks: (i) an eight-arm radial maze, spatial working memory task, (ii) a figure-eight track, delayed spatial alternation task, and (iii) a random food search task in a square chamber. Among 187 recorded units, very few exhibited any evidence of place-specific firing on any of the behavioral tasks, except to the extent that different spatial locations were related to distinct phases of the task. Furthermore, no prefrontal unit showed unambiguous spatially dependent delay activity that might mediate working memory for spatial locations. Rather, the cells exhibited diverse correlates that were generally associated with the behavioral requirements of performing the task. This included firing related to intertrial intervals, onset or end of trials, selection of specific arms on the eight-arm radial maze, delay periods, approach to or departure from goals, and selection of paths on the figure- eight track. Although a small number of cells showed similar behavioral correlates across tasks, the majority of cells showed no consistent correlate when recorded across multiple tasks. Furthermore, some units did not exhibit altered firing patterns in any of the three tasks, while others showed changes in firing that were not consistently related to specific behaviors or task components. These results are in agreement with previous lesion and behavioral studies in rats that suggest a prefrontal cortical role in encoding 'rules' (i.e. structural features) or behavioral sequences within a task but not in encoding allocentric spatial information. Given that the hippocampal projection to this cortical region is capable of undergoing LTP, our data lead to the hypothesis that the role of this projection is not to impose spatial representations upon prefrontal activity, but to provide a mechanism for learning the spatial context in which particular behaviors are appropriate.
• Redish, A. D., Redish, A. D., Mcnaughton, B. L., Mcnaughton, B. L., Barnes, C. A., & Barnes, C. A. (1998). Reconciling Barnes et al. (1997) and Tanila et al. (1997a,b).. Hippocampus, 8(5), 438-43. doi:10.1002/(sici)1098-1063(1998)8:5<438::aid-hipo4>3.0.co;2-z
• Shen, J., Kudrimoti, H. S., Mcnaughton, B. L., & Barnes, C. A. (1998). Reactivation of neuronal ensembles in hippocampal dentate gyrus during sleep after spatial experience.. Journal of sleep research, 7 Suppl 1(1), 6-16. doi:10.1046/j.1365-2869.7.s1.2.x
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  Patterns of neuronal activity recorded in CA1 of the hippocampus and in neocortex during waking-behavior, are reactivated during subsequent slow-wave sleep (SWS). It has been suggested that this reactivation may originate in the hippocampal CA3 region, where modifiable excitatory recurrent connections are abundant and where sharp-waves in which the reactivation is most robust, appear to arise. The present experiment investigated whether ensemble firing patterns of granule cells in the fascia dentata (FD), an area 'upstream' from CA3, are also reactivated during sleep. Populations of FD granule cells were recorded from during spatial behavior and during prior and subsequent SWS. firing rate correlations between cell-pairs with overlapping place fields were significantly enhanced during post behavioral sleep compared to pre behavioral sleep. Correlations between cells with non-overlapping place fields or which were silent during maze behavior, were not changed. Thus reactivation of experience-specific correlation states also occurs in granule cells during sleep. Because these cells do not have excitatory interconnections, but form a major input to CA3 pyramidal cells, current models predicted that sleep reactivation would appear first in CA3. There are, however, both extensive polysynaptic excitatory interactions among granule cells and feedback from CA3 pyramidal cells. Granule cells also receive indirect input from neocortical regions known to undergo trace reactivation. Although a simple model for a CA3 origin of the reactivation phenomenon cannot be confirmed, the present results extend our understanding of the generality of this phenomenon.
• Barnes, C. (1997). The effect of aging on experience-dependent plasticity of hippocampal place cells. Journal of Neuroscience, 17(17). doi:10.1523/jneurosci.17-17-06769.1997
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  The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i.e., there was 'phase precession,' as reported by others). The net phase shift did not differ between age groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, so that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.
• Barnes, C., Rao, G., & Shen, J. (1997). Age-related decrease in the N-methyl-D-aspartate(R)-mediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiology of Aging, 18(4). doi:10.1016/S0197-4580(97)00044-4
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  Glutamatergic fast synaptic transmission is known to be altered with age in a region-specific manner in hippocampus of memory-impaired old rats. In the present experiment, presynaptic fiber potentials and non-N-methyl-D-aspartate (NMDA(R)) and NMDA(R)-mediated synaptic responses in CA1 were compared in three ages of behaviorally characterized male F-344 rats. In the CA1 region, old rats showed approximately equivalent reductions in non-NMDA(R) and NMDA(R)-excitatory postsynaptic potential amplitudes for a given size of presynaptic fiber potential. There was no change in magnitude of the presynaptic response itself at any stimulus level. These results are consistent with the hypothesis that there is a reduction in the number of Schaffer collateral synapses per presynaptic axon. This pattern of results in CA1 is very different from what is known to occur at the perforant path-granule cell synapse. In fascia dentata the non-NMDA(R)-mediated excitatory postsynaptic potential is increased in amplitude, although the NMDA(R)-mediated excitatory postsynaptic potential is reduced for a given presynaptic input. These data suggest that age-related functional alterations in neurotransmitter receptor subtypes occur differentially between closely-related anatomical subregions.
• Barnes, C., Suster, M., Shen, J., & McNaughton, B. (1997). Multistability of cognitive maps in the hippocampus of old rats. Nature, 388(6639). doi:10.1038/40859
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  Hippocampal neurons provide a population code for location. In young rats, environments are reliably 'mapped' by groups of neurons that have firing locations ('place fields') that can be stable for several months. Old animals exhibit deficits in spatial memory, raising the question of whether the quality or stability of their hippocampal 'cognitive maps' is altered. By recording from large groups of neurons, we observed the hippocampal spatial code to be multistable. In young rats, the place field maps were reliable both within and between episodes in a familiar environment. In old rats, place field maps were accurate and stable during an episode, but frequently exhibited complete rearrangements between episodes. In a spatial memory task, both young and old rats exhibited bimodal performance, consistent with map multistability early in training. However, the performance of young rats became almost unimodal with further training, whereas that of old rats remained markedly bimodal. The multistability of the hippocampal map provides an insight into the dynamics of neural coding in high-level cortical structures and their changes during ageing, and may provide an explanation for the frequent failure of place recognition in elderly humans.
• Lanahan, A., Lyford, G., Stevenson, G., Worley, P., & Barnes, C. (1997). Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. Journal of Neuroscience, 17(8). doi:10.1523/jneurosci.17-08-02876.1997
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  Normal human aging is associated with selective changes in cognition that are attributable, in part, to dysfunction of hippocampal pathways. Rodents also exhibit age-dependent hippocampal dysfunction that results in spatial memory deficits and a correlated reduction in the maintenance of long-term potentiation (LTP). Although suprathreshold stimulus protocols result in normal LTP induction in aged rats, the ability to sustain this increase in synaptic efficacy is reduced in the old animals. The maintenance phase of LTP is known to be dependent on rapid, transcriptional events, and recent studies have identified signal transduction mechanisms that link glutamate-induced responses at the synapse with transcriptional responses at the nucleus. To examine the integrity of these signaling pathways in aged hippocampus, we monitored the induction of a panel of immediate early genes (IEGs) that are known to be transcriptionally activated after LTP-inducing stimuli, using a 'reverse Northern' strategy. Here we report that a broad representation of lEGs are similarly induced in awake, behaving young adult and aged, memory-impaired rats. This indicates a general preservation of these presumptive signaling pathways during the aging process. Induced levels of c-fos mRNA, however, are significantly higher in the aged animals. These observations suggest that age-dependent hippocampal dysfunction may be associated with a selective change in the dynamic activity of signaling pathways upstream of c-fos, possibly involving calcium regulation.
• Mcnaughton, B. L., Skaggs, W. E., Barnes, C. A., & Qin, Y. L. (1997). Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles.. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 352(1360), 1525-33. doi:10.1098/rstb.1997.0139
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  Hippocampal cells that fire together during behaviour exhibit enhanced activity correlations during subsequent sleep, with some preservation of temporal order information. Thus, information reflecting experiences during behaviour is re-expressed in hippocampal circuits during subsequent 'offline' periods, as postulated by some theories of memory consolidation. If the hippocampus orchestrates the reinstatement of experience-specific activity patterns in the neocortex, as also postulated by such theories, then correlation patterns both within the neocortex and between hippocampus and neocortex should also re-emerge during sleep. Ensemble recordings were made in the posterior parietal neocortex, in CA1, and simultaneously in both areas, in seven rats. Each session involved an initial sleep episode (S1), behaviour on a simple maze (M), and subsequent sleep (S2). The ensemble activity-correlation structure within and between areas during S2 resembled that of M more closely than did the correlation pattern of S1. Temporal order (i.e. the asymmetry of the cross-correlogram) was also preserved within, but not between, structures. Thus, traces of recent experience are re-expressed in both hippocampal and neocortical circuits during sleep, and the representations in the two areas tend to correspond to the same experience. The poorer preservation of temporal firing biases between neurons in the different regions may reflect the less direct synaptic coupling between regions than within them. Alternatively, it could result from a shift, between behavioural states, in the relative dominance relations in the corticohippocampal dialogue. Between-structure order will be disrupted, for example, if, during behaviour, neocortical patterns tend to drive corresponding hippocampal patterns, whereas during sleep the reverse occurs. This possibility remains to be investigated.
• Mehta, M., Barnes, C., & Mcnaughton, B. (1997). Experience-dependent, asymmetric expansion of hippocampal place fields. Proceedings of the National Academy of Sciences of the United States of America, 94(16). doi:10.1073/pnas.94.16.8918
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  Theories of sequence learning based on temporally asymmetric, Hebbian long-term potentiation predict that during route learning the spatial firing distributions of hippocampal neurons should enlarge in a direction opposite to the animal's movement. On a route AB, increased synaptic drive from cells representing A would cause cells representing B to fire earlier and more robustly. These effects appeared within a few laps in rats running on closed tracks. This provides indirect evidence for Hebbian synaptic plasticity and a functional explanation for why place cells become directionally selective during route following, namely, to preserve the synaptic asymmetry necessary to encode the sequence direction.
• Rosenzweig, E., Rao, G., McNaughton, B., & Barnes, C. (1997). Role of temporal summation in age-related long-term potentiation-induction deficits. Hippocampus, 7(5). doi:10.1002/(SICI)1098-1063(1997)7:5<549::AID-HIPO10>3.0.CO;2-0
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  Hippocampal long-term potentiation (LTP) is reduced in aged relative to young F-344 rats when peri-threshold stimulation protocols (several stimulus pulses at 100-200 Hz) are used. The present study was designed to examine the possibility that this LTP-induction deficit is caused by a reduced overlap of Schaffer-collateral inputs onto CA1 pyramidal cells (input cooperativity). This reduced input cooperativity would decrease the levels of postsynaptic depolarization during LTP induction, which might account for the age-related LTP deficit. Both behavioral data (Morris Water Maze) and electrophysiological data (intracellular recordings from hippocampal slices) were collected from adult and aged F-344 rats. To counter the effects of reduced input cooperativity, stimulus intensities were adjusted to elicit baseline excitatory postsynaptic potentials (EPSPs) of equivalent amplitude in aged and young rats. Contrary to expectations, however, an age-related LTP-induction deficit was still observed. Further evaluation of the electrophysiological data revealed that temporal summation of multiple EPSPs during high-frequency stimulation was impaired in the aged rats. Thus, despite the equalization across age groups of the baseline EPSP amplitudes, the cells of aged rats were less depolarized during the LTP-inducing stimulation than were those of young rats. This reduced total depolarization was not an artifact of the higher stimulus intensity used on aged animals, nor was it caused by a failure of aged rats' CA1 afferents to follow high-frequency stimulation. The present data therefore suggest that there is a deficit in the ability of aged rats' synapses to provide the sustained depolarization necessary to activate the LTP-induction cascade.
• Shen, J., Barnes, C. A., Mcnaughton, B. L., Skaggs, W. E., & Weaver, K. L. (1997). The Effect of Aging on Experience-Dependent Plasticity of Hippocampal Place Cells. The Journal of Neuroscience, 17(17), 6769-6782. doi:10.1523/jneurosci.17-17-06769.1997
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  The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i.e., there was “phase precession,” as reported by others). The net phase shift did not differ between age groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, so that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.
• Barnes, C. (1996). Effects of the nucompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. European Journal of Neuroscience, 8(3).
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  Chronic treatment of adult male F-344 rats (9-12 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for >8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses recorded in the fascia dentata in vivo. In contrast, there was no effect of memantine on baseline synaptic responses or population spikes. Likewise, short-term exploratory modulation of these hippocampal evoked responses was not different between memantine-treated and control rats. Both groups of rats were able to learn the spatial version of the Morris water task equally well, but the memantine-treated group showed a strong tendency to show more selective spatial search patterns in the training quadrant of the water pool during a final probe trial. As such, these studies provide the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provide preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients. © European Neuroscience Association.
• Barnes, C. A., Erickson, C. A., Jung, M. W., & Mcnaughton, B. L. (1996). Contribution of single-unit spike waveform changes to temperature-induced alterations in hippocampal population spikes.. Experimental brain research, 107(3), 348-60. doi:10.1007/bf00230417
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  Brain temperature changes accompany exploratory behavior and profoundly affect field potential amplitudes recorded in hippocampus. The waveform alterations in fascia dentata include a reduction in population spike area, which might be explained by fewer granule cells firing in response to a given stimulus or by an alteration in the size or shape of the individual action potentials. This study was designed to assess these alternate possibilities. In experiment 1, changes in the shape and firing rates of single cells recorded in the fascia dentata of awake rats were compared with changes in the population spike before and after a bout of activity. Single-unit amplitudes were significantly reduced following exploration, and there was a small (< 3%) change in unit spike-width. These changes, however, were insufficient to account, in a linear fashion, for the entire decline in the population spike. In experiment 2, radiant heat was used to manipulate brain temperature in anesthetized rats. As in the first experiment, the magnitude of change in the extracellular units was much smaller than the change in population spike amplitude. The spontaneous firing rates of the cells were also modified by brain temperature changes. In experiment 3, the polysynaptic, contralateral commissural response (which covaries with changes in the ipsilateral population spike at a fixed temperature) was measured as a function of either exploratory behavior or radiant heat. The relationship between the ipsilateral population spike and corresponding polysynaptic commissural response was altered following exploration and passive warming in a manner consistent with a reduction in net granule cell output, reduced transmission efficacy through the polysynaptic circuit, or a combination of these. Taken together these data suggest that at least two factors contribute to temperature-dependent changes in the perforant path-evoked population spikes recorded in the fascia dentata: changes in the size of individual action potentials and alterations in discharge of action potentials in response to a given stimulus.
• Barnes, C. A., Gerrard, J. L., Gothard, K. M., Jung, M. W., Knierim, J. J., Kudrimoti, H. S., Mcnaughton, B. L., Qin, Y., Skaggs, W. E., Suster, M., & Weaver, K. L. (1996). DECIPHERING THE HIPPOCAMPAL POLYGLOT: THE HIPPOCAMPUS AS A PATH INTEGRATION SYSTEM. The Journal of Experimental Biology, 199(1), 173-185. doi:10.1242/jeb.199.1.173
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  Hippocampal 'place' cells and the head-direction cells of the dorsal presubiculum and related neocortical and thalamic areas appear to be part of a preconfigured network that generates an abstract internal representation of two-dimensional space whose metric is self-motion. It appears that viewpoint-specific visual information (e.g. landmarks) becomes secondarily bound to this structure by associative learning. These associations between landmarks and the preconfigured path integrator serve to set the origin for path integration and to correct for cumulative error. In the absence of familiar landmarks, or in darkness without a prior spatial reference, the system appears to adopt an initial reference for path integration independently of external cues. A hypothesis of how the path integration system may operate at the neuronal level is proposed.
• Barnes, C. A., Gerrard, J. L., Gothard, K. M., Jung, M. W., Knierim, J. J., Kudrimoti, H. S., Mcnaughton, B. L., Qin, Y., Skaggs, W. E., Suster, M., & Weaver, K. L. (1996). Deciphering the hippocampal polyglot: the hippocampus as a path integration system.. The Journal of experimental biology, 199(Pt 1), 173-85. doi:10.1242/jeb.199.1.173
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  Hippocampal 'place' cells and the head-direction cells of the dorsal presubiculum and related neocortical and thalamic areas appear to be part of a preconfigured network that generates an abstract internal representation of two-dimensional space whose metric is self-motion. It appears that viewpoint-specific visual information (e.g. landmarks) becomes secondarily bound to this structure by associative learning. These associations between landmarks and the preconfigured path integrator serve to set the origin for path integration and to correct for cumulative error. In the absence of familiar landmarks, or in darkness without a prior spatial reference, the system appears to adopt an initial reference for path integration independently of external cues. A hypothesis of how the path integration system may operate at the neuronal level is proposed.
• Barnes, C. A., Rao, G., & Mcnaughton, B. L. (1996). Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats.. Learning & memory (Cold Spring Harbor, N.Y.), 3(2-3), 124-37. doi:10.1101/lm.3.2-3.124
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  Previous studies have reported a lack of an age effect in the induction of long-term potentiation (LTP) at CA1 synapses, using robust (supramaximal) stimulation parameters, but an apparent age effect on the induction threshold of LTP using less robust stimulation, in the perithreshold region. These findings have led to the suggestion that old animals may experience an alteration either in the efficacy of activation of N-methyl-D-aspartate (NMDA) receptors or in the metabolic processes subsequent to NMDA receptor activation that lead to LTP expression. An alternative explanation for the apparent threshold change in old animals is that, because of the known reduction of the intracellularly recorded, compound EPSP magnitude in old rats, equivalent electrical stimulation results in a smaller effective depolarization of the postsynaptic cells and a consequently less effective activation of NMDA receptors, which are otherwise functionally normal. To distinguish between these two hypotheses, weak orthodromic stimulation was paired with intracellularly applied current pulses, thus holding constant the degree of postsynaptic depolarization. No differences in LTP induction threshold or magnitude were observed in a large sample of rats from three age groups. It is concluded that the NMDA receptor mechanisms and associated biochemical processes leading to LTP induction are not altered in aged F-344 rats. The reduced compound EPSP in old animals was reconfirmed in the present study, and a significant correlation was found in old rats between the magnitude of the EPSP at a fixed stimulus level and their performance on a spatial memory task.
• Barnes, C., Rao, G., & McNaughton, B. (1996). Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats. Learning Memory, 3(2-3). doi:10.1101/lm.3.2-3.124
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  Previous studies have reported a lack of an age effect in the induction of long-term potentiation (LTP) at CA1 synapses, using robust (supramaximal) stimulation parameters, but an apparent age effect on the induction threshold of LTP using less robust stimulation, in the perithreshold region. These findings have led to the suggestion that old animals may experience an alteration either in the efficacy of activation of N-methyl-D-aspartate (NMDA) receptors or in the metabolic processes subsequent to NMDA receptor activation that lead to LTP expression. An alternative explanation for the apparent threshold change in old animals is that, because of the known reduction of the intracellularly recorded, compound EPSP magnitude in old rats, equivalent electrical stimulation results in a smaller effective depolarization of the postsynaptic cells and a consequently less effective activation of NMDA receptors, which are otherwise functionally normal. To distinguish between these two hypotheses, weak orthodromic stimulation was paired with intracellularly applied current pulses, thus holding constant the degree of postsynaptic depolarization. No differences in LTP induction threshold or magnitude were observed in a large sample of rats from three age groups. It is concluded that the NMDA receptor mechanisms and associated biochemical processes leading to LTP induction are not altered in aged F-344 rats. The reduced compound EPSP in old animals was reconfirmed in the present study, and a significant correlation was found in old rats between the magnitude of the EPSP at a fixed stimulus level and their performance on a spatial memory task.
• Shen, J., & Barnes, C. A. (1996). Age-related decrease in cholinergic synaptic transmission in three hippocampal subfields.. Neurobiology of aging, 17(3), 439-51. doi:10.1016/0197-4580(96)00020-6
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  The present study was designed to examine the effect of age on cholinergic synaptic transmission in the three principal hippocampal subregions, and to assess whether these effects covary with age-related behavioral deficits. Young (3 week), adult (9 month), and old (24-27 month) rats were first tested on the Morris water task, and most of the old rats were severely impaired on the spatial version. The cholinergic slow epsp was induced by tetanic stimulation of stratum oriens or stratum granulosum, and recorded intracellularly in vitro from CA1 and CA3 pyramidal cells and granule cells in the fascia dentata (FD). The amplitude of the slow epsp was significantly reduced in old rats in all areas (CA1 59%; CA3 55%; and FD 56%). This age-related decrease was also present following the blockade of glutamatergic and GABAergic transmission, ruling out possible artifactual contributions from these systems to the change in the slow epsp. Our data suggest that functional cholinergic transmission is compromised in all areas of the hippocampus during normal aging. Few statistically significant correlations, however, were found between the age-related deficit in spatial learning and the decrease in cholinergic synaptic function.
• Shen, J., Barnes, C. A., Wenk, G. L., & Mcnaughton, B. L. (1996). Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.. Behavioral neuroscience, 110(5), 1181-6. doi:10.1037//0735-7044.110.5.1181
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  The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory).
• Skaggs, W. E., Skaggs, W. E., Mcnaughton, B. L., Mcnaughton, B. L., Wilson, M. A., Wilson, M. A., Barnes, C. A., & Barnes, C. A. (1996). Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences.. Hippocampus, 6(2), 149-72. doi:10.1002/(sici)1098-1063(1996)6:2<149::aid-hipo6>3.0.co;2-k
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  O'Keefe and Recce [1993] Hippocampus 3:317-330 described an interaction between the hippocampal theta rhythm and the spatial firing of pyramidal cells in the CA1 region of the rat hippocampus: they found that a cell's spike activity advances to earlier phases of the theta cycle as the rat passes through the cell's place field. The present study makes use of large-scale parallel recordings to clarify and extend this finding in several ways: 1) Most CA1 pyramidal cells show maximal activity at the same phase of the theta cycle. Although individual units exhibit deeper modulation, the depth of modulation of CA1 population activity is about 50%. The peak firing of inhibitory interneurons in CA1 occurs about 60 degrees in advance of the peak firing of pyramidal cells, but different interneurons vary widely in their peak phases. 2) The first spikes, as the rat enters a pyramidal cell's place field, come 90 degrees-120 degrees after the phase of maximal pyramidal cell population activity, near the phase where inhibition is least. 3) The phase advance is typically an accelerating, rather than linear, function of position within the place field. 4) These phenomena occur both on linear tracks and in two-dimensional environments where locomotion is not constrained to specific paths. 5) In two-dimensional environments, place-related firing is more spatially specific during the early part of the theta cycle than during the late part. This is also true, to a lesser extent, on a linear track. Thus, spatial selectivity waxes and wanes over the theta cycle. 6) Granule cells of the fascia dentata are also modulated by theta. The depth of modulation for the granule cell population approaches 100%, and the peak activity of the granule cell population comes about 90 degrees earlier in the theta cycle than the peak firing of CA1 pyramidal cells. 7) Granule cells, like pyramidal cells, show robust phase precession. 8) Cross-correlation analysis shows that portions of the temporal sequence of CA1 pyramidal cell place fields are replicated repeatedly within individual theta cycles, in highly compressed form. The compression ratio can be as much as 10:1. These findings indicate that phase precession is a very robust effect, distributed across the entire hippocampal population, and that it is likely to be inherited from the fascia dentata or an earlier stage in the hippocampal circuit, rather than generated intrinsically within CA1. It is hypothesized that the compression of temporal sequences of place fields within individual theta cycles permits the use of long-term potentiation for learning of sequential structure, thereby giving a temporal dimension to hippocampal memory traces.
• Treves, A., Skaggs, W., & Barnes, C. (1996). How much of the hippocampus can be explained by functional constraints?. Hippocampus, 6(6). doi:10.1002/(SICI)1098-1063(1996)6:6<666::AID-HIPO9>3.0.CO;2-E
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  In the spirit of Marr, we discuss an information-theoretic approach that derives, from the role of the hippocampus in memory, constraints on its anatomical and physiological structure. The observed structure is consistent with such constraints, and, further, we relate the quantitative arguments developed in earlier analytical studies to experimental measures extracted from neuronal recordings in the behaving rat.
• Treves, A., Treves, A., Skaggs, W. E., Skaggs, W. E., Barnes, C. A., & Barnes, C. A. (1996). How much of the hippocampus can be explained by functional constraints?. Hippocampus, 6(6), 666-74. doi:10.1002/(sici)1098-1063(1996)6:6<666::aid-hipo9>3.0.co;2-e
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  In the spirit of Marr, we discuss an information-theoretic approach that derives, from the role of the hippocampus in memory, constraints on its anatomical and physiological structure. The observed structure is consistent with such constraints, and, further, we relate the quantitative arguments developed in earlier analytical studies to experimental measures extracted from neuronal recordings in the behaving rat.
• Tsui, C., Barnes, C. A., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., & Worley, P. F. (1996). Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. The Journal of Neuroscience, 16(8), 2463-2478. doi:10.1523/jneurosci.16-08-02463.1996
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  Stimulus-linked RNA and protein synthesis is required for establishment of long-term neuroplasticity. To identify molecular mechanisms underlying long-term neuroplasticity, we have used differential cDNA techniques to clone a novel immediate-early gene (IEG) that is rapidly induced in neurons of the hippocampus and cortex by physiological synaptic activity. Analysis of the deduced amino acid sequence indicates homology to members of the pentraxin family of secreted lectins that include C-reactive protein and serum amyloid P component. Regions of homology include an 8 amino acid “pentraxin signature” sequence and a characteristic pentraxin calcium-binding domain. We have termed this gene and the encoded protein Narp (from neuronal activity- regulated pentraxin). Biochemical analyses confirm the presence of a functional signal sequence, and Narp is secreted by transfected COS-1 cells in culture. Additionally, Narp binds to agar matrix in a calcium- dependent manner consistent with the lectin properties of the pentraxin family. When cocultured with Narp-secreting COS-1 cells, neurons of cortical explants exhibit enhanced growth of neuronal dendritic processes. Neurite outgrowth-promoting activity is also observed using partially purified Narp and can be specifically immunodepleted, demonstrating that Narp is the active principle. Narp is fully active at a concentration of approximately 40 ng/ml, indicating a potency similar to known peptide growth factors. Because Narp is rapidly regulated by neuronal activity, its lectin and growth-promoting activities are likely to play role in the modification of cellular properties that underlie long-term plasticity.
• Barnes, C. (1995). Involvement of LTP in memory: Are we "searching under the street light"?. Neuron, 15(4). doi:10.1016/0896-6273(95)90166-3
• Barnes, C. A. (1995). Involvement of LTP in memory: are we "searching under the street light"?. Neuron, 15(4), 751-4. doi:10.1016/0896-6273(95)90166-3
• Lyford, G. L., Yamagata, K., Kaufmann, W. E., Barnes, C. A., Sanders, L. K., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Lanahan, A. A., & Worley, P. F. (1995). Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites.. Neuron, 14(2), 433-45. doi:10.1016/0896-6273(95)90299-6
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  Neuronal activity is an essential stimulus for induction of plasticity and normal development of the CNS. We have used differential cloning techniques to identify a novel immediate-early gene (IEG) cDNA that is rapidly induced in neurons by activity in models of adult and developmental plasticity. Both the mRNA and the encoded protein are enriched in neuronal dendrites. Analysis of the deduced amino acid sequence indicates a region of homology with alpha-spectrin, and the full-length protein, prepared by in vitro transcription/translation, coprecipitates with F-actin. Confocal microscopy of the native protein in hippocampal neurons demonstrates that the IEG-encoded protein is enriched in the subplasmalemmal cortex of the cell body and dendrites and thus colocalizes with the actin cytoskeletal matrix. Accordingly, we have termed the gene and encoded protein Arc (activity-regulated cytoskeleton-associated protein). Our observations suggest that Arc may play a role in activity-dependent plasticity of dendrites.
• Markus, E., Qin, Y., Leonard, B., Skaggs, W., McNaughton, B., & Barnes, C. (1995). Interactions between location and task affect the spatial and directional firing of hippocampal neurons. Journal of Neuroscience, 15(11). doi:10.1523/jneurosci.15-11-07079.1995
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  When rats forage for randomly dispersed food in a high walled cylinder the firing of their hippocampal 'place' cells exhibits little dependence on the direction faced by the rat. On radial arm mazes and similar tasks, place cells are strongly directionally selective within their fields. These tasks differ in several respects, including the visual environment, configuration of the traversable space, motor behavior (e.g., linear and angular velocities), and behavioral context (e.g., presence of specific, consistent goal locations within the environment). The contributions of these factors to spatial and directional tuning of hippocampal neurons was systematically examined in rats performing several tasks in either an enriched or a sparse visual environment, and on different apparati. Place fields were more spatially and directionally selective on a radial maze than on an open, circular platform, regardless of the visual environment. On the platform, fields were more directional when the rat searched for food at fixed locations, in a stereotypic and directed manner, than when the food was scattered randomly. Thus, it seems that place fields are more directional when the animal is planning or following a route between points of special significance. This might be related to the spatial focus of the rat's attention (e.g., a particular reference point). Changing the behavioral task was also accompanied by a change in firing location in about one-third of the cells. Thus, hippocampal neuronal activity appears to encode a complex interaction between locations, their significance and the behaviors the rat is called upon to execute.
• Anderson, K., Barnes, C. A., Kaufman, W., Worley, P. F., & Yamagata, K. (1994). Expression of a mitogen-inducible cyclooxygenase in brain neurons: Regulation by synaptic activity and glucocorticoids.. Japanese Journal of Pharmacology, 64, 123. doi:10.1016/s0021-5198(19)50134-2
• Andreasson, K. I., Barnes, C. A., Kaufmann, W. E., Lanahan, A., Papapavlou, M., Worley, P. F., & Yamagata, K. (1994). Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268.. Learning & Memory, 1(2), 140-152. doi:10.1101/lm.1.2.140
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  Programs of gene activation may underlie long-term adaptive cellular responses to extracellular ligands. We have used a differential cDNA cloning strategy to identify genes that are strongly induced by excitatory stimuli in the adult rat hippocampus. Here, we report the rat cDNA sequence of a zinc-finger transcription factor, Egr3/Pilot, and characterize its regulated mRNA expression in brain. Egr3 mRNA is rapidly and transiently induced in neurons of the hippocampus and cortex by electroconvulsive seizure. mRNA levels peak 2 hr after the seizure and remain elevated for as long as 8 hr. Egr3 mRNA is also rapidly induced in granule cells of the dentate gyrus by synaptic NMDA receptor activation elicited by patterned stimulation of the perforant pathway and by drugs that alter dopamine neurotransmission in the striatum. Basal levels of Egr3 mRNA in the cortex appear to be driven by natural synaptic activity because monocular deprivation rapidly decreases Egr3 mRNA in the deafferented visual cortex. Aspects of the protein structure, sequence-specific DNA binding, transcriptional activity, and regulation of Egr3 are highly similar to another zinc-finger transcription factor, Egr1/zif268. Moreover, we demonstrate colocalization of Egr3 and zif268 mRNAs in neurons of normal and stimulated cortex. Our studies suggest that interactions between these coregulated transcription factors may be important in defining long-term, neuroplastic responses.
• Barnes, C. A. (1994). Normal aging: regionally specific changes in hippocampal synaptic transmission.. Trends in neurosciences, 17(1), 13-8. doi:10.1016/0166-2236(94)90029-9
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  Results of electrophysiological investigations of aging in the rodent hippocampus contradict the popular conception of the aging process as one of general deterioration. Such studies have revealed a selective pattern of both degenerative change and functional sparing in different physiological parameters of the same cells. In synaptic transmission, changes have been observed that might even be considered compensatory. The selectivity of the aging process is further demonstrated by the fact that it exhibits clear regional specificity, even among the different subfields of the hippocampus. The future challenges will be to understand both how these specific patterns of age-related neurobiological change arise, and how they lead to the cognitive changes that arise during normal aging.
• Barnes, C., Jung, M., McNaughton, B., Korol, D., Andreasson, K., & Worley, P. (1994). LTP saturation and spatial learning disruption: Effects of task variables and saturation levels. Journal of Neuroscience, 14(10). doi:10.1523/jneurosci.14-10-05793.1994
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  The prediction that 'saturation' of LTP/LTE at hippocampal synapses should impair spatial learning was reinvestigated in the light of a more specific consideration of the theory of Hebblan associative networks, which predicts a nonlinear relationship between LTP 'saturation' and memory impairment. This nonlinearity may explain the variable results of studies that have addressed the effects of LTP 'saturation' on behavior. The extent of LTP 'saturation' in fascia dentata produced by the standard chronic LTP stimulation protocol was assessed both electrophysiologically and through the use of an anatomical marker (activation of the immediate-early gene zif268). Both methods point to the conclusion that the standard protocols used to induce LTP do not 'saturate' the process at any dorsoventral level, and leave the ventral half of the hippocampus virtually unaffected. LTP-inducing, bilateral perforant path stimulation led to a significant deficit in the reversal of a well- learned spatial response on the Barnes circular platform task as reported previously, yet in the same animals produced no deficit in learning the Morris water task (for which previous results have been conflicting). The behavioral deficit was not a consequence of any afterdischarge in the hippocampal EEG. In contrast, administration of maximal electroconvulsive shock led to robust zif268 activation throughout the hippocampus, enhancement of synaptic responses, occlusion of LTP produced by discrete high-frequency stimulation, and spatial learning deficits in the water task. These data provide further support for the involvement of LTP-like synaptic enhancement in spatial learning.
• Barnes, C., Treves, A., Rao, G., & Shen, J. (1994). Electrophysiological markers of cognitive aging: Region specificity and computational consequences. Seminars in Neuroscience, 6(6). doi:10.1006/smns.1994.1047
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  A major challenge facing those interested in understanding age-related changes in cognition, is the elucidation of which neurobiological changes contribute significantly to functional loss, and how individual changes make a specific impact on behavior. Functional compensation, preservation and deterioration of cell function have all been observed to occur in senescent hippocampus of memory deficient old animals. The suggestion is made that interpretation of these patterns of brain aging may be greatly facilitated by the use of computational simulation methods directed at the neural networks of interest. © 1994 Academic Press. All rights reserved.
• Chen, L. L., Lin, L. H., Barnes, C. A., & Mcnaughton, B. L. (1994). Head-direction cells in the rat posterior cortex. II. Contributions of visual and ideothetic information to the directional firing.. Experimental brain research, 101(1), 24-34. doi:10.1007/bf00243213
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  This study investigated the effects of visual and ideothetic cues on the spatial tuning of head-direction (HD) cells recorded in the rat posterior cortices. Extracellular, single unit responses were recorded from animals performing each of two different tasks, a spatial working memory task on a radial-arm maze and a passive rotation task on a modified "lazy Susan" platform. The influence of visual cues was assessed by manipulating the position of one white and three black cue-cards placed around the maze. We found three major categories of HD cells based on their response to cue manipulations in the maze tasks. Type A cells (10/41) rotated their preferred directions along with the rotation of the cues. The majority (type B, 25/41) of the HD cells were unaffected by the rotation of visual cues, maintaining their established preferred direction. Type C cells (6/41) showed complex responses to cue rotation, with the preferred direction reflecting either a combination of both type A and type B responses or an unpredictable response. The results indicate that the internal representation of directionality can be calibrated by visual cues and that some mnemonic processes may have been involved in the registration of the previous cue locations. Eleven cells were tested in both the maze task and the passive rotation task. Most (9/11) showed a significant directionality in the former task, but showed either no or weak directionality in the latter task, suggesting that movement-related ideothetic cues may be used in supporting the directional firing of these cells. Only two cells showed significant directionality in both tasks. Their established preferred directions did not rotate along with the cues in the maze task, but did rotate with the cues in the passive rotation task. We conclude that the dynamic aspect of the directional tuning in these cortical HD cells may represent on-line calibration of an angular coordinate representation.
• Chen, L. L., Lin, L. H., Green, E. J., Barnes, C. A., & Mcnaughton, B. L. (1994). Head-direction cells in the rat posterior cortex. I. Anatomical distribution and behavioral modulation.. Experimental brain research, 101(1), 8-23. doi:10.1007/bf00243212
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  We examined the behavioral modulation of head-directional information processing in neurons of the rat posterior cortices, including the medial prestriate (area Oc2M) and retrosplenial cortex (areas RSA and RSG). Single neurons were recorded in freely moving rats which were trained to perform a spatial working memory task on a radial-arm maze in a cue-controlled room. A dual-light-emitting diode (dual-LED) recording headstage, mounted on the animals' heads, was used to track head position and orientation. Planar modes of motion, such as turns, straight motion, and nonlocomotive states, were categorized using an objective scheme based upon the differential contributions of movement parameters, including linear and angular velocity of the head. Of 662 neurons recorded from the posterior cortices, 41 head-direction (HD) cells were identified based on the criterion of maintained directional bias in the absence of visual cues or in the dark. HD cells constituted 7 of 257 (2.7%) cells recorded in Oc2M, 26 of 311 (8.4%) cells in RSA, and 8 of 94 (8.5%) cells in RSG. Spatial tuning of HD cell firing was modulated by the animal's behaviors in some neurons. The behavioral modulation occurred either at the preferred direction or at all directions. Moreover, the behavioral selectivity was more robust for turns than straight motions, suggesting that the angular movements may significantly contribute to the head-directional processing. These behaviorally selective HD cells were observed most frequently in Oc2M (4/7, 57%), as only 5 of 26 (19%) of RSA cells and none of the RSG cells showed behavioral modulation. These data, taken together with the anatomical evidence for a cascade of projections from Oc2M to RSA and thence to RSG, suggest that there may be a simple association between movement and head-directionality that serves to transform the egocentric movement representation in the neocortex into an allocentric directional representation in the periallocortex.
• Chen, L., Lin, L., Barnes, C., & McNaughton, B. (1994). Head-direction cells in the rat posterior cortex - II. Contributions of visual and ideothetic information to the directional firing. Experimental Brain Research, 101(1). doi:10.1007/BF00243213
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  This study investigated the effects of visual and ideothetica cues on the spatial tuning of head-direction (HD) cells recorded in the rat posterior cortices. Extracellular, single unit responses were recorded from animals performing each of two different tasks, a spatial working memory task on a radial-arm maze and a passive rotation task on a modified "lazy Susan" platform. The influence of visual cues was assessed by manipulating the position of one white and three black cue-cards placed around the maze. We found three major categories of HD cells based on their response to cue manipulations in the maze tasks. Type A cells (10/41) rotated their preferred directions along with the rotation of the cues. The majority (type B, 25/41) of the HD cells were unaffected by the rotation of visual cues, maintaining their established preferred direction. Type C cells (6/41) showed complex responses to cue rotation, with the preferred direction reflecting either a combination of both type A and type B responses or an unpredictable response. The results indicate that the internal representation of directionality can be calibrated by visual cues and that some mnemonic processes may have been involved in the registration of the previous cue locations. Eleven cells were tested in both the maze task and the passive rotation task. Most (9/11) showed a significant directionality in the former task, but showed either no or weak directionality in the latter task, suggesting that movement-related ideothetic cues may be used in supporting the directional firing of these cells. Only two cells showed significant directionality in both tasks. Their established preferred directions did not rotate along with the cues in the maze task, but did rotate with the cues in the passive rotation task. We conclude that the dynamic aspect of the directional tuning in these cortical HD cells may represent on-line calibration of an angular coordinate representation. © 1994 Springer-Verlag.
• Chen, L., Lin, L., Green, E., Barnes, C., & McNaughton, B. (1994). Head-direction cells in the rat posterior cortex - I. anatomical distribution and behavioral modulation. Experimental Brain Research, 101(1). doi:10.1007/BF00243212
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  We examined the behavioral modulation of head-directional information processing in neurons of the rat posterior cortices, including the medial prestriate (area Oc2M) and retrosplenial cortex (areas RSA and RSG). Single neurons were recorded in freely moving rats which were trained to perform a spatial working memory task on a radial-arm maze in a cue-controlled room. A dual-light-emitting diode (dual-LED) recording headstage, mounted on the animals' heads, was used to track head position and orientation. Planar modes of motion, such as turns, straight motion, and nonlocomotive states, were categorized using an objective scheme based upon the differential contributions of movement parameters, including linear and angular velocity of the head. Of 662 neurons recorded from the posterior cortices, 41 head-direction (HD) cells were identified based on the criterion of maintained directional bias in the absence of visual cues or in the dark. HD cells constituted 7 of 257 (2.7%) cells recorded in Oc2M, 26 of 311 (8.4%) cells in RSA, and 8 of 94 (8.5%) cells in RSG. Spatial tuning of HD cell firing was modulated by the animal's behaviors in some neurons. The behavioral modulation occurred either at the preferred direction or at all directions. Moreover, the behavioral selectivity was more robust for turns than straight motions, suggesting that the angular movements may significantly contribute to the head-directional processing. These behaviorally selective HD cells were observed most frequently in Oc2M (4/7, 57%), as only 5 of 26 (19%) of RSA cells and none of the RSG cells showed behavioral modulation. These data, taken together with the anatomical evidence for a cascade of projections from Oc2M to RSA and thence to RSG, suggest that there may be a simple association between movement and head-directionality that serves to transform the egocentric movement representation in the neocortex into an allocentric directional representation in the periallocortex. © 1994 Springer-Verlag.
• Markus, E. J., Markus, E. J., Barnes, C. A., Barnes, C. A., Mcnaughton, B. L., Mcnaughton, B. L., Gladden, V. L., Gladden, V. L., Skaggs, W. E., & Skaggs, W. E. (1994). Spatial information content and reliability of hippocampal CA1 neurons: effects of visual input.. Hippocampus, 4(4), 410-21. doi:10.1002/hipo.450040404
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  The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 "complex spike" (CS) cells were studied in young and old Fischer-344 rats during food-motivated performance of a randomized, forced-choice task on an eight-arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms. In the dark, a lower proportion of CS cells had "place fields," and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields. Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness. While the task was simple and errors rare, rats that made fewer errors (i.e., re-entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention.
• Markus, E., Markus, E., Barnes, C., Barnes, C., McNaughton, B., McNaughton, B., Gladden, V., Gladden, V., Skaggs, W., & Skaggs, W. (1994). Spatial information content and reliability of hippocampal CA1 neurons: Effects of visual input. Hippocampus, 4(4). doi:10.1002/hipo.450040404
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  The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 “complex spike” (CS) cells were studied in young and old Fischer‐344 rats during food‐motivated performance of a randomized, forced‐choice task on an eight‐arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms. In the dark, a lower proportion of CS cells had “place fields,” and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields. Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness. While the task was simple and errors rare, rats that made fewer errors (i.e., re‐entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention. © 1994 Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc.
• Mcnaughton, B. L., Mizumori, S. J., Barnes, C. A., Leonard, B. J., Marquis, M., & Green, E. J. (1994). Cortical representation of motion during unrestrained spatial navigation in the rat.. Cerebral cortex (New York, N.Y. : 1991), 4(1), 27-39. doi:10.1093/cercor/4.1.27
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  Neural activity related to unrestrained movement through space was studied in rat sensorimotor and posterior parietal cortices during performance of an eight-arm, radial maze task. Nearly half of the cells exhibited movement-related activity that discriminated among three basic modes of locomotion: left turns, right turns, and forward motion. Correlates ranged from strong excitation (relative to the still condition) to strong inhibition, and were distributed among the movement modes in a variety of different ways. For example, cells that discriminated between clockwise and counterclockwise turns did so with either antagonistic responses or simple excitation or inhibition. Others showed either excitation or inhibition relative to both turning and the still condition, and hence were selective for forward motion. Many cells exhibited somatosensory responsiveness; however, in agreement with findings of others, motion correlates could rarely be sensibly explained by the somatosensory response. Moreover, movement correlates sometimes varied considerably with spatial context. Some cells exhibited more complex motion correlates, such as an apparent dependence on the nature of the preceding movement. Irrespective of the specific sensory or motor determinants of cell activity, which varied considerably among cells, the posterior neocortex of the rat appears to generate a robust and redundant internal representation of body motion through space. Such a representation could be useful in constructing "cognitive maps" of the environment.
• Mcnaughton, B. L., Shen, J., Rao, G., Foster, T. C., & Barnes, C. A. (1994). Persistent increase of hippocampal presynaptic axon excitability after repetitive electrical stimulation: dependence on N-methyl-D-aspartate receptor activity, nitric-oxide synthase, and temperature.. Proceedings of the National Academy of Sciences of the United States of America, 91(11), 4830-4. doi:10.1073/pnas.91.11.4830
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  The electrical excitability of Schaffer collateral axons and/or terminals was studied in hippocampal slices by monitoring single, CA3 pyramidal neurons activated antidromically from CA1 stratum radiatum. At 22 degrees C, weak, repetitive stimulation with as few as 10 impulses at 2 Hz led to a robust lowering of the antidromic activation threshold that lasted > 30 min. The effect was completely absent at 32 degrees C and was blocked by both the N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovalerate and the inhibitor of nitric-oxide synthase, L-nitro-arginine methyl ester. Such threshold lowering would alter the variance of synaptic responses from axons stimulated in the variable excitation region of their input-output functions. These results thus raise important doubts about the interpretation of experiments in which the so-called minimal-stimulation method has been used at reduced temperature to infer changes in quantal transmission during hippocampal long-term potentiation. In the present experiments, no changes were observed in the estimate of excitatory postsynaptic potential quantal content in long-term potentiation experiments at either temperature, which could not be accounted for by an artificial, temperature-dependent change in the responsiveness of presynaptic axons.
• Mcnaughton, B., Mizumori, S., Barnes, C., Leonard, B., Marquis, M., & Green, E. (1994). Cortical representation of motion during unrestrained spatial navigation in the rat. Cerebral Cortex, 4(1). doi:10.1093/cercor/4.1.27
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  Neural activity related to unrestrained movement through space was studied in rat sensorimotor and posterior parietal cortices during performance of an eight-arm, radial maze task. Nearly half of the cells exhibited movement-related activity that discriminated among three basic modes of locomotion: left turns, right turns, and forward motion. Correlates ranged from strong excitation (relative to the still condition) to strong inhibition, and were distributed among the movement modes in a variety of different ways. For example, cells that discriminated between clockwise and counterclockwise turns did so with either antagonistic responses or simple excitation or inhibition. Others showed either excitation or inhibition relative to both turning and the still condition, and hence were selective for forward motion. Many cells exhibited somatosensory responsiveness; however, in agreement with findings of others, motion correlates could rarely be sensibly explained by the somatosensory response. Moreover, movement correlates sometimes varied considerably with spatial context. Some cells exhibited more complex motion correlates, such as an apparent dependence on the nature of the preceding movement. Irrespective of the specific sensory or motor determinants of cell activity, which varied considerably among cells, the posterior neocortex of the rat appears to generate a robust and redundant internal representation of body motion through space. Such a representation could be useful in constructing "cognitive maps" of the environment. © 1994 Oxford University Press.
• Mcnaughton, B., Shen, J., Rao, G., Foster, T., & Barnes, C. (1994). Persistent increase of hippocampal presynaptic axon excitability after repetitive electrical stimulation: Dependence on N-methyl-D-aspartate receptor activity, nitric-oxide synthase, and temperature. Proceedings of the National Academy of Sciences of the United States of America, 91(11). doi:10.1073/pnas.91.11.4830
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  The electrical excitability of Schaffer collateral axons and/or terminals was studied in hippocampal slices by monitoring single, CA3 pyramidal neurons activated antidromically from CA1 stratum radiatum. At 22°C, weak, repetitive stimulation with as few as 10 impulses at 2 Hz led to a robust lowering of the antidromic activation threshold that lasted >30 min. The effect was completely absent at 32°C and was blocked by both the N-methyl- D-aspartate receptor antagonist, 2-amino-5-phosphonovalerate and the inhibitor of nitric-oxide synthase, L-nitroarginine methyl ester. Such threshold lowering would alter the variance of synaptic responses from axons stimulated in the variable excitation region of their input-output functions. These results thus raise important doubts about the interpretation of experiments in which the so-called minimal-stimulation method has been used at reduced temperature to infer changes in quantal transmission during hippocampal long-term potentiation. In the present experiments, no changes were observed in the estimate of excitatory postsynaptic potential quantal content in long-term potentiation experiments at either temperature, which could not be accounted for by an artifactual, temperature-dependent change in the responsiveness of presynaptic axons.
• Davis, S., Markowska, A., Wenk, G., & Barnes, C. (1993). Acetyl-l-carnitine: Behavioral, electrophysiological, and neurochemical effects. Neurobiology of Aging, 14(1). doi:10.1016/0197-4580(93)90030-F
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  -Aged rats were chronically administered acetyl-l-carnitine (AC) for 10 months. During this period they were tested on learning and sensorimotor tasks and were then subsequently tested electrophysiologically to assess induction and decay rates of long-term synaptic enhancement (LTE) in the hippocampus. Four groups were tested: young controls (4 mo-con), middle-aged controls (16 mo-con), old controls (24 mo-con), and old AC-treated rats (24 mo-AC). After completion of electrophysiological testing, each rat was sacrificed and investigated for age- or drug-related changes in three neurotransmitter markers; including, NMDA-sensitive glutamate receptors, high affinity choline uptake, and adenosine receptor number in the neocortex, hippocampus or caudate nucleus. Aging impaired spatial learning and there was a robust positive correlation between NMDA receptors in the hippocampus and acquisition of the spatial learning task. Induction of hippocampal LTE was reduced in 24 mo-AC rats and NMDA receptor number and high-affinity choline uptake in the frontal cortex was increased. Several suggestions are offered to explain the action of AC on these neurobiological parameters in old rats. © 1993.
• Barnes, C. A., Markowska, A. L., Ingram, D. K., Kametani, H., Spangler, E. L., Lemken, V. J., & Olton, D. S. (1990). Acetyl-1-carnitine. 2: Effects on learning and memory performance of aged rats in simple and complex mazes.. Neurobiology of aging, 11(5), 499-506. doi:10.1016/0197-4580(90)90110-l
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  Acetyl-1-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agent's action on behavior are suggested.
• Barnes, C., Markowska, A., Ingram, D., Kametani, H., Spangler, E., Lemken, V., & Olton, D. (1990). Acetyl-1-carnitine 2: Effects on learning and memory performance of aged rats in simple and complex mazes. Neurobiology of Aging, 11(5). doi:10.1016/0197-4580(90)90110-L
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  Acetyl-l-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agent's action on behavior are suggested. © 1990.
• Markowska, A. L., Ingram, D. K., Barnes, C. A., Spangler, E. L., Lemken, V. J., Kametani, H., Yee, W., & Olton, D. S. (1990). Acetyl-1-carnitine. 1: Effects on mortality, pathology and sensory-motor performance in aging rats.. Neurobiology of aging, 11(5), 491-8. doi:10.1016/0197-4580(90)90109-d
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  Three different test sites assessed the effects of acetyl-1-carnitine (AC) on age-related changes in general health, sensory-motor skills, learning, and memory. Two groups of rats began the experiments at 16 months of age. One group (OLD-AC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group (OLD-CON) was treated identically except it was not given the drug. Beginning at 22 months of age, these rats and a group of young (3-4 months old) rats (YG-CON) were given a series of sensory-motor tasks. AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity. An age-related decline of performance occurred in most of the sensory-motor tasks; locomotor activity was reduced in a novel environment and in a runwheel, and the ability to prevent falling was reduced in tests on a taut wire, rotorod, inclined screen, and several types of elevated bridges. An age-related decline of performance did not occur in grooming, or in the latency to initiate several different behaviors. AC had no effect on performance in any sensory-motor task. These data indicate that the improvements produced by AC in some tests of spatial memory may be due to the effects of AC on cognitive abilities rather than on sensory-motor skills.
• Markowska, A., Ingram, D., Barnes, C., Spangler, E., Lemken, V., Kametani, H., Yee, W., & Olton, D. (1990). Acetyl-l-carnitine 1: Effects on mortality, pathology and sensory-motor performance in aging rats. Neurobiology of Aging, 11(5). doi:10.1016/0197-4580(90)90109-D
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  Three different test sites assessed the effects of acetyl-l-carnitine (AC) on age-related changes in general health, sensory-motor skills, learning, and memory. Two groups of rats began the experiments at 16 months of age. One group (OLD-AC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group (OLD-CON) was treated identically except it was not given the drug. Beginning at 22 months of age, these rats and a group of young (3-4 months old) rats (YG-CON) were given a series of sensory-motor tasks. AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity. An age-related decline of performance occurred in most of the sensory-motor tasks; locomotor activity was reduced in a novel environment and in a runwheel, and the ability to prevent falling was reduced in tests on a taut wire, rotorod, inclined screen, and several types of elevated bridges. An age-related decline of performance did not occur in grooming, or in the latency to initiate several different behaviors. AC had no effect on performance in any sensory-motor task. These data indicate that the improvements produced by AC in some tests of spatial memory may be due to the effects of AC on cognitive abilities rather than on sensory-motor skills. © 1990.
• Barnes, C., Eppich, C., & Rao, G. (1989). Selective improvement of aged rat short-term spatial memory by 3,4-diaminopyridine. Neurobiology of Aging, 10(4). doi:10.1016/0197-4580(89)90045-6
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  Young (10 month) and old (28 month) Fischer 344 rats were injected (IP) with 3,4-diaminopyridine (3,4-DAP) or saline 10 minutes before training on two tests of spatial memory (the Barnes circular platform and the radial 8-arm maze). This agent has been found to block potassium channels in neurons, thereby increasing calcium influx, prolonging the action potential, and leading to increased transmitter release. The circular platform task assessed the drug's effect on spatial reference memory over 24 hour intertrial intervals, and the radial maze assessed its effect on short-term working memory within a 5 minute test session. 3,4-DAP was found to selectively improve memory performance of the old animals, and, within that age group, only improved performance on the short-term memory task. 3,4-DAP may therefore be effective for only a restricted set of age-related memory problems. © 1989.
• Castro, C., Silbert, L., McNaughton, B., & Barnes, C. (1989). Recovery of spatial learning deficits after decay of electrically induced synaptic enhancement in the hippocampus. Nature, 342(6249). doi:10.1038/342545a0
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  A WIDESPREAD interest in a long-lasting form of synaptic enhancement in hippocampal circuits1,2 has arisen largely because it might reflect the activation of physiological mechanisms that underlie rapid associative learning. As its induction normally requires the 'Hebbian'3 association of activity on a number of input fibres4, we refer to the process as long-term enhancement (LTE) rather than long-term potentiation (LTP), to emphasize its distinction from the ubiquitous, non-associative 'potentiation' phenomena that occur at most synapses, including those exhibiting LTE5. Among other evidence6-8 that LTE might actually have a role in associative memory is the demonstration that repeated high-frequency stimulation, which saturated the induceable LTE, caused a severe deficit in spatial learning, although it had no effect on well established spatial memory9. These results were consistent with a widespread view that information need only temporarily be stored in the hippocampal formation in order for long-term memories to be established in neocortical circuits10,11. In this context, it is important to understand whether the possible underly-ing synaptic changes are of a permanent character, or are relatively transient. A second question is whether the actual cause of the observed learning deficit is the distruption of the synaptic weight distribution, and/or the limitation of further synaptic change, which presumably results from experimental saturation of the LTE mechanism. Alternatively, the deficit could be a consequence of some unobserved secondary effect of the high-frequency electrical stimulation. Here we demonstrate that learning capacity recovers in about the same time that it takes LTE to decay, which strongly favours the first possibility and supports the idea that LTE-like processes actually underlie associative memory. © 1989 Nature Publishing Group.
• McNaughton, B., Barnes, C., Meltzer, J., & Sutherland, R. (1989). Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge. Experimental Brain Research, 76(3). doi:10.1007/BF00248904
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  The effects of massive destruction of granule cells of the fascia dentata on the spatial and temporal firing characteristics of pyramidal cells in the CA1 and CA3 subfields of the hippocampus were examined in freely moving rats. Microinjections of the neurotoxin colchicine were made at a number of levels along the septo-temporal axis of the dentate gyri of both hemispheres, resulting in destruction of over 75% of the granule cells. By contrast there was relatively little damage to the pyramidal cell fields. As assessed by three different behavioral tests, the colchicine treatment resulted in severe spatial learning deficits. Single units were recorded from the CA1 and CA3 subfields using the stereotrode recording method while the animals performed a forced choice behavioral task on the radial 8-arm maze. Considering the extent of damage to the dentate gyrus, which has hitherto been considered to be the main source of afferent information to the CA fields, there was remarkably little effect on the spatial selectivity of "place cell" discharge on the maze, as compared to recordings from control animals. There was, however, a change in the temporal firing characteristics of these cells, which was manifested primarily as an increase in the likelihood of burst discharge. The main conclusion derived from these findings is that most of the spatial information exhibited by hippocampal pyramidal cells is likely to be transmitted from the cortex by routes other than the traditional "trisynaptic circuit". These routes may include the direct projections from entorhinal layers II and III to CA3 and CA1, respectively. © 1989 Springer-Verlag.
• Mizumori, S., Barnes, C., & McNaughton, B. (1989). Reversible inactivation of the medial septum: selective effects on the spontaneous unit activity of different hippocampal cell types. Brain Research, 500(1-2). doi:10.1016/0006-8993(89)90303-X
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  The contribution of septal afferents to spontaneous hippocampal single unit activity was examined by reversibly inactivating the medial septal nucleus using microinjections of the local anethetic lidocaine. Septal inactivation reduced spontaneous firing of cells in stratum granulosum and in the hilar/CA3 region for periods of up to about 15 min. The firing rates of CA1 complex-spike (pyramidal) cells, however, were not changed, although CA1 theta cells (inhibitory interneurons) exhibited a significant reduction in spontaneous rate. One interpretation of this pattern of results is that the output of CA1 pyramidal cells is maintained roughly constant in spite of reduced input from CA3 because of a proportional reduction in feedforward inhibition. This interpretation is consistent with Marr's22 formulation of the manner in which the hippocampus implements distributed associative memory. Alternatively, afferents to CA1 originating from regions other than CA3 may play a larger role in regulating CA1 output than previously assumed. © 1989.
• Mizumori, S., McNaughton, B., & Barnes, C. (1989). A comparison of supramammillary and medial septal influences on hippocampal field potentials and single-unit activity. Journal of Neurophysiology, 61(1). doi:10.1152/jn.1989.61.1.15
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  A comparison was made between the influences of supramammillary (SUM) and medial septal (MS) nuclei on hippocampal physiology in Nembutal-anesthetized rats. Specifically, the effects of prestimulation of the SUM or MS on the perforant path-dentate field potential, on spontaneous activity of single units, and on perforant path-induced unit activation were assessed. Another series of experiments addressed the issue of whether the SUM and MS effects on the perforant path-dentate field response are independent. Prestimulation of the SUM or MS significantly facilitated the perforant path-dentate population spike with no clear effect on the field excitatory postsynaptic potential (EPSP) recorded in the subgranular zone of the dentate hilus. Prestimulation of either nucleus also reduced the threshold for spike onset. The major differences between the two spike facilitation effects were the magnitude of the change and possibly the optimal interstimulus intervals required to obtain the effects. Acute transection of the ipsilateral column of fornix or dorsal fornix eliminated the SUM population spike facilitation effect. MS lesion or dorsal fornix/fimbria transection eliminated the MS spike facilitation effect. The MS lesion did not alter the effects of SUM prestimulation. Cingulum or medial forebrain bundle transection affected neither SUM- nor MS-mediated spike facilitation. Thus the SUM and MS influences on the dentate field response appear to be independent of one another. The relevant SUM afferents travel through the ipsilatral column of fornix and dorsal fornix, whereas MS afferents project through the dorsal fornix/fimbria. Single units recorded in stratum granulosum (SG) were assessed with respect to several parameters. These included the mean firing rate, whether or not excitation occurred prior to the field population spike and at lower threshold, and whether or not a driven unit respond to a second perforant path stimulus delivered at short latency following the first (during the period of population spike depression). The latter parameter in particular appeared to separate SG cells into two classes. The cells that were not activated during the second field potential were classified as granule cells, whereas those that were activated were classified as basket cells. Based on this distinction, significant differences were also found between the two cell classes on the other parameters. In particular, cells classified as granule cells often had very low firing rates. We conclude that many previous studies have mistakenly identified as granule cells inhibitory interneurons, which are much more commonly encountered (at least partly due to their higher discharge rates). This misidentification has led to several hypotheses concerning the mechanism of heterosynaptically induce population spike facilitation that we now conclude are untenable. Stimulation of the SUM or MS alone resulted in a reduction in the spontaneous firing rate of more than one-half of the cells recorded in the SG. Based on one or more of the above criteria, these cells were classified as basket cells. Also, stimulation of the SUM or MS prior to perforant path stimulation significantly reduced the probability of basket cell activation by the perforant path stimulus. Roughly 15% of SG cells recorded showed increased firing in response to SUM or MS stimulation. These cells had very low spontaneous rats and were therefore classified as granule cells. Relatively little change was observed in the firing rates of CA1, CA3, or hilar complex-spike cells. Roughly equal proportions of CA1 theta cells responsed with reduced or elevated firing. Thus, although additional mechanisms may also contribute, the heterosynaptic facilitation of the granule cell population spike is probably largely due to the suppression of inhibitory interneurons, as orginally suggested by Bilkey and Goddard for the MS-induced effect, on the basis of field potential studies.
• Mizumori, S., McNaughton, B., Barnes, C., & Fox, K. (1989). Preserved spatial coding in hippocampal CA1 pyramidal cells during reversible suppression of CA3c output: Evidence for pattern completion in hippocampus. Journal of Neuroscience, 9(11). doi:10.1523/jneurosci.09-11-03915.1989
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  Medial septal modulation of hippocampal single-unit activity was examined by assessing the behavioral and physiological consequences of reversibly inactivating the medial septum via microinjection of a local anesthetic (tetracaine) in freely behaving rats trained to solve a working memory problem on a radial maze. Reversible septal inactivation resulted in a dramatic, but temporary (15-20 min), impairment in choice accuracy. In addition, movement-induced theta (θ) modulation of the hippocampal EEG was eliminated. Septal injection of tetracaine also produced a significant reduction in location-specific firing by hilar/CA3c complex-spike cells (about 50%), with no significant change in the place-specific firing properties of CA1 complex-spike units. The mean spontaneous rates of stratum granulosum and CA1 theta cells were temporarily reduced by about 50% following septal injection of tetracaine. Although there was a significant reduction in the activities of inhibitory interneurons (theta cells) in CA1, there was no loss of spatial selectivity in the CA1 pyramidal cell discharge patterns. We interpret these results as support for the proposal originally put forth by Marr (1969, 1971) that hippocampal circuits perform pattern completion on fragmentary input information as a result of a normalization operation carried out by inhibitory interneurons. A second major finding in this study was that location specific firing of CA1 cells can be maintained in the virtual absence of the hippocampal θ-rhythm.
• Rasmussen, M., Barnes, C., & McNaughton, B. (1989). A systematic test of cognitive mapping, working-memory, and temporal discontiguity theories of hippocampal function. Psychobiology, 17(4). doi:10.3758/BF03337792
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  A completely between-subjects design was used to test three specific hypotheses of hippocampal function: O’Keefe and Nadel’s cognitive mapping theory, Olton’s working-memory theory, and Rawlins’s temporal discontiguity hypothesis. The performance of rats with entorhinal lesions was compared with that of controls on a variety of spatial and nonspatial reference- and working-memory tasks using the same apparatus. The effects of massed versus distributed trials were also investigated. The entorhinal-lesioned animals were impaired on all tests of allocentric localization, regardless of the type of memory tested. The results were entirely consistent with the predictions of cognitive mapping theory, and failed to support the working-memory and temporal discontiguity theories. The results do not rule out the possibility that the cognitive mapping theory might, nevertheless, be a specific case of other, more general theories. © 1989, Psychonomic Society, Inc.. All rights reserved.
• Sharp, P., McNaughton, B., & Barnes, C. (1989). Exploration-dependent modulation of evoked responses in fascia dentata: Fundamental observations and time course. Psychobiology, 17(3). doi:10.1007/BF03337777
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  The hippocampal formation is thought to be involved in spatial learning. A role as a more general, intermediate-term memory store has also been suggested. In this report, we address a moderately persistent change in propagation of excitation through hippocampal circuitry which resulted from exposure of animals to environments in which they were free to move and explore. Rats were prepared for chronic recording of perforant path-evoked dentate granule-cell population responses. A large increase in the synaptic component of this response developed over the first several minutes after the animals were transferred to a different but not necessarily novel environment, and decayed with a time constant of about 5 min. This apparent growth in synaptic strength was remarkably well correlated with the animal’s recent history of exploratory behavior, and was not due simply to handling or to the electrical stimulation. The amplitude of the population-spike component also varied over time, but was not obviously correlated with changes in the synaptic component. These response changes were different in both apparent mechanism and time course from previously reported, longer lasting, environmentally induced changes in the population-spike component. They also differed from the behavioral state-dependent gating effect reported by Winson and Abzug (1977) to the extent that the present effects long outlasted the behaviors that produced them. Although further analysis is required, it is possible that this phenomenon may reflect one mode of information storage in the hippocampal formation. © 1989, Psychonomic Society, Inc.. All rights reserved.
• Barnes, C. A. (1988). Aging and the physiology of spatial memory.. Neurobiology of aging, 9(5-6), 563-8. doi:10.1016/s0197-4580(88)80114-3
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  Evidence for age-related changes in spatial memory in rodents and humans is presented, along with data that suggest that the hippocampal formation is necessary for normal performance on spatial tasks in both species. An examination of the electrophysiological characteristics of this structure in rats suggests that the changes that occur with age in the hippocampus are selective, but that at least two primary types of alterations contribute to the spatial cognitive impairment seen in these animals. These include a deficit in the ability to maintain synaptic enhancement and a reduction in the accuracy of information processing ability of single hippocampal neurons.
• Barnes, C. A. (1988). Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat.. Trends in neurosciences, 11(4), 163-9. doi:10.1016/0166-2236(88)90143-9
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  Abstract There are a number of ways to approach the problem of how nervous systems are modified in response to an organism's interaction with its environment. One of these has been the study of learning and memory processes in the rat and their underlying physiological mechanisms, an endeavor that has contributed significantly to the overall understanding of the neural basis of behavior. As an example, the neurobiological properties of the rat hippocampal formation in relation to spatial information processing are reviewed, including a variety of behavioral analyses in conjunction with lesion and electrophysiological recording techniques. These approaches have furthered our understanding of cognitive operations that involve the integration of multiple sensory stimuli leading to the production of complex adaptive responses.
• Barnes, C., Mizumori, S., Lovinger, D., Sheu, F., Murakami, K., Chan, S., Linden, D., Nelson, R., & Routtenberg, A. (1988). Selective decline in protein F1 phosphorylation in hippocampus of senescent rats. Neurobiology of Aging, 9(C). doi:10.1016/S0197-4580(88)80086-1
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  Certain forms of neuronal plasticity have been found to be expressed through alterations in brain protein phosphorylation, and its regulation by protein kinase activity. Of interest in this regard is the possibility that the decline in neuronal plasticity and cognitive function that occurs in advanced age may result in part from altered phosphorylation of specific proteins. As a first attempt to identify age-related changes in phosphoproteins, we assayed in vitro phosphorylation of proteins in hippocampus, cerebellum, entorhinal cortex, and frontal cortex from Fischer-344 rats of 5 months, I I months, and 25 months of age. Compared to the middle-aged animals, the aged rats showed a selective 46% decline in phosphorylation of the 47 kDa protein (F1) in hippocampus, with no change in the phosphorylation of other proteins measured in this structure. Aged animals also showed decreased phosphorylation relative to young animals. No age-related change was observed in any protein band for the other brain areas examined. Since protein F1 is phosphorylated by protein kinase C (PKC), the cytosolic and membrane distribution of this enzyme was compared across age groups. The activity of PKC in hippocampus did not change across age. The explanation of this age-related decline in protein F1 phosphorylation is likely to be a decline in the substrate protein itself. The results are discussed in terms of protein F1's possible role in age-related decline of hippocampal synaptic plasticity. © 1988 Pergamon Journals Ltd.
• Barnes, C. A. (1987). Neurological and behavioral investigations of memory failure in aging animals.. International journal of neurology, 21-22, 130-6.
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  Aged organisms show a decline in their ability to learn and remember in certain situations. For example, it appears that both aged humans and aged rats exhibit spatial memory deficits. It is more difficult for older organisms to learn about and to navigate accurately within a familiar environment than it is for younger organisms. Because the brain structure that is critically involved in this type of behavior (the hippocampus) is relatively well understood in the rat, a correlation of spatial behavior with hippocampal physiology has been particularly useful in the delineation of some of the potential brain changes responsible for memory changes with age. Evidence for an age-related deficit in spatial memory is presented that emphasizes the importance of the contribution of the spatial component to the learning/memory changes seen with age in rats. The contribution of changes in hippocampal synaptic plasticity and in the information processing characteristics of single hippocampal cells of old rats is also discussed in terms of the potential influence on old animals' performance on spatial tasks.
• Barnes, C. A., Green, E. J., J, B., Johnson, W. E., Baldwin, J., Ej, G., & We, J. (1987). Behavioural and neurophysiological examples of functional sparing in senescent rat.. Canadian journal of psychology, 41(2), 131-40.
• Barnes, C. A., Rao, G., & Mcnaughton, B. L. (1987). Increased electrotonic coupling in aged rat hippocampus: a possible mechanism for cellular excitability changes.. The Journal of comparative neurology, 259(4), 549-58. doi:10.1002/cne.902590405
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  The effects of aging on the intercellular transfer of the low molecular weight fluorescent dye 5,6-carboxyfluorescein was studied in subfields fascia dentata, CA1, and CA3 of rat hippocampal slices maintained in vitro. All three areas exhibited a statistically significant increase in dye coupling with age. The increased dye coupling was accompanied by an apparent increase in postsynaptic excitability as assessed by the ratio of the population spike to EPSP components of the extracellulary recorded field potential. The possibility that artifactual dye coupling due to cell fusion contributed significantly to these results was ruled out by the demonstrations that a high molecular weight, dextran-coupled fluorescein compound did not produce multiple fills and that dye coupling with carboxyfluorescein could be prevented by prior intracellular loading with Ca++, a procedure that decouples gap junctions in other tissue. The increase in extent of electrical coupling suggested by these data may largely account for the apparent increase in cellular excitability of this tissue with age and may reflect the mechanism by which the senescent hippocampus compensates for the loss of afferent input during the course of normal aging. The additional possibility is raised that increased electrical coupling may reflect a mechanism for permanent associative storage of information in this system.
• Barnes, C., Green, E., Baldwin, J., & Johnson, W. (1987). Behavioural and neurophysiological examples of functional sparing in senescent rat.. Canadian journal of psychology, 41(2).
• Barnes, C., Rao, G., & McNaughton, B. (1987). Increased electrotonic coupling in aged rat hippocampus: A possible mechanism for cellular excitability changes. Journal of Comparative Neurology, 259(4). doi:10.1002/cne.902590405
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  The effects of aging on the intercellular transfer of the low molecular weight fluorescent dye 5,6‐carboxyfluorescein was studied in subfields fascia dentata, CA1, and CA3 of rat hippocampal slices maintained in vitro. All three areas exhibited a statistically significant increase in dye coupling with age. The increased dye coupling was accompanied by an apparent increase in postsynaptic excitability as assessed by the ratio of the population spike to EPSP components of the extracellulary recorded field potential. The possibility that artifaciual dye coupling due to cell fusion contributed significantly to these results was ruled out by the demonstrations that a high molecular weight, dextran‐coupled fluorescein compound did not produce multiple fills and that dye coupling with carboxyfluorescein could be prevented by prior intracellular loading with Ca++, a procedure that decouples gap junctions in other tissue. The increase in extent of electrical coupling suggested by these data may largely account for the apparent increase in cellular excitability of this tissue with age and may reflect the mechanism by which the senescent hippocampus compensates for the loss of afferent input during the course of normal aging. The additional possibility is raised that increased electrical couping may reflect a mechanism for permanent associative storage of information in this system. Copyright © 1987 Alan R. Liss, Inc.
• Leonard, B. J., Mcnaughton, B. L., & Barnes, C. A. (1987). Suppression of hippocampal synaptic plasticity during slow-wave sleep.. Brain research, 425(1), 174-7. doi:10.1016/0006-8993(87)90496-3
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  The influence of behavioral state on the induction of long-term enhancement (LTE) of hippocampal synapses was studied in chronically prepared animals. Perforant path evoked field potentials and EEG were recorded from fascia dentata during slow-wave sleep (SWS) and waking. LTE was strongly suppressed during SWS, suggesting that hippocampal information storage may be inactivated at certain phases of the sleep cycle. Normal LTE was observed in the same animals while awake.
• Nadel, L., Barnes, C., Gallagher, M., Kolb, B., & Willner, J. (1987). Editorial. Psychobiology, 15(1). doi:10.3758/BF03327258
• Rao, G., Barnes, C. A., & Mcnaughton, B. L. (1987). Occlusion of hippocampal electrical junctions by intracellular calcium injection.. Brain research, 408(1-2), 267-70. doi:10.1016/0006-8993(87)90385-4
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  Low-molecular weight dyes such as Lucifer yellow or carboxyfluorescein have been used to investigate the electrical connectivity of neurons via gap junctions. The interpretation that such dye passage is mediated through intercellular channels has been controversial and difficult to corroborate with direct techniques in mammalian brain. We report here that elevated intracellular free Ca2+, a treatment shown to cause gap junction occlusion in other tissues, significantly blocks dye transfer between hippocampal cells. Furthermore, intracellular injection of FITC-dextran (which is too large to cross gap junctions) never resulted in multiple hippocampal cell fills. These data lend strong support to the argument that the extent of dye-coupling provides a good estimate of the number of intercellular communication channels, and raises the possibility that these channels may be physiologically modulated.
• Rao, G., Barnes, C., & McNaughton, B. (1987). Occlusion of hippocampal electrical junctions by intracellular calcium injection. Brain Research, 408(1-2). doi:10.1016/0006-8993(87)90385-4
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  Low-molecular weight dyes such as Lucifer yellow or carboxyfluorescein have been used to investigate the electrical connectivity of neurons via gap junctions. The interpretation that such dye passage is mediated through intercellular channels has been controversial and difficult to corroborate with direct techniques in mammalian brain. We report here that elevated intracellular free Ca2+, a treatment shown to cause gap junction occlusion in other tissues, significantly blocks dye transfer between hippocampal cells. Furthermore, intracellular injection of FITC-dextran (which is too large to cross gap junctions) never resulted in multiple hippocampal cell fills. These data lend strong support to the argument that the extent of dye-coupling provides a good estimate of the number of intercellular communication channels, and raises the possibility that these channels may be physiologically modulated. © 1987.
• Sharp, P., Barnes, C., & McNaughton, B. (1987). Effects of Aging on Environmental Modulation of Hippocampal Evoked Responses. Behavioral Neuroscience, 101(2). doi:10.1037/0735-7044.101.2.170
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  Evoked responses in the dentate gyrus of the hippocampal formation undergo a long-term enhancement following high-frequency stimulation of the perforant pathway. A similar change results from exposure of animals to a complex spatial environment. The effect of aging on the development and decay of this environmentally induced response enhancement was examined in the present study. Previously it was shown that electrically induced enhancement reaches the same asymptotic level in young and old animals but decays more quickly in old animals. It has been suggested that this faster decay may underlie the faster forgetting of spatial information observed in old animals. Chronic recordings were made from young (14 month) and old (32 month) rats. After exposure to an enriched environment for 11 days, the population spike component of the response increased about 125% over baseline in both groups. No changes were seen in either group in the synaptic component. Following the enrichment treatment, animals were returned to their home cages. The decay of the enhanced population spike during this period differed markedly between age-groups (time constants of 30 and 11 days for the young and old groups, respectively). These results suggest that the factors governing the decay of electrically and environmentally induced response enhancement are similarly affected by the aging process and may share a common mechanism. © 1987 American Psychological Association.
• McNaughton, B., Barnes, C., Rao, G., Baldwin, J., & Rasmussen, M. (1986). Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information. Journal of Neuroscience, 6(2). doi:10.1523/jneurosci.06-02-00563.1986
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  The hypothesis that memories are stored as a specific distribution of strengths in a population of modifiable synapses was examined by the bilateral induction of long-term enhancement in synapses of the main afferent fiber system to the hippocampal formation in rats. Brief, high-frequency activation of the perforant pathway in chronically prepared animals resulted in a persistent increase in the field EPSP and population spike, measured extracellularly in fascia dentata. This treatment resulted in a profound and persistent deficit in the acquisition of new spatial information in a task requiring spatial 'reference' memory, and disruption of recently acquired spatial information. Well-established spatial memory was completely unaffected, however, as was the acquisition of spatial information into short-term 'working' memory. These results support the hypothesis that, during the formation of 'cognitive maps', spatial information must be temporarily stored at modifiable synapses at the input stage to the hippocampal formation, but that this information is not needed once the representation of the environment is well established. Spatial working memory, in a familiar environment, appears not to depend on the distribution of synaptic strengths in this system at all.
• Rao, G., Barnes, C., & McNaughton, B. (1986). Intracellular fluorescent staining with carboxyfluorescein: a rapid and reliable method for quantifying dye-coupling in mammalian central nervous system. Journal of Neuroscience Methods, 16(4). doi:10.1016/0165-0270(86)90050-6
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  Previous studies investigating electrotonic coupling in mammalian central nervous system have used the fluorescent marker Lucifer Yellow as an indicator of the presence of intercellular junctions between neurons. The fluorescent dye 5,6-carboxyfluorescein is known to have approximately 5 times the fluorescent yield of Lucifer Yellow. We have investigated the use of this dye as a potential alternative fluorescent marker on two types of neurons in the rat hippocampus in vitro. Unfixed hippocampal slices were mounted in a mixture of n-propyl gallate in glycerol and viewed with epifluorescence optics. Injections of small, brief hyperpolarizing currents through carboxyfluorescein-filled glass pipettes reliably produced neuronal fills of good quality. Both dendritic spines and axonal arborizations (including the thin mossy fibers of the dentate gyrus) were frequently observable. In addition to single cell fills, clusters consisting of 2-6 neurons were observed. No correlation was found between the number of cells per cluster and the ejection time. In addition, even cells exhibiting poor electrophysiological characteristics, or cells impaled only briefly, frequently exhibited good quality dye filling. This method will be particularly useful when large sample sizes are necessary to compare regional variations in the extent of electrotonic coupling in the mammalian brain. © 1986.
• Barnes, C., & McNaughton, B. (1985). An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behavioral Neuroscience, 99(6). doi:10.1037/0735-7044.99.6.1040
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  Age differences in the rates of acquisition and forgetting of a spatial memory problem were compared with corresponding differences in the rates of increase and decay of long-term synaptic enhancement (LTE) of hippocampal synapses, induced by high-frequency stimulation of perforant path fibers. Old animals approached their final asymptotic performance levels more slowly than did the young animals and exhibited faster rates of forgetting of the problem. Similarly, LTE reached its maximum more slowly in the old animals and decayed more quickly. Although the absolute rates of behavioral acquisition and forgetting were different from the corresponding rates of increase and decay of LTE, the relative differences between age groups were rather similar. This was particularly true for the comparison of forgetting with LTE decay. The relation of these data to the hypothesis that LTE underlies spatial learning and memory is discussed.
• Lovinger, D., Akers, R., Nelson, R., Barnes, C., McNaughton, B., & Routtenberg, A. (1985). A selective increase in phosphorylation of protein F1, a protein kinase C substrate, directly related to three day growth of long term synaptic enhancement. Brain Research, 343(1). doi:10.1016/0006-8993(85)91167-9
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  Increased in vitro phosphorylation of the 47 kdalton, 4.5 pI protein F1 was observed in dorsal hippocampal tissue from animals exhibiting long term enhancement (LTE) three days after high frequency stimulation of the perforant pathway, as compared to tissue from low frequency stimulated controls or from unoperated animals. The increase in protein F1 phosphorylation was related to LTE rather than simple activation of perforant path-dentate gyrus synapses. This is the first report of a change in brain protein phosphorylation accompanying synaptic enhancement lasting days. The extent of growth of LTE over the three days following stimulation was directly related (r = +0.66, P < 0.05) to protein F1 phosphorylation. Among the phosphorylation. Among the phosphoproteins studied this relationship between LTE and phosphorylation was selective for protein F1. This suggests that protein F1 may regulate growth of synaptic plasticity for at least a three day period. The mechanism for the LTE-related increase in protein F1 phosphorylation has not been established. However, recent evidence from this laboratory indicates: (1) that protein F1 is phosphorylated by the calcium/phospholipid-dependent protein kinase C; and (2) that kinase C is activated 1 h after LTE. Therefore, the increase in protein F1 phosphorylation following LTE may result from long term activation of protein C kinase. © 1985.
• Mcnaughton, B., & Barnes, C. (1985). The hippocampus, synaptic enhancement, and intermediate-term memory. Behavioral and Brain Sciences, 8(3). doi:10.1017/S0140525X00001412
• Sharp, P., McNaughton, B., & Barnes, C. (1985). Enhancement of hippocampal field potentials in rats exposed to a novel, complex environment. Brain Research, 339(2). doi:10.1016/0006-8993(85)90105-2
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  The hippocampus plays a crucial role in place learning in rodents and also exhibits a long-term enhancement of synaptic strength and postsynaptic excitability following electrical stimulation of its principal afferents. In the present report we suggest that these two observations may be related, by demonstrating an increase in synaptic and postsynaptic field potential amplitudes resulting from exposure to a spatially complex environment. © 1985.
• McNaughton, B., Barnes, C., & O'Keefe, J. (1984). The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats. Experimental Brain Research, 54(1). doi:10.1007/BF00235832
• Barnes, C. A., & Mcnaughton, B. L. (1983). Excitability changes in hippocampal granule cells of senescent rat.. Progress in brain research, 58, 445-51. doi:10.1016/s0079-6123(08)60047-3
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  Publisher Summary Research on senescent nervous systems has tended to emphasize processes of deterioration, which may be among the most obvious and important kinds of alterations to occur over the lifespan. A number of recent findings, however, suggest that preservation of function, in spite of deteriorative change, occurs at many levels of the nervous system. One example of a seemingly compensatory change in senescent rat brain function is an increased electrical excitability of hippocampal granule cells in the face of a considerable reduction in the afferent fiber population. This chapter examines one possible mechanism of this change.
• Barnes, C. A., Mcnaughton, B. L., & O'keefe, J. (1983). Loss of place specificity in hippocampal complex spike cells of senescent rat.. Neurobiology of aging, 4(2), 113-9. doi:10.1016/0197-4580(83)90034-9
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  Firing characteristics of "place" cells in dorsal CA1 of hippocampus were recorded from 5 young (10-14 months) and 5 old (25-29 months) Fischer-344 rats. Animals were trained to obtain food reward on a radial 8-arm maze. Entry to the arms was controlled by the experimenter so that all 8-arm were visited in random sequence from trial to trial. For each cell, 8 such trials were given (64 arm choices) in order that statistical reliability could be obtained for firing rates over the maze surface. Single unit activity and the animal's position on the maze were continuously monitored by digital computer. Twenty-seven cells from each age group were studied in this way. No statistically significant differences were found between age groups in unit spike height, width or firing rates. A large, statistically significant difference, however, was found in both spatial specificity and reliability of firing patterns from trial to trial. These results are discussed in terms of a possible deficit in spatial information processing in the older animals.
• Barnes, C., McNaughton, B., & O'Keefe, J. (1983). Loss of place specificity in hippocampal complex spike cells of senescent rat. Neurobiology of Aging, 4(2). doi:10.1016/0197-4580(83)90034-9
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  Firing characteristics of "place" cells in dorsal CA1 of hippocampus were recorded from 5 young (10-14 months) and 5 old (25-29 months) Fischer-344 rats. Animals were trained to obtain food reward on a radial 8-arm maze. Entry to the arms was controlled by the experimenter so that all 8-arm were visited in random sequence from trial to trial. For each cell, 8 such trials were given (64 arm choices) in order that statistical reliabilty could be obtained for firing rates over the maze surface. Single unit activity and the animal's position on the maze were continuously monitored by digital computer. Twenty-seven cells from each age group were studied in this way. No statistically significant differences were found between age groups in unit spike height, width or firing rates. A large, statistically significant difference, however, was found in both spatial specificity and reliability of firing patterns from trial to trial. These results are discussed in terms of a possible deficit in spatial information processing in the older animals. © 1983.
• Mcnaughton, B. L., Barnes, C. A., & O'keefe, J. (1983). The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats.. Experimental brain research, 52(1), 41-9. doi:10.1007/bf00237147
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  Isolated single units in rat dorsal hippocampus and fascia dentata were classified as 'Theta' or 'Complex-Spike' cells, and their firing characteristics were examined with respect to position, direction and velocity of movement during forced choice, food rewarded search behavior on a radial eight arm maze. Most spikes from CS cells occurred when the animal was located within a particular place on the maze and moving in a particular direction. Theta cells had very low spatial selectivity. Both cell categories had discharge probabilities which increased somewhat as a function of running velocity but tended to asymptote well before half-maximal velocity. The place/direction specificity of CS cells was significantly higher in CA1 than in CA3 and CA3 CS cells exhibited a striking preference for the inward radial direction. The pronounced directional selectivity of CS cells, at least in the present environment, suggests that they fire in response to complex, but specific, stimulus features in the extramaze world rather than to absolute place in a non-egocentric space. An alternative possibility is that the geometrical constraints of the maze surface have a profound influence on the shapes of the response fields of CS cells.
• Mcnaughton, B. L., O'keefe, J., & Barnes, C. A. (1983). The stereotrode: a new technique for simultaneous isolation of several single units in the central nervous system from multiple unit records.. Journal of neuroscience methods, 8(4), 391-7. doi:10.1016/0165-0270(83)90097-3
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  A new method is described for the recording and discrimination of extracellular action potentials in CNS regions with high cellular packing density or where there is intrinsic variation in action potential amplitude during burst discharge. The method is based on the principle that cells with different ratios of distances from two electrode tips will have different spike-amplitude ratios when recorded on two channels. The two channel amplitude ratio will remain constant regardless of intrinsic variation in the absolute amplitude of the signals. The method has been applied to the rat hippocampal formation, from which up to 5 units have been simultaneously isolated. The construction of the electrodes is simple, relatively fast, and reliable, and their low tip impedances result in excellent signal to noise characteristics.
• Wigstrom, H., Mcnaughton, B. L., & Barnes, C. A. (1982). Long-term synaptic enhancement in hippocampus is not regulated by postsynaptic membrane potential.. Brain research, 233(1), 195-9. doi:10.1016/0006-8993(82)90941-6
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  The contributions of membrane potential and postsynaptic discharge during afferent fibre tetanization to the generation of long-lasting synaptic enhancement was studied by intra- and extracellular recording in the CAl region of hippocampal slices. Neither parameter affected the magnitude of intracellular synaptic enhancement. Thus, if postsynaptic integration is involved in the control of the enhancement process, the integration must be chemically rather than electrically mediated.
• Mcnaughton, B. L., Barnes, C. A., & Andersen, P. (1981). Synaptic efficacy and EPSP summation in granule cells of rat fascia dentata studied in vitro.. Journal of neurophysiology, 46(5), 952-66. doi:10.1152/jn.1981.46.5.952
• Barnes, C. A., Honig, W. K., & Nadel, L. (1980). Spatial memory deficit in senescent rats.. Canadian journal of psychology, 34(1), 29-39. doi:10.1037/h0081022
• Barnes, C., & McNaughton, B. (1980). Physiological compensation for loss of afferent synapses in rat hippocampal granule cells during senescence.. The Journal of Physiology, 309(1). doi:10.1113/jphysiol.1980.sp013521
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  1. The effects of senescence on the input‐output characteristics of the perforant path projection to granule cells of the fascia dentata were studied in rats using extracellular techniques in vivo, and both extra‐ and intracellular recording in vitro. 2. Senescent animals exhibited a significant reduction in the perforant path excitatory synaptic field potential at all stimulus intensities tested. This was associated with a reduction in the size of the afferent fibre response, although there was no apparent change in the threshold for fibre activation. These data support the anatomical literature which indicates a loss of afferent synapses with advanced age. 3. For a given magnitude of afferent fibre response, however, the old animals exhibited a larger synaptic field potential, suggesting that the remaining synapses were in fact more powerful. Furthermore, the magnitude of the extracellular population spike, an index of the number of discharging granule cells, was greater in the old animals when plotted as a function of extracellular e.p.s.p. amplitude. 4. Intracellular recording from a total of 190 granule cells in the transverse hippocampal slice preparation revealed a 17% reduction in the voltage threshold for synaptically elicited granule cell discharge, and a 13% reduction in the latency of the action potential in old compared to young rats. Resting potentials, action potential amplitudes, whole neurone time constants, the relations between applied current and input resistance, and the discharge threshold following depolarizing current pulses, were not different between age groups. 5. These data indicate that granule cells could partly compensate for a loss of synapses during senescence by an increase in their electrical responsiveness to synaptic activation and possibly by an increase in synaptic efficacy. © 1980 The Physiological Society
• Barnes, C., Nadel, L., & Honig, W. (1980). Spatial memory deficit in senescent rats.. Canadian journal of psychology, 34(1). doi:10.1037/h0081022
• Barnes, C. (1979). Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat. Journal of Comparative and Physiological Psychology, 93(1). doi:10.1037/h0077579
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  Neurophysiological and behavioral measures were obtained from 32 senescent (28-34 mo) and 32 mature adult (10-26 mo) Long-Evans hooded rats. Extracellularly recorded synaptic responses were obtained from electrodes chronically implanted in the fascia dentata and perforant path. Ss were first tested on a circular platform, which favored the use of spatial cues for its solution; the senescent Ss exhibited poorer memory for the rewarded place. When granule cell synaptic responses were recorded after a single session of very brief high-frequency stimulation, the amount of elevation and time course of decline were equivalent between age groups. After 3 repetitions, however, young Ss maintained the increased synaptic strength for at least 14 days, whereas old Ss declined after the 1st session. The amount of synaptic enhancement was statistically correlated with the ability to perform the circular platform task both within and between groups. Furthermore, the aftereffects of the high-frequency stimulation selectively impaired the old Ss' spontaneous alternation behavior on a -T maze. Results are discussed in terms of the synaptic theory of memory formation and the aging process. (78 ref) (PsycINFO Database Record (c) 2006 APA, all rights reserved). © 1979 American Psychological Association.
• Barnes, C. A. (1979). Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat.. Journal of comparative and physiological psychology, 93(1), 74-104. doi:10.1037/h0077579
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  Neurophysiological and behavioral measures were obtained from 32 senescent (28--34 mo) and 32 mature adult (10--16 mo) rats. Extracellularly recorded synaptic responses were obtained from electrodes chronically implanted in the fascia dentata and perforant path. The rats were first tested on a circular platform, which favored the use of spatial cues for its solution, and the senescent rats were shown to exhibit poorer memory for the rewarded place. When granule cell synaptic responses were recorded after a single session of very brief high-frequency stimulation, the amount of elevation and time course of decline were equivalent between age groups. Af ter three repetitions, however, the young rats maintained the increased synaptic strength for at least 14 days, whereas the old rats declined after the first session. The amount of synaptic enhancement was statistically correlated with the ability to perform the circular platform task both within and between groups. Furthermore, the aftereffects of the high-frequency stimulation selectively impaired the old rats' spontaneous alternation behavior on a T-maze. Certain other neurophysiological and electroencephalographic measures did not distinguish between age groups. The results are discussed in terms of the synaptic theory of memory formation and of their relevance to the aging process.
• Barnes, C., & McNaughton, B. (1979). Neurophysiological comparison of dendritic cable properties in adolescent, middle-aged, and senescent rats. Experimental Aging Research, 5(3). doi:10.1080/03610737908257198
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  Relative dendritic atrophy has been reported in hippocampal granule cells of senescent (25 month) as compared to young (3 month) rats. An electrophysiological study of synaptic response waveform was undertaken to determine whether these anatomical changes have physiological correlates of functional significance to the integrative capacity of the granule cells. The variable of interest was the rise time of the extracellularly recorded population synaptic response because this parameter (under appropriate conditions) has been shown to reflect relative electrotonic distance of active synapses from the spike generating zone located near the cell body. By selectively stimulating small subsets of perforant path fibers along its medio-lateral axis, synapses at increasing distances from the soma may be activated and the response waveform recorded. Systematic observations were made on both hemispheres of 3 adolescent (2 months), three middle-aged (12 months), and 3 senescent (28 months) rats. There were no significant differences in the mean, variance, or range of the frequency distributions of synaptic response rise times. However, the medians of the distributions revealed a small shift towards lower values with advanced age. Although the latter finding is consistent with the anatomical changes, the magnitude of the differences were so small as to make their functional significance dubious. © 1979 Taylor & Francis Group, LLC.
• Barnes, C., Mcnaughton, B., Goddard, G., Douglas, R., & Adamec, R. (1977). Circadian rhythm of synaptic excitability in rat and monkey central nervous system. Science, 197(4298). doi:10.1126/science.194313
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  Synaptic responses in hippocampal granule cells to stimulation of their afferent fibers from the entorhinal cortex fluctuate with a 24-hour period. The phase of this cycle for rats and monkeys depends on whether the animal is naturally nocturnal or diurnal. In a rat blinded by enucleation, the rhythm persists but drifts out of phase with the rhythm of sighted controls.
• McNaughton, B., & Barnes, C. (1977). Physiological identification and analysis of dentate granule cell responses to stimulation of the medial and lateral perforant pathways in the rat. Journal of Comparative Neurology, 175(4). doi:10.1002/cne.901750404
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  Stimulation of the dorsomedial or ventrolateral perforant pathways resulted in quantitatively different extracellularly recorded EPSPs in the fascia dentata of the rat. The two potential differed in latency to peak and in width at half amplitude in a manner consistent with the different locus of termination of the two pathways on the granule cell dendrites. Both potentials were able to follow brief stimulus trains of 100 Hz, which suggests that they are monosynaptic. Medially elicited responses had their peak negativity approximately 100 to 180 μm deeper in the molecular layer than laterally elicited responses. Stimulation at short intervals along a dorsomedial to ventrolateral track in the angular bundle yielded a step function rather than a continuum of EPSP peak latency and half‐width, in agreement with Hjorth‐Simonsen's ('72) evidence for the separateness of the two pathways. Both pathways were able to induce granule cell discharge. Laterally elicited spikes, however, were delayed. Stimulation at intermediate locations frequently elicited double spikes from granule cell population. Population spikes elicited by either pathway were inhibited for as long as 100 msec after a single discharge. Both pathways showed facilitation with double stimuli at short intervals, and both showed post‐tetanic potentiation lasting at least 30 minutes. Under conditins where it could be shown that the two pathways at least partially converged onto the same granule cells, the response of one pathway did not increase when long lasting potentiation was induced on the other. Copyright © 1977 The Wistar Institute Press
• Barnes, C., & Fried, P. (1974). Tolerance to δ9-THC in adult rats with differential δ9-THC exposure when immature or during early adulthood. Psychopharmacologia, 34(3). doi:10.1007/BF00421959
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  Tolerance to δ9-tetrahydrocannabinol (THC) was examined in 96 rats, 48 of which were immature (30 days) at the start of the study and 48 of which were adults (90 days). For both age groups the treatments consisted of three phases and during each phase, lasting at least twenty days, animals received either THC or a control drug. Behavioral measures were taken during the third phase and, at the end of the study, weights of various organs were determined. The results revealed that degrees of tolerance exist and that the age of the subject at the time of initial chronic THC experience interacts with the later development of tolerance to the drug. In addition, heart and brain weights were reduced in those subjects receiving chronic THC injections while immature. © 1974 Springer-Verlag.

Proceedings Publications

• Dieckhaus, L. A., Comrie, C. J., McDermott, K. E., Gray, D. T., Barnes, C. A., & Hutchinson, E. B. (2022, May). Beyond Fractional Anisotropy: A Comparative Study of Myelin Water Fraction and Propagator Anisotropy in the Bonnet Macaque Brain. In International Society for Magnetic Resonance in Medicine.
• Barnes, C. A., Hutchinson, E. B., Gray, D. T., McDermott, K. E., & Dieckhaus, L. A. (2021, Fall). MRI micro- and macrostructural biomarkers linked to nonpathological brain aging in macaques. In Society for Neuroscience.
• Bilgin, A., Do, L., Martin, P. A., Lockhart, E., Bernstein, A. S., Ugonna, C., Dieckhaus, L., Comrie, C., Hutchinson, E. B., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2021). Accelerating Diffusion Tensor Imaging of the Rat Brain using Deep Learning. In Annual Meeting of the International Society for Magnetic Resonance in Medicine.
• Burkhart, J. C., Takamatsu, C., Gray, D. T., & Barnes, C. A. (2015).

  Understanding the Biological Basis of Cognitive Aging: The Role of Inhibitory Interneurons

  . In repository.arizona.edu.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Alzheimer's disease is not "brain aging": neuropathological, genetic, and epidemiological human studies.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Common Kibra alleles are associated with human memory performance.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Dynamics of the hippocampal ensemble code for space.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Imaging hippocampal function across the human life span: is memory decline normal or not?. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of KIBRA gene variants are associated with episodic memory in healthy elderly.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Survival after 100 years of age: a multivariate model of exceptional survival in Swedish centenarians.. In NA.
• Barnes, C. A. (2011). Faculty Opinions recommendation of Synaptic enhancement in fascia dentata: cooperativity among coactive afferents.. In NA.
• Mcnaughton, B. L., Terrazas, A., Barnes, C. A., & Battaglia, F. P. (2004).

  An hypothesis on the origin of variable spatial scaling along the septo-temporal axis of the rodent hippocampus

  . In 2004 IEEE International Joint Conference on Neural Networks (IEEE Cat. No.04CH37541), 1, 643-645.
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  The spatial scaling of place specific activity in the rodent hippocampus varies systematically from the septal pole (high spatial resolution) to the temporal pole (low spatial resolution). In principle, this variable scaling permits the read-out of spatial proximity relationships from spatial population vector correlations over much larger spaces than would be possible from a fixed scale encoding scheme such as might be inferred from the majority of in vivo hippocampal recordings, which have been conducted only in the septal portion of the hippocampus. Decoupling movement in space from ambulatory motion, by having the animal activate and ride on a mobile platform, results in marked attenuation of the amplitude of the local theta rhythm and a corresponding enlargement of the spatial scale factor in the dorsal hippocampus. These results lead to the hypothesis that the self-motion signal is embodied in the theta rhythm, whose gain may vary systematically along the septo-temporal axis of the hippocampus.

Presentations

• Barnes, C. A. (2020, February). Memory and the Aging Brain (Invited Keynote Address). 11th Annual Emerging Scientist Symposium, University of California. Irvine, CA.
• Barnes, C. A. (2020, January). Aging, Memory, and the Brain.. Tulane Brain Institute Distinguished Lecture. New Orleans, LA: Tulane University.
• Barnes, C. A. (2019, April). Impact of age on neural circuits critical to memory. The Cold Spring Harbor-Asia Francis Crick Symposium Transforming Neurosciences: Questions & Experiments. Suzhou Dushu Lake Conference Center, Suzhou, China.
• Barnes, C. A. (2019, April). Memory and the Aging Brain. New Member Research Briefings, Class II - National Academy of Sciences.
• Barnes, C. A. (2019, April). Neurobiological correlates of aging memory.. International Conference on Learning and Memory. Huntington Beach, CA.
• Barnes, C. A. (2019, February). Session Lead: Immediate Early Genes, Arc and Beyond in Health and Disease. Winter Conference on Neural Plasticity 2019. Moorea, French Polynesia.
• Barnes, C. A. (2019, January). Age-related cognitive decline in rodents and monkeys.. Arthur M. Sackler Colloquia of the National Academy of Sciences – Using Monkey Models to Understand and Treat Human Brain Disorders. Arnold and Mabel Beckman Center, Irvine, CA: National Academy of Sciences.
• Barnes, C. A. (2019, January). Aging cognition across species.. 2019 Dallas Aging and Cognition Conference. Center for Longevity: Dallas, TX.
• Barnes, C. A. (2019, June). Behavioral consequences in brain aging (Keynote Address). International Behavioral Neuroscience 27th Annual Meeting. Cairns, Australia.
• Barnes, C. A. (2019, March). Impact of age on neural circuits critical to memory.. HKIAS Symposium on Advances in Neuroscience. Hong Kong, China: City University of Hong Kong.
• Barnes, C. A. (2019, May). Memory and the Aging Brain. Annual Scientific Meeting of the European Society for Clinical Investigation (ESCI 2019). Coimbra Portugal: European Society for Clinical Investigation.
• Barnes, C. A. (2019, September). Life trajectories for successful aging: evidence from animal models of aging.. Life Trajectories and Interventions that Support Successful Neurocognitive Aging Meeting. Montreal Neurological Institute, McGill University, Montreal, Canada.
• Barnes, C. A. (2018, February). Normal brain aging: Impact on circuits critical for memory.. Georgia Tech Neuro Seminar Series. Atlanta, GA: Georgia Tech University.
• Barnes, C. A. (2018, June). Interrogating the navigation circuit: Many paths to the final destination.. Medial Temporal Lobe Computations Session - 2nd Interdisciplinary Navigation Symposium. Quarter Tremblant, Canada: Interdisciplinary Navigation Symposium.
• Barnes, C. A. (2018, June). Memory and the Aging Brain.. Museum of Contemporary Art. Tucson, AZ: Museum of Contemporary Art.
• Barnes, C. A. (2018, March). Neural mechanisms of age-dependent memory loss: Depends on where you look.. Hebb Lecture - Dalhousie University. Halifax, Nova Scotia: Dalhousie University.
• Barnes, C. A. (2018, May). Age-related changes in memory across species: Brain circuit specificity.. UC Davis Perspectives in Neuroscience Seminar Series - Center for Neuroscience. University of California @ Davis, Davis, CA: University of California @ Davis.
• Barnes, C. A. (2018, November). Spatial cognition in animal models of aging.. DZNE Interdisciplinary Symposium on Spatial Cognition in Aging & Neurodegeneration (ISCAN). Magdeburg, Germany: DZNE.
• Barnes, C. A. (2018, September). Normal lifespan changes in brain circuits critical for memory. Aging of Memory Functions: Where are we Now?. International Bordeaux Neurocampus Conferences. Bordeaux, France: University of Bordeaux.
• Barnes, C. A. (2017, April). Animal models of brain adaptation and compensation in aging. Cognitive Aging Summit III. Bethesda, MD: National Institute on Aging.
• Barnes, C. A. (2017, April). Behavioral Models of Age-related Cognitive Decline Session: Cross-species decline in cognition with aging: why don’t mammals other than humans spontaneously get Alzheimer’s disease. ASPET Annual Meeting at Experimental Biology 2017. Chicago, IL.
• Barnes, C. A. (2017, August). Neal Miller Distinguished Lecture: Temporal and frontal lobe correlates of memory decline in aging. American Psychological Association (APA) Convention. Washington, DC: American Psychological Association.
• Barnes, C. A. (2017, February). Aging is not a disease: Normal lifespan changes in brain circuits critical for memory. Distinguished Sackler Visiting Lecture, Collaborative Program in Neuroscience. Toronto, Ontario, Canada: University of Toronto.
• Barnes, C. A. (2017, February). An aging delimma: should I boost sustained or flexible attention. Winter Conference on Neural Plasticity. Grenada, Caribbean.
• Barnes, C. A. (2017, January). Impact of aging on neural circuits critical for memory. Graduate Program in Neuroscience Seminar Series. Seattle, WA: University of Washington.
• Barnes, C. A. (2017, June). Session Chair: Fixing memory: Interventions that target the hippocampus. Spring Hippocampal Research Conference. Taormina, Italy.
• Barnes, C. A. (2017, March). Brain circuit changes that contribute to age-related declines in cognition. Hagey Lecture. Waterloo, Canada: University of Waterloo.
• Barnes, C. A. (2017, March). Precision aging, how to keep your brain healthy as you age. UA Foundation Board of Trustees & National Leadership Council. UA Foundation, Tucson, AZ: University of Arizona.
• Barnes, C. A. (2017, March). The ‘youngfield’ of neuroscience: one senior scientists’ retrospective. Student Colloquium. Waterloo, Canada: University of Waterloo.
• Barnes, C. A. (2017, November). Beyond Place Cells (Minimsymposium): Temporal lobe activity in nonhuman primates: Locomotion versus restraint. Society for Neuroscience Annual Meeting. Washington, DC: Society for Neuroscience.
• Barnes, C. A. (2017, October). Aging neural circuits: Impact on cognition. Department of Psychology Quad-L Lecture. Albuquerque, NM: University of New Mexico.
• Barnes, C. A. (2017, October). Animal models of cognition and cognitive assessment. U13 Bedside-to-Bench Conference Series. Sensory Impairment and Cognitive Decline. Bethesda, MD: American Geriatric Socity.
• Barnes, C. A. (2017, September). Impact of age on neural circuits critical to memory. Bryan Kolb Lecture in Behavioral Neuroscience. University of Calgary, Calgary: Calgary, Alberta, Canada.
• Do, L., Bernstein, A., Bharadwaj, P. K., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2017, November). Advanced Techniques for Characterizing Rodent Brains with Diffusion MRI. Neuroscience 2017. Washington, DC: Society for Neuroscience.
• Barnes, C. A. (2016, April). Impact of aging on temporal lobe circuits critical for memory. Special Seminar, Kyoto University. Kyoto Japan.
• Barnes, C. A. (2016, April). Impact of normal aging on brain circuits critical for memory function. Special Seminar, Okinawa Institute. Okinawa, Japan.
• Barnes, C. A. (2016, August). Memory circuits in normal aging: excitability and adaptation. GRC on Mechanisms of Epilepsy and Neuronal Synchronization. Melia Golf Vichy Catalan Business and Convention Center, Girona, Spain.
• Barnes, C. A. (2016, February). Hippocampal cell activity in unrestrained nonhuman primates, session: Place cells across animal species. Winter Conference on Neural Plasticity. Maui, HI.
• Barnes, C. A. (2016, February). Impact of normal aging on circuits critical for memory. Neuroscience and Animal Behavior Graduate Program Lecture Series. Emory University, Atlanta, GA,.
• Barnes, C. A. (2016, January). Does the neural hardware in archicortex of birds, turtles, rats and monkeys perform similar computations?. Neuroscience Community Data Blitz. Museum of Contemporary Art, Tucson, AZ.
• Barnes, C. A. (2016, January). How does normal aging affect brain function and memory. Institute of Learning at Sun City Sampler Series. Catalina Visa Center in Sun City, Oro Valley, AZ.
• Barnes, C. A. (2016, July). Impact of aging on brain circuits critical for memory (Keynote address). 6th International Conference on Memory. Budapest, Hungary.
• Barnes, C. A. (2016, July). Impact of aging on circuits critical for normal memory function. John G. Nicholls Lecture, Neural Systems and Behavioral Course. Marine Biological Laboratory, Woods Hole, MA,.
• Barnes, C. A. (2016, June). Recent progress in recording from completely unrestrained primates. 1st Interdisciplinary Navigation Symposium. Bad Gastein, Austria.
• Barnes, C. A. (2016, March). Aging is not a disease: normal lifespan changes in brain circuits critical for memory. William G. Lutte Lectureship in Neuroscience. University of Florida, Gainesville, FL,.
• Barnes, C. A. (2016, March). Cognition/Perception: Primate work on normative brain and cognitive aging. International Future Primate Neuroscience Symposium, Shenzhen Institute of Advanced Technology. Shenzhen, China.
• Barnes, C. A. (2016, May). Impact of aging on brain circuits critical for memory. Stanford Neuroscience Institute Seminar Series. Stanford University, Los Angeles, CA.
• Barnes, C. A. (2016, May). Normative brain aging: Why does it result in memory impairments?. Neuroscience Research Colloquia. University of British Columbia, Vancouver, Canada.
• Lukas, R., Fulton, G. W., Wesslehoft, M., & Barnes, C. A. (2016, September). (Panel Discussion), Beyond Alzheimer’s. Cavendish Health Impact Forum sponsored by Arizona Bioscience Community. Phoenix, AZ.
• Barnes, C. A. (2015, April). Impact of aging on neural circuits critical for memory. UT Austin Conference on Learning and Memory. Austin, TX: University of Austin.
• Barnes, C. A. (2015, April). Normal aging; what is the impact on the brain and memory?. UA Science Lecture Series. Ventana Canyon Golf and Racquet Club, Tucson, AZ: University of Arizona.
• Barnes, C. A. (2015, February). Normal aging: what is the impact on the brain and on memory?. Special Education Lecture. Yuma, AZ: Yuma Friends of the University of Arizona Health Sciences.
• Barnes, C. A. (2015, January). Learning and Memory in Aging. Yale Club Luncheon. Arizona Inn, Tucson, AZ: The Yale Club of Southern Arizona.
• Barnes, C. A. (2015, June). Extent of remapping due to context change differs along the CA1 proximo-distal axis. Functional specialization along the transverse axis of the hippocampus session. Spring Hippocampal Research Conference. Taormino, Sicily.
• Barnes, C. A. (2015, June). Session Leader: Temporal lobe contributions to representations in memory Session. Spring Hippocampal Research Conference. Taormino, Sicily.
• Barnes, C. A. (2015, March). Normal brain aging: Impact of circuits and memory. Cheves Smythe Distinguished Lecture Speake. Houston, TX: UT Health Medical School.
• Barnes, C. A. (2015, May). Impact of aging on brain circuits and behavior. Advances in Neural Systems Conference, Center for Learning, Memory and Emotion. New York, NY: New York University.
• Barnes, C. A. (2015, November). Impact of aging on brain circuits critical for normal memory function. Barrow Neurological Institute Neuroscience Conference. Phoenix, AZ: Barrow Neurological Institute.
• Barnes, C. A. (2015, October). Memory and the aging brain. Cognitive Sciences Working Group Meeting. Deerfield, IL: Takeda Pharmaceuticals.
• Barnes, C. A. (2015, October). Memory and the aging brain. WiseGuise II Lunch Group. Scottsdale, AZ.
• Barnes, C. A. (2015, September). Normal brain aging: Impact on circuits critical for memory. Neuroscience Graduate Program Distinguished Speaker Series. Los Angeles, CA: University of Southern California.
• Barnes, C. A. (2014, April). Impact on circuits for memory across species. 2014 Picower Institute Lecture. Cambridge, MA: Picower Institute for Learning and Memory, MIT.
• Barnes, C. A. (2014, August). Memory and the Aging Brain. Arizona Now Campaign. , La Jolla Country Club, La Jolla, CA.
• Barnes, C. A. (2014, August). Memory and the Aging Brain. Arizona Now Campaign. 21 Oceanfront Restaurant, Newport Beach, CA,.
• Barnes, C. A. (2014, August). Temporal lobe correlates of memory decline in normal aging. 2014 APA Annual Convention. Washington, DC.
• Barnes, C. A. (2014, February). Are the functionally important changes in aging specific to white matter alterations?. White Matter Meeting: Everything You Need and Want to Know about White Matter. Trondheim, Norway: Norwegian Institute of Science and Technology.
• Barnes, C. A. (2014, February). Hippocampal state: contributes from motor and sensor inputs. Session entitled Neural signals for memory in the primate medical temporal lobe. Winter Conference on Neural Plasticity. Vieques Island, Caribbean.
• Barnes, C. A. (2014, January). Memory and the aging brain. Keynote Speaker, Cognitive Aging Symposium. Nijmegan, The Netherlands: Donders Institute.
• Barnes, C. A. (2014, January). The aging brain: Keeping neurons healthy and active. Canyon Ranch Social Center. Green Valley, AZ.
• Barnes, C. A. (2014, January). The aging brain: Keeping neurons healthy and active. Pima Council on Aging Speaker Series. Canoa Hills Social Center, Green Valley, AZ.
• Barnes, C. A. (2014, July). Cognitive Circuitry Session Discussion Leader. Gordon Research Conference on Neurobiology of Cognition. Newry, ME.
• Barnes, C. A. (2014, July). Information processing and behavioral changes during aging. Gordon Research Conference on Neurobiology of Brain Disorders. Girona, Spain.
• Barnes, C. A. (2014, May). Ideas from animal models for effective human therapeutic targets. Scripps Spring Workshop on the Biology of Aging “Therapeutic Approaches for Extensing Healthspan: The Next 10 Years”. Jupiter, FL.
• Barnes, C. A. (2014, September). Aging and the Normal Brain. Congressional Biomedical Research Caucus.. Washington, DC: Sponsored by Coalition of Life Sciences.
• Barnes, C. A. (2013, August). Keynote Address: Related Changes in Brain Plasticity: Principles Derived from Medial Temporal Lobe Memory and Perceptual Systems – Are They Relevant for Understanding the Auditory System. NIA Workshop on Auditory Plasticity and Aging. Bethesda, MD.
• Barnes, C. A. (2013, December). Keynote Address: Effects of aging on brain circuits and behavior. Annual UA-ASU Cognitive Science Conclave. Tucsoon, AZ.
• Barnes, C. A. (2013, January). Closing the healthspan/lifespan gap: Scientific contributions from UA faculty. Annual Conference on Successful Aging. , University of Arizona, Tucson, AZ.
• Barnes, C. A. (2013, January). Memory and the aging brain. Canyon Ranch Brain Camp: An Integrative Approach to Brain & Body Wellness. Canyon Ranch, Tucson, AZ.
• Barnes, C. A. (2013, May). Keynote Address: Neural circuits that contribute to age-related cognitive decline. 2013 meeting of The Milwaukee Chapter of the Society for Neuroscience. Mikwaukee, WS.
• Barnes, C. A. (2013, November). Cognitive again across species. Brain, Cognition, and Genetics in Healthy Aging Symposium, 2013 Annual Meeting of the Society for Neuroscience. San Diego.
• Barnes, C. A. (2013, November). Effects of aging on behavior and temporal lobe circuits. Neuroscience Seminar Series, Pfizer Inc.,. Cambridge, MA.
• Barnes, C. A. (2013, November). Keynote Address: The evolving face of neuroscience: Role of women and globalization. Celebration of Women in Neuroscience Symposium, 2013 Annual Meeting of the Society for Neuroscience,. San Diego, CA.
• Barnes, C. A. (2013, September). Normal brain aging: Impact on circuits critical for memory. Institute of Science and Technology Colloquium Series. Klosterneuburg, Austria.
• Barnes, C. A. (2013, September). Some unexpected findings, and new approach. Systems Neuroscience lab meeting. Klosterneuburg, Austria.
• Barnes, C. A. (2014, January). From aging rats to aging monkeys: New finding, new approaches, Centre for Biology of Memory. Kavli Institute Seminar Series. Norwegian University of Science and Technology, Trondheim, Norway.
• Barnes, C. A. (2015, February). Hippocampal state: Contributions from motor and sensory inputs. Twenty-fifth Winter Conference on Neural Plasticity. Curacao, Netherland Antilles.

Poster Presentations

• Bilgin, A., Do, L., Martin, P., Lockhart, E., Bernstein, A. S., Ugonna, C., Diekhaus, L., Comrie, C., Hutchinson, E., Chen, N., Alexander, G., Barnes, C. A., & Trouard, . (2021, May). Accelerating Diffusion Tensor Imaging of the Rat Brain using Deep Learning.. International Society for Magnetic Resonance in Medicine Annual Meeting. Vancouver, BC, Canada.
• Crown, L. M., Gray, D. T., Schimanski, L. A., Barnes, C. A., & Cowen, S. L. (2021, January). Decreased dynamic range of hippocampal CA1 gamma in aged rats.. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Crown, L., Gray, D. T., Schimanski, L. A., Barnes, C. A., & Cowen, S. L. (2019, October). Spatial eye-blink learning but not age predicts theta-gamma coupling in the CA1 region of the hippocampus. Program No. 600.09. Neuroscience 2019. Chicago, IL: Society for Neuroscience.
• Do, L., Zempare, M. A., Bernstein, A. S., Bharadwaj, P., Ugonna, C., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. (2021, January). Quantitative and Volumetric and Diffusion Weighted MRI Analysis of Rodent Brains as a Function of Age and Cognition. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Gray, D. T., De la Peña, N. M., Umapathy, L., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2021, January). Auditory and visual system function and white matter condition is differentially impacted by normative aging in macaques.. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Khattab, S. O., Gray, D. T., McDermott, K., Sinakevitch, I., Schwyhart, R., Smith, A. C., Härtig, W., & Barnes, C. A. (2021, January). The relationship between microglia density and age-associated perineuronal net alterations in the retrosplenial cortex of rhesus macaques. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• McDermott, K., Sinakevitch, I., Gray, D. T., Khattab, S., Pyon, W. S., & Barnes, C. A. (2021, January). Age-associated alterations in locus coeruleus neuronal, glial cell, and vascular elements in cognitively assessed aged macaque monkeys.. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Sinakevitch, I., Deer, C., McDermott, K., Khattab, S., Gray, D. T., & Barnes, C. A. (2021, January). A 3D interactive representation of Locus Coeruleus nucleus morphology in aged macaque monkeys.. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Young, K. F., Zempare, M. A., Dalmendray, A. L., Gregolynskyi, A., Chawla, M. K., Guzowski, J. F., & Barnes, C. A. (2021, January). Effects of chronic, high-dose minocycline treatment on cognitive performance in aging rats.. SfN Global Connectome: A Virtual Event. Online: Society for Neuroscience.
• Do, L., Bernstein, A. S., Bharadwaj, P., Ugonna, C., Zempare, M. A., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. (2020, April). Quantitative MRI volumetric analysis of rodent brains as a function of age. ISMRM 28th Annual Meeting & Exhibition. Sydney, Australia.
• Barnes, C. A., & Pyon, W. (2019, October). Quantification of neuronal and astrocytic cells in the locus coeruleus of cognitively assessed, young and aged nonhuman primates, Program No. 600.10. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Barnes, C. A., Ekstrom, A. D., Vogt, J., Permenter, M., Meltzer, J., Stokes, J., & Kyle, C. (2019, November). Convolutional neural networks for fast and accurate 3D reconstruction of histological sections. Society for Neuroscience. Chicago, IL.
• Chawla, M. K., Zempare, M., Hruby, V., Barnes, C. A., & Cai, M. (2019, October). Age-related, specific changes in expression of several central melanocortin receptor subtypes in the rat. Program No. 600.15. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Eck, R., Chawla, M. K., Bagevalu Siddegowda, B., Carey, N. J., Zempare, M., Nguyen, C., Billheimer, D., Barnes, C. A., & Zarnescu, D. C. (2019, October). RNA stress granule components are dynamically expressed during aging and stress conditions in rats and fruit flies, Program No. 600.17. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Gray, D. T., Pyon, W., De la Pena, N. M., Schwyhart, R., Wallace, E., Puchta, J., Hartig, W., & Barnes, C. A. (2019, October). Perineuronal nets in the cerebral cortex of cognitively-assessed aged macaque monkeys. Program No. 600.11. 2019. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Gray, D. T., Umapathy, L., De la Pena, N. M., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2019, September). Auditory processing deficits are selectively associated with medial temporal lobe mnemonic function and white matter integrity in aging macaques. Arizona Postdoctoral Research Conference. University of Arizona, Phoenix Campus, Phoenix, AZ.
• Han, E., Schimanski, L. A., Ali, K., Barnes, C. A., & Tatsuno, M. (2019, August). Detection of hippocampal cell assemblies while rats learn a place-dependent eyeblink conditioning task.. Undergraduate Neuroscience Symposium. University of Alberta.
• Kyle, C., Stokes, J., Meltzer, J., Permenter, M. R., Vogt, J. A., Ekstrom, A. D., & Barnes, C. A. (2019, October). Estimation of non-rigid warps during 3D serial-section histology reconstruction optimization increases accuracy. Program No. 600.12. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Lester, A. W., Kapellusch, A. J., & Barnes, C. A. (2019, October). A computational model of aged head direction network updating in the presence of sudden spatial cue mismatch, Program No. 600.16. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Pyon, W., Gray, D. T., Schwyhart, R., Wallace, E., Pena, N. M., & Barnes, C. A. (2019, October). Quantification of neuronal and astrocytic cells in the locus coeruleus of cognitively assessed, young and aged nonhuman primates. Program No. 600.10. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Srivathsa, S. V., Khattab, S. O., Lester, A. W., & Barnes, C. A. (2019, October). Role of prefrontal-hippocampal interactions in age-related deficits in spatial working memory. Program No. 600.08. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Talboom, J. S., Haberg, A. K., De Both, M. D., Naymik, M. A., Schrauwen, I., Lewis, C. R., Siniard, A. L., Bertinelli, S. F., Hammersland, C., Myers, A. J., Hay, M., Barnes, C. A., Glisky, E., Ryan, L., & Huentelman, M. J. (2019, October). Physiological and Cognitive Factors Associated with Health Aging. Program No. 793.03. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Terrazas, A., Pyon, W., Zempare, M., Young, K. F., Dalmendray, A., Do, L., David, B., Bohne, K. M., Carey, N. J., Chawla, M. K., Trouard, T. P., Worley, P. F., & Barnes, C. A. (2019, October). Effects of NPTX2 knockout on behavior, brain volume by MRI and CA1 hippocampal single unit properties. Program No. 600.14. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Zempare, M., Carey, N. J., Dalmendray, A., Young, K. F., Bohne, K. M., Do, L., Trouard, T. P., Mitchell, K. D., Chawla, M. K., Huentelman, M. J., & Barnes, C. A. (2019, October). Effects of induced hypertension in middle aged CYP1A1-REN2 transgenic rats, Program No. 600.13. Neuroscience 2019 - Online. Chicago, IL: Society for Neuroscience.
• Barnes, C. A., Pyon, W., Gray, D. T., & Ashford, S. (2018, November). A direct comparison of dye- and imaging-based removal of lipofuscin-induced autofluorescence from primate brain tissue. Program No. 245.04. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Bleul, C., Chawla, M. K., DeBoth, M. D., Barnes, C. A., & Huentelman, M. J. (2018, November). Specificity of activity-regulated transcript localization in somatic and dendritic neuronal compartments. Program No. 245.09. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Carey, N. J., Zempare, M. A., Nguyen, C. J., Bohne, K. M., Chawla, M. K., Sinari, S., Huentelman, M. J., Billheimer, D., & Barnes, C. A. (2018, November). Age-dependent correlation between spatial and working memory does not extend to object recognition. Program No. 245.05. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Comrie, A. E., Lister, J. P., Chawla, M. K., & Barnes, C. A. (2018, April). Sparser representation of experience with age in rat entorhinal cortex. 2018 International Conference on Learning and Memory, Irvine. Irvine, CA: University of California, Irvine.
• Comrie, A., Lister, J. P., Chawla, M. K., & Barnes, C. A. (2018, November). Lateral but not medial entohinal cortex population representation become more sparse with age. Program No. 245.08. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• De La Pena, N. M., Gray, D. T., Umapathy, L., Burke, S. N., Trouard, T. P., & Barnes, C. A. (2018, November). Tract-Specific White Matter Correlates of Age-Related Reward Devaluation Deficits in Macaque Monkeys. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
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  Cognitive aging is known to alter reward-guided behaviors that require interactions between the orbitofrontal cortex (OFC) and amygdala. In macaques, OFC, but not amygdala volumes decline with age and correlate with performance on a reward devaluation (RD) task. The present study used diffusion magnetic resonance imaging (dMRI) methods to investigate whether the condition of the white matter associated with amygdala-OFC connectivity changes with age and relates to reward devaluation.
• De La Pena, N., Gray, D. T., Barnes, C. A., & Pyon, W. (2018, January). Tyrosine Hydroxylase and Calcium Binding Protein Expression in the Noradrenergic System of Aged Primates. Twenty-eighth Undergraduate Biology Research Program Conference. Tucson, AZ: University of Arizona.
• Eck, R. J., Chawla, M. K., Siddegowda, B., Carey, N. J., Zempare, M. A., Nguyen, C. J., Barnes, C. A., & Zarnescu, D. C. (2018, November). Dynamic expression of RNA stress granule components in behaviorally characterized young, middle aged and old rats. Program No. 245.07. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Gray, D. T., Burke, S. N., Engle, J. R., Umapathy, L., Trouard, T. P., & Barnes, C. A. (2018, November). Thalamocortical white-matter integrity and the relationship between auditory function and cognitive decline in aged macaque monkeys. Program No. 245.03. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Lester, A. W., Blum, C. J., Kappellusch, A. J., & Barnes, C. A. (2018, November). Aged-related impairments in spatial reference frame updating. Program No. 245.06. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Terrazas, A., Zempare, M., Carey, N. J., Bohne, K. M., Do, L., Trouard, T. P., Worley, P. F., & Barnes, C. A. (2018, November). NPTX2 knockout rats: A novel model for protection of synaptic function in aging and disease. Program No. 245.10. Neuroscience 2018. San Diego, CA: Society for Neuroscience.
• Annadurai, A., Corenblum, M. J., Ray, S., Kirwan, K., Reed, A., Barnes, C. A., & Madhavan, L. (2017, November). Enhanced Nrf2 expression improves neural stem cell function during a critical aging period. Program No. 459.08. Washington, DC: Society for Neuroscience.
• Bagevalu Sidddegowda, B., Chawla, M. K., Yao, S., Barnes, C. A., & Zarnescu, D. C. (2017, November). Dynamic expression of RNA stress granule components in aging brains: From flies to rats. Program No. 712.17. Washington, DC: Society for Neuroscience.
• Bagevalu Siddegowda, B., Chawla, M. K., Yao, S., Barnes, C. A., & Zarnescu, D. C. (2017, November). Dynamic expression of RNA stress granule components in aging brains: From flies to rats. Program No. 712.17. Washington, DC: Society for Neuroscience.
• Carey, N. J., Zempare, M. A., Nguyen, C. J., Bohne, K. M., Chawla, M. K., Sinari, S., Huentelman, M. J., Billheimer, D., & Barnes, C. A. (2017, November). Dissociation of performance in hippocampus- and prefrontal cortical-dependent tasks in aging fisher 344 rats. Program No. 712.18. Washington, DC.
• Chawla, M. K., Zhou, Y., Wang, L., Carey, N. J., Zempare, M. A., Nguyen, C. J., Hruby, V. J., & Barnes, C. A. (2017, November). Brain region-specific changes in melanocortin receptor expression in aged rat brain. Program No. 712.16. Washington, DC: Society for Neuroscience.
• Comrie, A., Lister, J. P., Chawla, M. K., & Barnes, C. A. (2017, November). Sparser representation of experience by aged rat Lateral Entorhinal Cortex. Program No. 712.14. 2017. Washington, DC: Society for Neuroscience.
• Cowen, S. L., Gray, D. T., Weigand, J., Schimanski, L. A., & Barnes, C. A. (2017, November). Age-associated changes in awake hippocampal sharp-wave ripples during spatial eyeblink conditioning. Program No. 712.21. Washington, DC: Society for Neuroscience.
• Do, L., Trouard, T. P., Bharadwaj, P., Barnes, C. A., Bernstein, A., Alexander, G. E., Xiao, J., Xiao, J., Bernstein, A., Alexander, G. E., Bharadwaj, P., Barnes, C. A., Do, L., & Trouard, T. P. (2017, May). Bias Correction Method Improves Automatic Brain Extraction in Rodent MR Imaging. Arizona Alzheimer's Consortium Scientific MeetingArizona Alzheimer's Consortium.
• Gray, D. T., Smith, A. C., Burke, S. N., & Barnes, C. A. (2017, November). The alpha-2 noradrenergic receptor agonist guanfacine impairs flexible attention in young and aged macaques. Program No. 712.12. 2017 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience.
• Kapellusch, A. J., Lester, A. W., Schwartz, B. A., Brewster, J. R., & Barnes, C. A. (2017, November). Deficits in aged rats on the W-track continuous spatial alternation task suggest impaired hippocampal-prefrontal interactions. Program No. 712.19. Washington, DC: Society for Neuroscience.
• Kyle, C., Smith, A. C., Gray, D. T., Burke, S. N., & Barnes, C. A. (2017, November). Temporal contiguity predicts reward association learning in bonnet macaques. Program No. 712.10. 2017 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience.
• Malem-Shinitski, N., Gray, D. T., Burke, S. N., Smith, A., Barnes, C. A., & Ba, D. (2017, November). A separable state-space model of learning across trials and days in an aging study in macaque monkeys. Program No. 712.11. 2017 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience.
• Pyon, W., Gray, D. T., Chawla, M. K., & Barnes, C. A. (2017, November). An alternative to dye-based approaches to remove lipofuscin-induced background autofluorescence from primate brain tissue. Program No. 712.13. 2017 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience.
• Samson, R. D., Duarte, L., & Barnes, C. A. (2017, November). Preserved overall basal firing rates in aged rat basolateral complex of the amygdala, but neurons from aged rats are more engaged in anticipation of rewards compared to young rats. Program No. 712.20. Washington, DC: Society for Neuroscience.
• Shinitski, N. M., Zhang, Y., Gray, D. T., Burke, S. N., Barnes, C. A., & Demba, B. (2017, February). Can you teach an old monkey a new trick?. Computational and Systems Neuroscience (Cosyne). Salt Lake City, UT.
• Somasundar, V., Padmanabhan, R., Roysam, R., & Barnes, C. A. (2017, November). Semi-automated layer classification tool for defining cortical architecture. Program No. 712.15. Washington, DC: Society for Neuroscience.
• Andersh, K. M., Gray, D. T., Smith, A. C., Burke, S. N., Gazzaley, A., & Barnes, C. A. (2016, November). Age-related attentional control and set shifting impairments arise independently in macaque monkeys. Program No. 182.14. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Andersh, K., Gray, D. T., & Barnes, C. A. (2016, January). Age-related reversal learning impairment in bonnet macaques. Twenty-seventh Annual Undergraduate Biology Research Program. Tucson, AZ.
• Bleul, C., Chawla, M. K., Carey, N. J., Siniard, A. L., DeBoth, M. D., Barnes, C. A., & Huentelman, M. J. (2016, November). Activity regulated transcript identification in the hippocampus and the genetic association with AD risk. Program No. 182.07. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Chawla, M. K., Nguyen, C., Sadacher, G. S., Gray, D. T., Huentelman, M. J., & Barnes, C. A. (2016, November). Arc mRNA induction thresholds following electro-convulsive shock treatment may be regulated by dendritic Ca++ plateau potentials. Program No. 182.08. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Comrie, A. E., Gray, D. T., Burke, S. N., Smith, A. C., & Barnes, C. A. (2016, April). Different monkey models of human cognitive aging exhibit disparities in learning and performance of memory tasks. 20th Annual Posters on the Hill. Washington, DC.
• Comrie, A. E., Lister, J. P., Chawla, M. K., & Barnes, C. A. (2016, January). Effects of age and odors on neuronal population activity in rat lateral entorhinal cortex during track-running behavior. Twenty-seventh Annual Undergraduate Biology Research Program. Tucson, AZ.
• Comrie, A. E., Lister, J. P., Chawla, M. K., & Barnes, C. A. (2016, November). Activation of neuronal populations in young and aged rat Lateral Entorhinal Cortex during track-running behavior with odors. Program No. 182.09. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Corenblum, M. J., Ray, S., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2016, February). A novel role of Nrf2 in the age-related decline in neural stem cell function. Stem Cell Models of Neural Regeneration and Disease. Dresden, Germany.
• Corenblum, M. J., Ray, S., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2016, November). An analysis of nrf2 expression and its effects on aging hippocampal neural stem cell function. Program No. 177.17. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• DeBoth, M., Ianov, L., Chawla, M. K., Rani, A., Kennedy, A. J., Piras, I., Day, J. J., Sinaird, A. L., Kumar, A., Sweatt, J. D., Foster, T. C., Barnes, C. A., & Huentelman, M. J. (2016, November). Transcriptional differences among hippocampal subregions. Program No. 182.06. 2016 Neuroscience Meeting Planne. San Diego, CA: Society for Neuroscience.
• Gilliland, A. G., Chawla, M. K., & Barnes, C. A. (2016, January). Classification of cognitive aptitudes using the Morris swim task during the entire rodent life span. Twenty-seventh Annual Undergraduate Biology Research Program. Tucson, AZ.
• Gray, D. T., Wiegand, J. P., Schimanski, L. A., Cowen, S. L., & Barnes, C. A. (2016, November). Age-related reduction in signal-to-noise ratio of sharp-wave ripple oscillations following behavior in aged rats. Program No. 182.11. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Ianov, L., DeBoth, M. D., Chawla, M. K., Rani, A., Kennedy, A. J., Piras, I., Day, J. J., Siniard, A. L., Kumar, A., Sweatt, J. D., Barnes, C. A., Huentelman, M., & Foster, T. C. (2016, November). Transcriptomic profile for determining regional vulnerability to age and cognitive impairment. Program No. 182.05. 2016 Neuroscience Meeting Planner. San Diego, CA:: Society for Neuroscience.
• Kyle, C. T., Bennett, J. L., Stokes, J. D., Permenter, M. R., Vogt, J. A., Ekstrom, A. D., & Barnes, C. A. (2016, November). Histology informed probabilistic hippocampal atlases of young and old rhesus macaques. Program No. 182.16. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Kyle, C., Stokes, J., Meltzer, J., Permenter, M. R., Vogt, J. A., Eckstrom, A. D., & Barnes, C. A. (2017, November). Convolutional neural networks for fast and accurate 3D reconstruction of histological sections. Program No. 245.01. Neuroscience 2017. Washington, DC: Society for Neuroscience.
• Lester, A. W., Kapellusch, A. J., Screen, R. T., & Barnes, C. A. (2016, November). Aged rats fail to integrate conflicting spatial reference frames. Program No. 182.10. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Madhavan, L., Corenblum, M. J., Ray, S., Long, M., Harder, B., Zhang, D. D., & Barnes, C. A. (2016, November). Targeting the Nrf2 pathway to improve neural stem cell function. Program No. 198.07. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Nguyen, M., Chawla, M. K., & Barnes, C. A. (2016, April). Arc fluorescence in situ hybridization in cleared whole brains utilizing hybridization chain reaction amplification. American Society for Biochemistry and Molecular Biology 2016 Annual Meeting. San Diego, CA.
• Nguyen, M., Chawla, M. K., & Barnes, C. A. (2016, January). Visualization of neurokinin B neurons in cleared whole brains. Twenty-seventh Annual Undergraduate Biology Research Program. University of Arizona.
• Pyon, W., Gray, D. T., Andersh, K. M., Permenter, M. R., Vogt, J. A., & Barnes, C. A. (2016, November). Cell counts of midbrain dopamine neurons in memory-impaired aged non-human primates. Program No. 182.15. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Samson, R. D., Duarte, L., & Barnes, C. A. (2016, November). Expectation of large rewards elicits bursts of beta-band oscillations in the aged rat amygdala. Program No. 182.12. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Umapathy, L., Gray, C. T., Burke, S. N., Trouard, T. P., & Barnes, C. A. (2016, November). Uncinate fasciculus integrity assessed in young and aged bonnet macaques. Program No. 182.13. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience.
• Wang, C., Pacheco, S., Baggett, B., Chawla, M., Gray, D., Utzinger, U., Barnes, C., Barnes, C. A., & Liang, R. (2016, April). Whole brain imaging with a scalable microscope, Clinical and Translational Biophotonics Conference. Clinical and Translational Biophotonics Conference. Ft. Lauderdale, FL.
• Andersh, K., Gray, D. T., & Barnes, C. A. (2015, November). Age-related reversal learning impairments in bonnet macaques. Annual Biomedical Research Conference for Minority Students. Seattle, WA.
• Bharadwaj, P. K., Burke, S. N., Trouard, T. P., Chen, K., Moeller, J. R., Barnes, C. A., & Alexander, G. E. (2015, October). Age-associated regional network pattern of MRI gray matter in the bonnet macaque. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Chance, F. S., Maurer, A. P., Burke, S. N., & Barnes, C. A. (2015, July). Different weightings of input components to hippocampal CA1 place cells in young and aged rats. 24th Annual Computational Neuroscience Meeting. Prague, Czech Republic.
• Chawla, M. K., Gray, D. T., Huentelman, <. K., & Barnes, C. A. (2015, October). Is Arc mRNA expression regulated by the threshold for dendritic Ca++ plateau potentials generated from integration of entorhinal cortical inputs to granule cells?. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Comrie, A. E., Chawla, M. K., Gray, D. T., Baggett, B. K., Utzinger, U., & Barnes, C. A. (2015, January). Novel methods for behavior-driven molecular and structural investigation in rodent whole brain. Twenty-sixth Annual Undergraduate Biology Research Program. Tucson, AZ: UBRP.
• Comrie, A., Gray, D. T., Burke, S. N., Smith, A. C., & Barnes, C. A. (2015, October). Species- and aged-related differences in learning and performance on working memory tasks in two species of macaque monkeys. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2015, January). A novel role for nrf2 in neural stem cell function during aging. The Keap1/Nrf2 Pathway in Health Disease Conference. Cambridge, UK: Biochemical Society.
• Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2015, June). A role for Nrf2 in neural stem cell function during aging. International Society for Stem Cell Research 2015 Annual Meetin. Stockholm, Sweden.
• Duarte, L., Samson, R. D., & Barnes, C. A. (2015, October). Enhanced beta band activity in the aged amygdala during probabilistic decision making. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Gray, D. T., Ashford, S. L., Pyon, W., Burke, S. N., Smith, A. C., & Barnes, C. A. (2015, October). Behavioral evidence for enhanced interference during working memory and associative learning tasks in aged macaques. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Koutia, A. J., Lester, A. W., & Barnes, C. A. (2015, January). Studying the effects of age on visual cue-based spatial navigation using a novel behavioral apparatus. Twenty-sixth Annual Undergraduate Biology Research Program. University of Arizona, Tucson: Undergraduate Biology Research Program.
• Kyle, C., Permenter, M. R., Vogt, J. A., & Barnes, C. A. (2015, October). Behavioral impact of long-term chronic implantation of neural recording devices in the rhesus macaque. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Lester, A. W., Koutia, A. J., & Barnes, C. A. (2015, October). Age-related changes in external cue-based navigation in the medial entorhinal-hippocampal network. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Liang, R., Wang, C., Pacheco, S., Baggett, B. K., Chawla, M. K., Gray, D. T., Utzinger, U., & Barnes, C. A. (2015, October). Understanding behavioral networks: A novel, scalable microscope designed to enable whole brain imaging of behavior-driven circuits with subcellular resolution. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Madhavan, L., Corenblum, M. J., Ray, S., Long, M., Harder, B., Zhang, D., & Barnes, C. A. (2015, October). A role for Nrf2 in neural stem cell function during aging. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Nguyen, M., Chawla, M. K., & Barnes, C. A. (2015, December). Visualization of neurokinin B neurons in cleared whole brains. The American Society for Cell Biology Annual Meeting. San Diego, CA..
• Samson, R. D., & Barnes, C. A. (2015, March). Age differences in strategy selection and risk preference during risk-based decision making. Decision Neuroscience and Aging Conference. Miami, FL.
• Samson, R. D., Duarte, L., & Barnes, C. A. (2015, October). Enhanced single unit firing to unexpected large rewards in aged amygdala neurons. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Takamatsu, C., Gray, D. T., Uprety, A. R., Espinoza, A. I., Koutia, A. K., Zavilla, A., Comrie, A. E., & Barnes, C. A. (2015, January). Understanding the role of inhibitory interneurons in cognitive aging. Twenty-sixth Annual Undergraduate Biology Research Program. University of Arizona, Tucson: Undergraduate Biology Research Program.
• Weigand, J. P., Gray, D. T., Schimanski, L. A., Lipa, P., Barnes, C. A., & Cowen, S. L. (2015, October). Time-dependent decrease in the peak frequency and power of hippocampal sharp-wave ripples and high-gamma events during post-behavior sleep in aged and young rats. 2015 Annual Meeting of the Society for Neuroscience. Chicago, IL.
• Chawla, M. K., Gray, D. T., Comrie, A. E., Baggett, B. K., Utzinger, U., & Barnes, C. A. (2014, November). Novel method for behavior-driven molecular and structural investigation in rodent whole brain. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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• Corenblum, M. J., Ray, S., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2014, December). Nfe2l2 modulates neural stem cell function during aging. Stem Cell Energetics Symposium. Berkeley, CA.
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• Cowen, S. L., Wiegand, J., Gray, D. T., Schimanski, L. A., Lipa, P., & Barnes, C. A. (2014, November). Age-associated changes in spike-timing of hippocampal principal cells and interneurons during ripple oscillations. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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• Espinoza, A. I., Uprety, A. R., Lipa, P., Thorne, A., Hindley, T. R., & Barnes, C. A. (2014, January). Frontal cortical gamma frequency slowing in aging: Can C6 rescue cortical synchrony and decision speed?. Twenty-fifth Annual Undergraduate Biology Research Program.
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• Fakurnejad, S., Engle, J. R., Gray, D. T., Burke, S. N., Plange, K., Recanzone, G. H., & Barnes, C. A. (2014, April). Normal aging is associated with sensory impairments in non-human primates. Twenty-fifth Annual Undergraduate Research, Scholarship and Creative Activities Conference. University of California at Davis: Davis, CA.
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• Gray, D. T., Thome, A., Erickson, C. A., Lipa, P., Takamatsu, C. L., Comrie, A. E., & Barnes, C. A. (2014, November). Selective changes in inhibitory networks of the medical temporal lobe correlate with behavioral and electrophysiological deficits in aged rhesus macaques. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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• Han, P., Permenter, M. R., Vog, J. A., Engle, J. R., Barnes, C. A., & Shi, J. (2014, November). PACAP expression is downregulated in aged nonhuman primates. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Insel, N., & Barnes, C. A. (2014, July). Neuron population activity in the medial prefrontal cortex suggests superimposed codes for situation and situation value. Twenty-third Annual Computational Neuroscience Meeting. Quebec City, Canada.
• Miller, M. A., Mehravar, S., Gray, D. T., Koshy, A. A., Cabral, C. M., Chawla, M. K., Kieu, K. Q., Barnes, C. A., & Cowen, S. L. (2014, November). Non-linear optical imaging: A powerful new technique for acquiring high-resolution brain images and possible application for identifying cell types and neuronal activity. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Richards, A., Uprety, A. R., Alexander, G. E., Trouard, T. P., Mitchell, K. D., & Barnes, C. A. (2014, January). Cognitive and physiological changes that occur with gradual induction of hypertension in a Cyp1a1-Ren2 middle age transgenic rodent model. Twenty-fifth Annual Undergraduate Biology Research Program.
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  (Abstract)
• Samson, F. D., Lester, A. W., Lipa, P., & Barnes, C. A. (2014, November). Aging is associated with altered intrinsic neural dynamics in the basolateral complex of the amygdala. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Siniard, A. L., Schrauwen, I., Corneveaux, J. J., Peden, J., Turk, M. N., De Both, M. D., Richholt, R. F., Mueller, M., Langbaum, J., Reiman, E., Caselli, R., Coleman, P., Barnes, C., Glisky, E., Ryan, L., & Huentelman, M. J. (2014, November). The influence of demographic and disease risk factors on paired associates learning in an internet recruited cohort of over 29,000 individuals. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Uprety, A. R., Espinoza, A. I., Richards, A., Smith, A. C., & Barnes, C. A. (2014, November). Behavioral of normal aged rats mimics the pattern of task performance of rats with hippocampal lesions on a W-track continuous spatial alternation task. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Wiegand, J., Gray, D. T., Schimanski, L. A., Lipa, P., Barnes, C. A., & Cowen, S. L. (2014, November). Age-related changes in high-frequency local field activity in the rodent hippocampus during ripple and inter-ripple periods. 2014 Annual Meeting of the Society for Neuroscience. Washington, DC.
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  (Abstract)
• Burke, S. N., Maurer, A. P., Cowen, S. L., & Barnes, C. A. (2013, November). Perirhinal cortical interneurons exhibit reduced firing rate with advanced age. Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Change, F. S., Maurer, A. P., Burke, S. N., & Barnes, C. A. (2013, November). Dual input component models of CA1 activity in young and aged rats. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Chawla, M. K., Sedhadia, N., Olson, K., Alme, C. B., Moser, E. I., Moser, M. -., McNaughton, B. L., & Barnes, C. A. (2013, November). Mass trial induced under-expression of Arc mRNA in rat hippocampal neurons. 2013 Annual Meeting of the Society for Neuroscience. San Diego, cA.
• Engle, J. R., Archibeque, M. J., Permenter, M. R., Vogt, J. A., Dugger, B. N., Beach, T. G., & Barnes, C. A. (2013, November). Cerebral amyloid deposition and phosphorylated tau: relationships between age and cognitive status in the rhesus macaque. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Espinoza, A. I., Uprety, A., Thome, A., & Barnes, C. A. (2013, Jan). Rescuing age-related behavioral slowing via pharmacological enhancement of cortical gamma oscillations. Twenty-Fourth Annual Undergraduate Biology Research Program. Twenty-fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Ferng, J. J., Burke, S. B., & Barnes, C. A. (2013, January). Hippocampal place field activity in rats trained to walk forward and backwards. Twenty-fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Hay, M., Constantopoulos, E., Uprety, A. J., Samareh-Jahani, F., Barnes, C. A., & Konhilas, J. P. (2013, November). Cognitive dysfunction in heart failure and a protective role for angiotensin (1-7). 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Lester, A. W., Maurer, A. P., Burke, S. M., & Barnes, C. A. (2013, November). Preserved neural dynamics during reverse locomotion. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Liang, J., Lister, J. P., & Barnes, C. A. (2013, January). Aging does not affect the proportion of dorsal medial entorhinal cortex cells active during track running behavior. Twenty-fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Lister, J. P., Liang, J., & Barnes, C. A. (2013, November). Effect of age and changing odors on population activity in the medial entorhinal cortex during track running behavior. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Lu, L., Leutgeb, J. K., Tsao, A., Henriksen, E. J., Leutgeb, S., Barnes, C. A., Witter, M. P., Moser, M. -., & Moser, E. I. (2013, November). Impaired hippocampal rate remapping following lesions in the lateral entorhinal cortex. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Maurer, A. P., Thome, A., Bohne, K. M., Archibeque, M. J., Permenter, M. R., Vogt, J. A., Sprawla, K., Engle, J. R., & Barnes, C. A. (2013, November). Telemetric recordings from temporal lobe of a freely moving primate. 2013 Annual Meeting of the Society for Neuroscience,. San Diego, CA.
• Plange, K., Engle, J. R., Burke, S. N., Gray, D. T., & Barnes, C. A. (2013, November). Changes in sensory function are correlated with cognitive impairments in bonnet monkeys. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Salt, I., Kumar, S., Lister, J. P., & Barnes, C. A. (2013, January). Expression of the immediate early gene Arc while running on a wheel is similar to when exploring a spatial environment. Twenty-Fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Siniard, A. L., Corneveaux, J. J., Allen, A. N., Chawla, M. K., Turk, M. N., Reiman, R. A., Rose, H. E., Barnes, C. A., & Huentelman, M. J. (2013, November). Activity regulated transcript identification in the hippocampus and the genetic association with AD. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Thome, A., Chawla, M. K., Ramirez, V., Marrone, D. F., Lipa, P., Ellmore, T. M., McNaughton, B. L., & Barnes, C. A. (2013, November). Large scale molecular imaging of hippocampal network activity during real and virtual navigation in freely behaving primates. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Uprety, A. R., Lipa, P., Thome, A., Espinoza, A. I., Hindley, T. R., & Barnes, C. A. (2013, November). Frontal cortical gamma frequency slowing in aging: Can C6 rescue cortical synchrony and decision speed?. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.
• Veeravelli, S., Yoshimaru, E., Hoang, L. T., Valdez, M., Alvarez, A., Barnes, C. A., & Trouard, T. P. (2013, January). Magnetic resonance imaging of the neurological effects of hypertension. Twenty-fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Xiong, M., Lister, J. P., & Barnes, C. A. (2013, January). Columnarity measurements and changes in cognitive performance in the aging brain. Twenty-fourth Annual Undergraduate Biology Research Program. University of Arizona, Tucson, AZ.
• Xiong, M., Morrison, W., Lister, J. P., Barnes, C. A., Cruze, L. R., & Rosene, D. L. (2013, November). Effect of aging on the microcolumnar structure of entorhinal cortex: correlation with performance on the spatial Morris water maze test. 2013 Annual Meeting of the Society for Neuroscience. San Diego, CA.

Reviews

• Barnes, C. A., Huentelman, M. J., Talboom, J. S., Chen, Z., & Lewis, C. R. (2020. Reinventing neuroaging research in the digital age.(pp 17–23). 43.
• Hay, M., Barnes, C. A., Huentelman, M., Brinton, R., & Ryan, L. (2020. Hypertension and age-related cognitive impairment: commons risk factors and a role for precision aging.. doi: 10.1007/s11906-020-01090-w.
• Gray, D. T., & Barnes, C. A. (2019. Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function.(pp 26247-26254). 116.
• Ryan, L., Hay, M., Huentelmann, M. J., Duarte, A., Rundek, T., Levin, B., Soldan, A., Pettigrew, C., Mehl, M., & Barnes, C. A. (2019. Precision Aging: Applying precision medicine to the field of cognitive aging.(p. 128). 11.
• Stern, Y., Barnes, C. A., Grady, C., Jones, R. N., & Raz, N. (2019. Brain reserve, cognitive reserve, compensation, and maintenance: operationalization, validity, and mechanisms of cognitive resilience. Neurobiology of Aging, 83:124-129(pp 124-129). 83.
• Burke, S. N., Gaynor, L. S., Barnes, C. A., Bauer, R. M., Roberson, E. D., & Ryan, L. (2018. Shared Functions of Perirhinal and Parahippocampal Cortices: Implications for Cognitive Aging.(pp 349-359). 41.
• Barnes, C. A. (2017. The aging navigational system.(pp 1019-1035). 9.

Others

• Barnes, C. A., Ryan, L., & Peterson, M. A. (2020, August). Nadel special issue introduction. Hippocampus.