Shaowen Bao

Interests

Teaching

Systems Physiology PSIO 603Systems Neuroscience NRSC 560

Research

Auditory perceptual learningDevelopmental brain disorderHearing loss and related pathologyTraumatic brain injury

Courses

Scholarly Contributions

Journals/Publications

• Liu, K., Sun, W., Zhou, X., Bao, S., Gong, S., & He, D. Z. (2022). Editorial: Hearing Loss and Cognitive Disorders. Frontiers in neuroscience, 16, 902405.
• Masri, S., Bao, S., Zhang, J., Luo, H., Wang, W., & Deng, D. (2022). Contributions of Hearing Loss and Traumatic Brain Injury to Blast-Induced Cortical Parvalbumin Neuron Loss and Auditory Processing Deficits. Journal of Neurotrauma. doi:10.1089/neu.2022.0179
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  Auditory processing disorder is the most common problem affecting veterans after blast exposure, but the distinct impacts of blast-related traumatic brain injury and blast-related hearing loss are unknown. Independently, both hearing loss and blast exposure affect the entire auditory processing pathway at the molecular and physiological levels. Here, we identified distinct changes to the primary auditory cortex (AI) and temporal processing in mice following blast exposure both with and without protected hearing. Our results show that blast-exposure alone activated microglia in AI, but hearing loss was required for reductions in the density of parvalbumin-expressing interneurons. Although blast exposure impaired the temporal following response, these impairments were more severe with concurrent unilateral hearing loss, further resulting in impairments in behavioral gap detection. Taken together, these results indicate that protecting hearing during blast exposure can prevent most impairments to auditory processing but does not fully protect temporal processing.
• Masri, S., Deng, D., Wang, W., Luo, H., Zhang, J., & Bao, S. (2022). Contributions of Hearing Loss and Traumatic Brain Injury to Blast-Induced Cortical Parvalbumin Neuron Loss and Auditory Processing Deficits. Journal of neurotrauma.
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  Auditory processing disorder is the most common problem affecting veterans after blast exposure, but the distinct impacts of blast-related traumatic brain injury and blast-related hearing loss are unknown. Independently, both hearing loss and blast exposure affect the entire auditory processing pathway at the molecular and physiological levels. Here, we identified distinct changes to the primary auditory cortex (AI) and temporal processing in mice following blast exposure both with and without protected hearing. Our results show that blast-exposure alone activated microglia in AI, but hearing loss was required for reductions in the density of parvalbumin-expressing interneurons. Although blast exposure impaired the temporal following response, these impairments were more severe with concurrent unilateral hearing loss, further resulting in impairments in behavioral gap detection. Taken together, these results indicate that protecting hearing during blast exposure can prevent most impairments to auditory processing but does not fully protect temporal processing.
• Pak, S., Choi, G., Roy, J., Poon, C. H., Lee, J., Cho, D., Lee, M., Lim, L. W., Bao, S., Yang, S., & Yang, S. (2022). Altered synaptic plasticity of the longitudinal dentate gyrus network in noise-induced anxiety. iScience, 25(6), 104364.
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  Anxiety is characteristic comorbidity of noise-induced hearing loss (NIHL), which causes physiological changes within the dentate gyrus (DG), a subfield of the hippocampus that modulates anxiety. However, which DG circuit underlies hearing loss-induced anxiety remains unknown. We utilize an NIHL mouse model to investigate short- and long-term synaptic plasticity in DG networks. The recently discovered longitudinal DG-DG network is a collateral of DG neurons synaptically connected with neighboring DG neurons and displays robust synaptic efficacy and plasticity. Furthermore, animals with NIHL demonstrate increased anxiety-like behaviors similar to a response to chronic restraint stress. These behaviors are concurrent with enhanced synaptic responsiveness and suppressed short- and long-term synaptic plasticity in the longitudinal DG-DG network but not in the transverse DG-CA3 connection. These findings suggest that DG-related anxiety is typified by synaptic alteration in the longitudinal DG-DG network.
• Wang, W., Deng, D., Jenkins, K., Zinsmaier, A. K., Zhou, Q., & Bao, S. (2022). Correlation of Electrophysiological and Gene Transcriptional Dysfunctions in Single Cortical Parvalbumin Neurons After Noise Trauma. Neuroscience, 482, 87-99.
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  Parvalbumin-expressing (PV+) interneurons in the sensory cortex form powerful inhibitory synapses on the perisomatic compartments and axon initial segments of excitatory principal neurons (PNs), and perform diverse computational functions. Impaired PV+ interneuron functions have been reported in neural developmental and degenerative disorders. Expression of the unique marker parvalbumin (PV) is often used as a proxy of PV+ interneuron functions. However, it is not entirely clear how PV expression is correlated with PV+ interneuron properties such as spike firing and synaptic transmission. To address this question, we characterized electrophysiological properties of PV+ interneurons in the primary auditory cortex (AI) using whole-cell patch clamp recording, and analyzed the expression of several genes in samples collected from single neurons using the patch pipettes. We found that, after noise induced hearing loss (NIHL), the spike frequency adaptation increased, and the expression of PV, glutamate decarboxylase 67 (GAD67) and Shaw-like potassium channel (KV3.1) decreased in PV+ neurons. In samples prepared from the auditory cortical tissue, the mRNA levels of the target genes were all pairwise correlated. At the single neuron level, however, the expression of PV was significantly correlated with the expression of GAD67, but not KV3.1, maximal spike frequency, or spike frequency adaptation. The expression of KV3.1 was correlated with spike frequency adaptation, but not with the expression of GAD67. These results suggest separate transcriptional regulations of PV/GAD67 vs. KV3.1, both of which are modulated by NIHL.
• Lee, M., Lee, S., Kim, J., Lim, J., Lee, J., Masri, S., Bao, S., Yang, S., Ahn, J., & Yang, S. (2021). Graphene-electrode array for brain map remodeling of the cortical surface. NPG Asia Materials, 13(1), 65.
• Shulman, A., Wang, W., Luo, H., Bao, S., Searchfield, G., & Zhang, J. (2021). Neuroinflammation and Tinnitus. Current topics in behavioral neurosciences, 51, 161-174.
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  Neuroinflammation is the central nervous system's response to: injury, infection, and abnormal neural activity. Inflammatory processes are known to mediate many diseases, and recently evidence indicates that neuroinflammation underlies hearing disorders such as presbyacusis, middle-ear disease, ototoxicity, noise-induced hearing loss, and tinnitus. This chapter provides a review of the role of neuroinflammation in the etiology and treatment of tinnitus. Specifically, our research team has demonstrated that both tumor necrosis factor alpha (TNF-α) and calpain signaling pathways are involved in noise-induced tinnitus and that blocking them yielded therapeutic effects on tinnitus. Other efforts such as controlling acute inflammatory response via specialized pro-resolving mediators may help provide insight into preventing and treating tinnitus-related inflammatory processes.
• Xia, D., Zhang, X., Deng, D., Ma, X., Masri, S., Wang, J., Bao, S., Hu, S., & Zhou, Q. (2021). Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules. Frontiers in pharmacology, 12, 796179.
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  Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity and Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na and Ca channels. In contrast, large differences in cell adhesion molecules and K channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.
• Zinsmaier, A. K., Zhang, L. S., Wang, W., Schaub, D., Masri, S., Marsh, T., Chan, N., & Bao, S. (2021). Chemogenetic Activation of Cortical Parvalbumin-Positive Interneurons Reverses Noise-Induced Impairments in Gap Detection.. The Journal of neuroscience : the official journal of the Society for Neuroscience, JN-RM-2687-19. doi:10.1523/jneurosci.2687-19.2021
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  Exposure to loud noises not only leads to trauma and loss of output from the ear, but also alters downstream central auditory circuits. A perceptual consequence of noise-induced central auditory disruption is impairment in gap-induced prepulse inhibition, also known as gap detection. Recent studies have implicated cortical parvalbumin-positive (PV) inhibitory interneurons in gap detection and prepulse inhibition. Here we show that exposure to loud noises specifically reduces the density of cortical PV but not somatostatin-positive (SOM) interneurons in the primary auditory cortex (AI) in mice (C57BL/6) of both sexes. Optogenetic activation of PV neurons produced less cortical inhibition in noise-exposed than sham-exposed animals, indicative of reduced PV neuron function. Activation of SOM neurons resulted in similar levels of cortical inhibition in noise- and sham-exposed groups. Furthermore, chemogenetic activation of PV neurons with the hM3-based DREADD (designer receptor exclusively activated by designer drugs) completely reversed the impairments in gap detection for noise-exposed animals. These results support the notions that cortical PV neurons encode gap-in-sound, and that PV neuron dysfunction contributes to noise-induced impairment in gap detection.SIGNIFICANCE STATEMENTNoise induced hearing loss contributes to a range of central auditory processing deficits (CAPDs). The mechanisms underlying noise-induced CAPDs are still poorly understood. Here we show that exposure to loud noises results in dysfunction of parvalbumin-positive (PV), but not somatostatin-positive, inhibitory interneurons in the primary auditory cortex. In addition, cortical PV inhibitory neurons in noise exposed animals had reduced expression of glutamic acid decarboxylases and weakened inhibition on cortical activity. Noise exposure resulted in impaired gap detection, indicative of disrupted temporal sound processing and possibly tinnitus. We found that chemogenetic activation of cortical PV inhibitory interneurons alleviated the deficits in gap detection. These results implicate PV neuron dysfunction as a mechanism for noise-induced CAPDs.
• Deng, D., Masri, S., Yao, L., Ma, X., Cao, X., Yang, S., Bao, S., & Zhou, Q. (2020). Increasing endogenous activity of NMDARs on GABAergic neurons increases inhibition, alters sensory processing and prevents noise-induced tinnitus. Scientific reports, 10(1), 11969.
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  Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory-inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.
• Deng, D., Wang, W., & Bao, S. (2020). Diffusible Tumor Necrosis Factor-Alpha (TNF-α) Promotes Noise-Induced Parvalbumin-Positive (PV+) Neuron Loss and Auditory Processing Impairments. Frontiers in neuroscience, 14, 573047.
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  Neuroinflammation has been implicated in noise-induced auditory processing disorder and tinnitus. Certain non-auditory neurological disorders can also increase the levels of proinflammatory cytokines in the brain. To investigate the impact of increased brain proinflammatory cytokine levels on the central auditory pathway, we infused recombinant TNF-α into the right lateral cerebral ventricle, and examined auditory processing and cytoarchitecture of the auditory cortex. Microglial deramification was observed in the auditory cortex of mice that had received both TNF-α infusion and exposure to an 86-dB noise, but not in mice that had received either TNF-α infusion or noise exposure alone. In addition, we observed reduced cortical PV+ neuron density and impaired performances in gap detection and prepulse inhibition (PPI) only in mice that received both TNF-α infusion and the noise exposure. These results suggest that disease-related increase in brain proinflammatory cytokine release could be a risk factor for noise-induced auditory processing disorder and tinnitus.
• Schwartz, B. A., Wang, W., & Bao, S. (2020). Pharmacological DNA Demethylation Weakens Inhibitory Synapses in the Auditory Cortex and Re-opens the Critical Period for Frequency Map Plasticity. Neuroscience, 440, 239-248.
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  The critical period is a time of maximal plasticity within the cortex. The progression of the critical period is marked by experience-dependent transcriptional alterations in cortical neurons, which in turn shifts the excitatory-inhibitory balance in the brain, and accordingly reduces plasticity. Epigenetic mechanisms, such as DNA methylation, control the transcriptional state of neurons, and have been shown to be dynamically regulated during the critical period. Here we show that adult animals have a significantly higher concentration of DNA methylation than critical period animals. Pharmacological reduction of DNA methylation in adult animals re-establishes critical period auditory map plasticity. Furthermore, the reduction of DNA methylation in adult animals, reverted intrinsic characteristics of inhibitory synapses to an immature state. Our data suggest that accumulation of DNA methylation during the critical period confers a mature phenotype to cortical neurons, which in turn, facilitates the reduction in plasticity seen after the critical period.
• Zinsmaier, A. K., Wang, W., Zhang, L., Hossainy, N. N., & Bao, S. (2020). Resistance to noise-induced gap detection impairment in FVB mice is correlated with reduced neuroinflammatory response and parvalbumin-positive neuron loss. Scientific reports, 10(1), 20445.
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  Exposure to loud noises results in neuroinflammatory responses in the central auditory pathway. Noise-induced neuroinflammation is implicated in auditory processing deficits such as impairment in gap detection. In this study, we examined whether strain differences between the FVB and C57BL/6 mice in noise-induced impairment in gap detection are correlated with strain differences in neuroinflammatory responses. We found that noise induced more robust TNF-α expression in C57BL/6 than in FVB mice. Noise-induced microglial deramification was observed in C57BL/6 mice, but not in FVB mice. Furthermore, noise exposure resulted in a reduction in parvalbumin-positive (PV+) neuron density in the C57BL/6 mice, but not in FVB mice. These results suggest that neuroinflammatory responses and loss of PV+ neurons may contribute to strain differences in noise-induced impairment in gap detection.
• Miyakawa, A., Wang, W., Cho, S. J., Li, D., Yang, S., & Bao, S. (2019). Tinnitus Correlates with Downregulation of Cortical Glutamate Decarboxylase 65 Expression But Not Auditory Cortical Map Reorganization. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(50), 9989-10001.
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  Hearing loss is the biggest risk factor for tinnitus, and hearing-loss-related pathological changes in the auditory pathway have been hypothesized as the mechanism underlying tinnitus. However, due to the comorbidity of tinnitus and hearing loss, it has been difficult to differentiate between neural correlates of tinnitus and consequences of hearing loss. In this study, we dissociated tinnitus and hearing loss in FVB mice, which exhibit robust resistance to tinnitus following monaural noise-induced hearing loss. Furthermore, knock-down of glutamate decarboxylase 65 (GAD65) expression in auditory cortex (AI) by RNA interference gave rise to tinnitus in normal-hearing FVB mice. We found that tinnitus was significantly correlated with downregulation of GAD65 in the AI. By contrast, cortical map distortions, which have been hypothesized as a mechanism underlying tinnitus, were correlated with hearing loss but not tinnitus. Our findings suggest new strategies for the rehabilitation of tinnitus and other phantom sensation, such as phantom pain. Hearing loss is the biggest risk factor for tinnitus in humans. Most animal models of tinnitus also exhibit comorbid hearing loss, making it difficult to dissociate the mechanisms underlying tinnitus from mere consequences of hearing loss. Here we show that, although both C57BL/6 and FVB mice exhibited similar noise-induced hearing threshold increase, only C57BL/6, but not FVB, mice developed tinnitus following noise exposure. Although both strains showed frequency map reorganization following noise-induced hearing loss, only C57BL/6 mice had reduced glutamate decarboxylase 65 (GAD65) expression in the auditory cortex (AI). Knocking down GAD65 expression in the AI resulted in tinnitus in normal-hearing FVB mice. Our results suggest that reduced inhibitory neuronal function, but not sensory map reorganization, underlies noise-induced tinnitus.
• Wang, W., Zhang, L. S., Zinsmaier, A. K., Patterson, G., Leptich, E. J., Shoemaker, S. L., Yatskievych, T. A., Gibboni, R., Pace, E., Luo, H., Zhang, J., Yang, S., & Bao, S. (2019). Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models. PLoS biology, 17(6), e3000307.
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  Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss-related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation-two defining features of neuroinflammatory responses-in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-α) or pharmacologically blocking TNF-α expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-α into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-α knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-α expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss-related disorders.
• Masri, S., Zhang, L. S., Luo, H., Pace, E., Zhang, J., & Bao, S. (2018). Blast Exposure Disrupts the Tonotopic Frequency Map in the Primary Auditory Cortex. Neuroscience, 379, 428-434.
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  Blast exposure can cause various auditory disorders including tinnitus, hyperacusis, and other central auditory processing disorders. While this is suggestive of pathologies in the central auditory system, the impact of blast exposure on central auditory processing remains poorly understood. Here we examined the effects of blast shockwaves on acoustic response properties and the tonotopic frequency map in the auditory cortex. We found that multiunits recorded from the auditory cortex exhibited higher acoustic thresholds and broader frequency tuning in blast-exposed animals. Furthermore, the frequency map in the primary auditory cortex was distorted. These changes may contribute to central auditory processing disorders.
• Wang, W., Zinsmaier, A. K., Firestone, E., Lin, R., Yatskievych, T. A., Yang, S., Zhang, J., & Bao, S. (2018). Blocking Tumor Necrosis Factor-Alpha Expression Prevents Blast-Induced Excitatory/Inhibitory Synaptic Imbalance and Parvalbumin-Positive Interneuron Loss in the Hippocampus. Journal of neurotrauma, 35(19), 2306-2316.
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  Traumatic brain injury (TBI) is a major cause of neurological disorder and death in civilian and military populations. It comprises two components-direct injury from the traumatic impact and secondary injury from ensuing neural inflammatory responses. Blocking tumor necrosis factor-alpha (TNF-α), a central regulator of neural inflammation, has been shown to improve functional recovery after TBI. However, the mechanisms underlying those therapeutic effects are still poorly understood. Here, we examined effects of 3,6'-dithiothalidomide (dTT), a potentially therapeutic TNF-α inhibitor, in mice with blast-induced TBI. We found that blast exposure resulted in elevated expression of TNF-α, activation of microglial cells, enhanced excitatory synaptic transmission, reduced inhibitory synaptic transmission, and a loss of parvalbumin-positive (PV+) inhibitory interneurons. Administration of dTT for 5 days after the blast exposure completely suppressed blast-induced increases in TNF-α transcription, largely reversed blasted-induced synaptic changes, and prevented PV+ neuron loss. However, blocking TNF-α expression by dTT failed to mitigate blast-induced microglial activation in the hippocampus, as evidenced by their non-ramified morphology. These results indicate that TNF-α plays a major role in modulating neuronal functions in blast-induced TBI and that it is a potential target for treatment of TBI-related brain disorders.
• Yang, S., Chung, J., Jin, S. H., Bao, S., & Yang, S. (2018). A circuit mechanism of time-to-space conversion for perception. Hearing research, 366, 32-37.
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  Sensory information in a temporal sequence is processed as a collective unit by the nervous system. The cellular mechanisms underlying how sequential inputs are incorporated into the brain has emerged as an important subject in neuroscience. Here, we hypothesize that information-bearing (IB) signals can be entrained and amplified by a clock signal, allowing them to efficiently propagate along in a feedforward circuit. IB signals can remain latent on individual dendrites of the receiving neurons until they are read out by an oscillatory clock signal. In such a way, the IB signals pass through the next neurons along a linear chain. This hypothesis identifies a cellular process of time-to-space and sound-to-map conversion in primary auditory cortex, providing insight into a mechanistic principle underlying the representation and memory of temporal sequences of information.
• Bao, S. (2015). Perceptual learning in the developing auditory cortex. European Journal of Neuroscience, 41(5), 718-724. doi:10.1111/ejn.12826
• Bao, S. (2015). Perceptual learning in the developing auditory cortex. The European journal of neuroscience, 41(5), 718-24.
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  A hallmark of the developing auditory cortex is the heightened plasticity in the critical period, during which acoustic inputs can indelibly alter cortical function. However, not all sounds in the natural acoustic environment are ethologically relevant. How does the auditory system resolve relevant sounds from the acoustic environment in such an early developmental stage when most associative learning mechanisms are not yet fully functional? What can the auditory system learn from one of the most important classes of sounds, animal vocalizations? How does naturalistic acoustic experience shape cortical sound representation and perception? To answer these questions, we need to consider an unusual strategy, statistical learning, where what the system needs to learn is embedded in the sensory input. Here, I will review recent findings on how certain statistical structures of natural animal vocalizations shape auditory cortical acoustic representations, and how cortical plasticity may underlie learned categorical sound perception. These results will be discussed in the context of human speech perception.
• Bao, S., Kim, E. G., Tu, H., Luo, H., Liu, B., Zhang, J., & Xu, Y. (2015). 3D silicon neural probe with integrated optical fibers for optogenetic modulation. Lab on a Chip, 15(14), 2939-2949. doi:10.1039/c4lc01472c
• Yang, S., Yang, S., Park, J., Kirkwood, A., & Bao, S. (2014). Failed stabilization for long-term potentiation in the auditory cortex of FMR1 knockout mice. PloS one, 9(8), e104691.
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  Fragile X syndrome is a developmental disorder that affects sensory systems. A null mutation of the Fragile X Mental Retardation protein 1 (Fmr1) gene in mice has varied effects on developmental plasticity in different sensory systems, including normal barrel cortical plasticity, altered ocular dominance plasticity and grossly impaired auditory frequency map plasticity. The mutation also has different effects on long-term synaptic plasticity in somatosensory and visual cortical neurons, providing insights on how it may differentially affect the sensory systems. Here we present evidence that long-term potentiation (LTP) is impaired in the developing auditory cortex of the Fmr1 knockout (KO) mice. This impairment of synaptic plasticity is consistent with impaired frequency map plasticity in the Fmr1 KO mouse. Together, these results suggest a potential role of LTP in sensory map plasticity during early sensory development.
• Yang, S., Zhang, L. S., Gibboni, R., Weiner, B., & Bao, S. (2014). Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-α-deficient mice. Cerebral cortex (New York, N.Y. : 1991), 24(7), 1956-65.
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  Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.
• Bao, S. (2013). Early experience improves neural discrimination/recognition of natural complex sounds. Journal of the Acoustical Society of America, 134(5), 4086-4086. doi:10.1121/1.4830923
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  In natural environments, behaviorally relevant complex sounds are often produced with “speaker” variability and contaminated with environmental noises. To efficiently discriminate/recognize natural complex sounds, the auditory system has to tune to defining acoustic features and filter out random, meaningless features. In humans, for example, efficient speech recognition is achieved by enhancing perceptual contrast for native speech sounds, as well as reducing perceptual contrast for non-native speech sounds. The neural mechanisms underlying this perceptual transformation are still not well understood. We exposed juvenile rats to heterospecific vocalizations recorded in a natural environment, and subsequently examined their cortical complex sound representations. Cortical neurons became more responsive to dynamic and complex features of the complex sounds. In addition, more neurons were involved in representing the whole set of complex sounds, but fewer neurons actually responded to each individual sound. Cortical responses to different renderings of the same song motif were more similar, and responses to sounds of different motifs became more distinctive, indicating that cortical neurons were more selective to the defining features of the experienced sounds. These effects lead to better neural discrimination/recognition of the experienced complex sounds.
• Bao, S., Chang, E. F., Teng, C., Heiser, M. A., & Merzenich, M. M. (2013). Emergent categorical representation of natural, complex sounds resulting from the early post-natal sound environment. Neuroscience, 248, 30-42.
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  Cortical sensory representations can be reorganized by sensory exposure in an epoch of early development. The adaptive role of this type of plasticity for natural sounds in sensory development is, however, unclear. We have reared rats in a naturalistic, complex acoustic environment and examined their auditory representations. We found that cortical neurons became more selective to spectrotemporal features in the experienced sounds. At the neuronal population level, more neurons were involved in representing the whole set of complex sounds, but fewer neurons actually responded to each individual sound, but with greater magnitudes. A comparison of population-temporal responses to the experienced complex sounds revealed that cortical responses to different renderings of the same song motif were more similar, indicating that the cortical neurons became less sensitive to natural acoustic variations associated with stimulus context and sound renderings. By contrast, cortical responses to sounds of different motifs became more distinctive, suggesting that cortical neurons were tuned to the defining features of the experienced sounds. These effects lead to emergent "categorical" representations of the experienced sounds, which presumably facilitate their recognition.
• Hamilton, L. S., Sohl-Dickstein, J., Huth, A. G., Carels, V. M., Deisseroth, K., & Bao, S. (2013). Optogenetic activation of an inhibitory network enhances feedforward functional connectivity in auditory cortex. Neuron, 80(4), 1066-76.
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  The mammalian neocortex is a highly interconnected network of different types of neurons organized into both layers and columns. Overlaid on this structural organization is a pattern of functional connectivity that can be rapidly and flexibly altered during behavior. Parvalbumin-positive (PV+) inhibitory neurons, which are implicated in cortical oscillations and can change neuronal selectivity, may play a pivotal role in these dynamic changes. We found that optogenetic activation of PV+ neurons in the auditory cortex enhanced feedforward functional connectivity in the putative thalamorecipient circuit and in cortical columnar circuits. In contrast, stimulation of PV+ neurons induced no change in connectivity between sites in the same layers. The activity of PV+ neurons may thus serve as a gating mechanism to enhance feedforward, but not lateral or feedback, information flow in cortical circuits. Functionally, it may preferentially enhance the contribution of bottom-up sensory inputs to perception.
• Kim, H., & Bao, S. (2013). Experience-dependent overrepresentation of ultrasonic vocalization frequencies in the rat primary auditory cortex. Journal of neurophysiology, 110(5), 1087-96.
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  Cortical sensory representation is highly adaptive to the environment, and prevalent or behaviorally important stimuli are often overrepresented. One class of such stimuli is species-specific vocalizations. Rats vocalize in the ultrasonic range >30 kHz, but cortical representation of this frequency range has not been systematically examined. We recorded in vivo cortical electrophysiological responses to ultrasonic pure-tone pips, natural ultrasonic vocalizations, and pitch-shifted vocalizations to assess how rats represent this ethologically relevant frequency range. We find that nearly 40% of the primary auditory cortex (AI) represents an octave-wide band of ultrasonic vocalization frequencies (UVFs; 32-64 kHz) compared with
• Kim, H., Gibboni, R., Kirkhart, C., & Bao, S. (2013). Impaired critical period plasticity in primary auditory cortex of fragile X model mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(40), 15686-92.
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  Fragile X syndrome, the most common form of heritable mental retardation, is a developmental disorder with known effects within sensory systems. Altered developmental plasticity has been reported in the visual and somatosensory systems in Fmr1 knock-out (KO) mice. Behavioral studies have revealed maladaptive auditory responses in fragile X syndrome patients and Fmr1 KO mice, suggesting that adaptive plasticity may also be impaired in the auditory system. Here we show that, whereas tonotopic frequency representation develops normally in Fmr1 KO mice, developmental plasticity in primary auditory cortex is grossly impaired. This deficit can be rescued by pharmacological blockade of mGluR5 receptors. These results support the mGluR hypothesis of fragile X mental retardation and suggest that deficient developmental plasticity may contribute to maladaptive auditory processing in fragile X syndrome.
• Köver, H., Gill, K., Tseng, Y. L., & Bao, S. (2013). Perceptual and neuronal boundary learned from higher-order stimulus probabilities. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(8), 3699-705.
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  During an early epoch of development, the brain is highly adaptive to the stimulus environment. Exposing young animals to a particular tone, for example, leads to an enlarged representation of that tone in primary auditory cortex. While the neural effects of simple tonal environments are well characterized, the principles that guide plasticity in more complex acoustic environments remain unclear. In addition, very little is known about the perceptual consequences of early experience-induced plasticity. To address these questions, we reared juvenile rats in complex multitone environments that differed in terms of the higher-order conditional probabilities between sounds. We found that the development of primary cortical acoustic representations, as well as frequency discrimination ability in adult animals, were shaped by the higher-order stimulus statistics of the early acoustic environment. Our results suggest that early experience-dependent cortical reorganization may mediate perceptual changes through statistical learning of the sensory input.
• Yang, S., & Bao, S. (2013). Homeostatic mechanisms and treatment of tinnitus. Restorative neurology and neuroscience, 31(2), 99-108.
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  Tinnitus, the phantom percept of sound, is a potentially debilitating disorder affecting up to ten percent of the general population. After decades of effort, we still lack an effective treatment for tinnitus, partly because of its diverse underlying etiology. Recent studies have yielded hypotheses for central mechanisms underlying hearing loss-induced tinnitus, the most common form of tinnitus. Here we review recent evidence that homeostatic down-regulation of phasic and tonic inhibition is a mechanism underlying hearing loss-induced tinnitus. We propose to treat tinnitus through novel strategies of sensory training and targeted pharmacological intervention to reverse the homeostatic changes induced by hearing loss.
• Yang, S., Su, W., & Bao, S. (2012). Long-term, but not transient, threshold shifts alter the morphology and increase the excitability of cortical pyramidal neurons. Journal of neurophysiology, 108(6), 1567-74.
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  Partial hearing loss often results in enlarged representations of the remaining hearing frequency range in primary auditory cortex (AI). Recent studies have implicated certain types of synaptic plasticity in AI map reorganization in response to transient and long-term hearing loss. How changes in neuronal excitability and morphology contribute to cortical map reorganization is less clear. In the present study, we exposed adult rats to a 4-kHz tone at 123 dB, which resulted in increased thresholds over their entire hearing range. The threshold shift gradually recovered in the lower-frequency, but not the higher-frequency, range. As reported previously, two distinct zones were observed 10 days after the noise exposure, an enlarged lower-characteristic frequency (CF) zone displaying normal threshold and enhanced cortical responses and a higher-CF zone showing higher threshold and a disorganized tonotopic map. Membrane excitability of layer II/III pyramidal neurons increased only in the higher-CF, but not the lower-CF, zone. In addition, dendritic morphology and spine density of the pyramidal neurons were altered in the higher-CF zone only. These results indicate that membrane excitability and neuronal morphology are altered by long-term, but not transient, threshold shift. They also suggest that these changes may contribute to tinnitus but are unlikely to be involved in map expansion in the lower-CF zone.
• Yang, S., Weiner, B. D., Zhang, L. S., Cho, S., & Bao, S. (2011). Homeostatic plasticity drives tinnitus perception in an animal model. Proceedings of the National Academy of Sciences of the United States of America, 108(36), 14974-9.
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  Hearing loss often results in tinnitus and auditory cortical map changes, leading to the prevailing view that the phantom perception is associated with cortical reorganization. However, we show here that tinnitus is mediated by a cortical area lacking map reorganization. High-frequency hearing loss results in two distinct cortical regions: a sensory-deprived region characterized by a decrease in inhibitory synaptic transmission and a normal hearing region showing increases in inhibitory and excitatory transmission and map reorganization. Hearing-lesioned animals displayed tinnitus with a pitch in the hearing loss range. Furthermore, drugs that enhance inhibition, but not those that reduce excitation, reversibly eliminated the tinnitus behavior. These results suggest that sensory deprivation-induced homeostatic down-regulation of inhibitory synapses may contribute to tinnitus perception. Enhancing sensory input through map reorganization may plausibly alleviate phantom sensation.
• Insanally, M. N., Albanna, B. F., & Bao, S. (2010). Pulsed noise experience disrupts complex sound representations. Journal of neurophysiology, 103(5), 2611-7.
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  Cortical sound representations are adapted to the acoustic environment. Early exposure to exponential frequency-modulated (FM) sweeps results in more neurons selective to the experienced sounds. Here we examined the influence of pulsed noise experience on the development of sound representations in the primary auditory cortex (AI) of the rat. In naïve animals, FM sweep direction selectivity depends on the characteristic frequency (CF) of the neuron--low CF neurons tend to select for upward sweeps and high CF neurons for downward sweeps. Such a CF dependence was not observed in animals that had received weeklong exposure to pulsed noise in periods from postnatal day 8 (P8) to P15 or from P24 to P39. In addition, AI tonotopicity, tuning bandwidth, intensity threshold, tone-responsiveness, and sweep response magnitude were differentially affected by the noise experience depending on the exposure time windows. These results are consistent with previous findings of feature-dependent multiple sensitive periods. The different effects induced here by pulsed noise and previously by FM sweeps further indicate that plasticity in cortical complex sound representations is specific to the sensory input.
• Köver, H., & Bao, S. (2010). Cortical plasticity as a mechanism for storing Bayesian priors in sensory perception. PloS one, 5(5), e10497.
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  Human perception of ambiguous sensory signals is biased by prior experiences. It is not known how such prior information is encoded, retrieved and combined with sensory information by neurons. Previous authors have suggested dynamic encoding mechanisms for prior information, whereby top-down modulation of firing patterns on a trial-by-trial basis creates short-term representations of priors. Although such a mechanism may well account for perceptual bias arising in the short-term, it does not account for the often irreversible and robust changes in perception that result from long-term, developmental experience. Based on the finding that more frequently experienced stimuli gain greater representations in sensory cortices during development, we reasoned that prior information could be stored in the size of cortical sensory representations. For the case of auditory perception, we use a computational model to show that prior information about sound frequency distributions may be stored in the size of primary auditory cortex frequency representations, read-out by elevated baseline activity in all neurons and combined with sensory-evoked activity to generate a perception that conforms to Bayesian integration theory. Our results suggest an alternative neural mechanism for experience-induced long-term perceptual bias in the context of auditory perception. They make the testable prediction that the extent of such perceptual prior bias is modulated by both the degree of cortical reorganization and the magnitude of spontaneous activity in primary auditory cortex. Given that cortical over-representation of frequently experienced stimuli, as well as perceptual bias towards such stimuli is a common phenomenon across sensory modalities, our model may generalize to sensory perception, rather than being specific to auditory perception.
• Geller, S. F., Guerin, K. I., Visel, M., Pham, A., Lee, E. S., Dror, A. A., Avraham, K. B., Hayashi, T., Ray, C. A., Reh, T. A., Bermingham-McDonogh, O., Triffo, W. J., Bao, S., Isosomppi, J., Västinsalo, H., Sankila, E., & Flannery, J. G. (2009). CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. PLoS genetics, 5(8), e1000607.
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  Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5-6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT-PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT-PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.
• Insanally, M. N., Köver, H., Kim, H., & Bao, S. (2009). Feature-dependent sensitive periods in the development of complex sound representation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(17), 5456-62.
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  Simple tonal stimuli can shape spectral tuning of cortical neurons during an early epoch of brain development. The effects of complex sound experience on cortical development remain to be determined. We exposed rat pups to a frequency-modulated (FM) sweep in different time windows during early development, and examined the effects of such sensory experience on sound representations in the primary auditory cortex (AI). We found that early exposure to a FM sound resulted in altered characteristic frequency representations and broadened spectral tuning in AI neurons, whereas later exposure to the same sound only led to greater selectivity for the sweep rate and direction of the experienced FM sound. These results indicate that cortical representations of different acoustic features are shaped by complex sounds in a series of distinct sensitive periods.
• Kim, H., & Bao, S. (2009). Selective increase in representations of sounds repeated at an ethological rate. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(16), 5163-9.
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  Exposure to sounds during early development causes enlarged cortical representations of those sounds, leading to the commonly held view that the size of stimulus representations increases with stimulus exposure. However, representing stimuli based solely on their prevalence may be inefficient, because many frequent environmental sounds are behaviorally irrelevant. Here, we show that cortical plasticity depends not only on exposure time but also on the temporal modulation rate of the stimulus set. We examined cortical plasticity induced by early exposure to 7 kHz tone pips repeated at a slow (2 Hz), fast (15 Hz), or ethological (6 Hz) rate. Certain rat calls are modulated near 6 Hz. We found that spectral representation of 7 kHz increased only in the ethological-rate-reared animals, whereas improved entrainment of cortical neurons was seen in animals reared in the slow- and fast-rate condition. This temporal rate dependence of spectral plasticity may serve as a filtering mechanism to selectively enlarge representations of species-specific vocalizations. Furthermore, our results indicate that spectral and temporal plasticity can be separately engaged depending on the statistical properties of the input stimuli.
• Sanes, D. H., & Bao, S. (2009). Tuning up the developing auditory CNS. Current opinion in neurobiology, 19(2), 188-99.
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  Although the auditory system has limited information processing resources, the acoustic environment is infinitely variable. To properly encode the natural environment, the developing central auditory system becomes somewhat specialized through experience-dependent adaptive mechanisms that operate during a sensitive time window. Recent studies have demonstrated that cellular and synaptic plasticity occurs throughout the central auditory pathway. Acoustic-rearing experiments can lead to an over-representation of the exposed sound frequency, and this is associated with specific changes in frequency discrimination. These forms of cellular plasticity are manifest in brain regions, such as midbrain and cortex, which interact through feed-forward and feedback pathways. Hearing loss leads to a profound re-weighting of excitatory and inhibitory synaptic gain throughout the auditory CNS, and this is associated with an over-excitability that is observed in vivo. Further behavioral and computational analyses may provide insights into how theses cellular and systems plasticity effects underlie the development of cognitive functions such as speech perception.
• Kim, H., & Bao, S. (2008). Distributed representation of perceptual categories in the auditory cortex. Journal of computational neuroscience, 24(3), 277-90.
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  Categorical perception is a process by which a continuous stimulus space is partitioned to represent discrete sensory events. Early experience has been shown to shape categorical perception and enlarge cortical representations of experienced stimuli in the sensory cortex. The present study examines the hypothesis that enlargement in cortical stimulus representations is a mechanism of categorical perception. Perceptual discrimination and identification behaviors were analyzed in model auditory cortices that incorporated sound exposure-induced plasticity effects. The model auditory cortex with over-representations of specific stimuli exhibited categorical perception behaviors for those specific stimuli. These results indicate that enlarged stimulus representations in the sensory cortex may be a mechanism for categorical perceptual learning.
• Semerdjian, J. H., Kover, H., Insanally, M. N., Han, Y. K., & Bao, S. (2007). Early experience impairs perceptual discrimination.. Nature neuroscience, 10(9), 1191-7. doi:10.1038/nn1941
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  Sensory experience can reorganize cortical sensory representations in an epoch of early development. During this period, cortical sensory neurons may shift their response selectivity and become tuned to more frequently occurring stimuli. Although this enlarged cortical representation is believed to underlie improved sensory processing of the experienced stimuli, its precise perceptual consequences are still unknown. We show that rearing rats in a single-frequency tonal environment results in enlarged cortical representations of the frequencies near that of the experienced tone, but the animals are impaired in perceptual discrimination of the over-represented frequencies. By contrast, discrimination of the neighboring under-represented frequencies is substantially improved. Computational analysis indicated that the altered perceptual ability could be fully accounted for by the sound exposure-induced reorganization of cortical primary auditory representations. These results indicate that early experience shapes sensory perception. The same plasticity processes may be important in optimizing phonemic representations in humans.
• de Villers-Sidani, E., Chang, E. F., Bao, S., & Merzenich, M. M. (2007). Critical period window for spectral tuning defined in the primary auditory cortex (A1) in the rat. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27(1), 180-9.
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  Experience-dependent plasticity during development results in the emergence of highly adapted representations of the external world in the adult brain. Previous studies have convincingly shown that the primary auditory cortex (A1) of the rat possesses a postnatal period of sensory input-driven plasticity but its precise timing (onset, duration, end) has not been defined. In the present study, we examined the effects of pure-tone exposure on the auditory cortex of developing rat pups at different postnatal ages with a high temporal resolution. We found that pure-tone exposure resulted in profound, persistent alterations in sound representations in A1 only if the exposure occurred during a brief period extending from postnatal day 11 (P11) to P13. We also found that postnatal sound exposure in this epoch led to striking alterations in the cortical representation of sound intensity.
• Bart, E., Bao, S., & Holcman, D. (2005). Modeling the spontaneous activity of the auditory cortex. Journal of computational neuroscience, 19(3), 357-78.
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  We present a rate model of the spontaneous activity in the auditory cortex, based on synaptic depression. A Stochastic integro-differential system of equations is derived and the analysis reveals two main regimes. The first regime corresponds to a normal activity. The second regime corresponds to epileptic spiking. A detailed analysis of each regime is presented and we prove in particular that synaptic depression stabilizes the global cortical dynamics. The transition between the two regimes is induced by a change in synaptic connectivity: when the overall connectivity is strong enough, an epileptic activity is spontaneously generated. Numerical simulations confirm the predictions of the theoretical analysis. In particular, our results explain the transition from normal to epileptic regime which can be induced in rats auditory cortex, following a specific pairing protocol. A change in the cortical maps reorganizes the synaptic connectivity and this transition between regimes is accounted for by our model. We have used data from recording experiments to fit synaptic weight distributions. Simulations with the fitted distributions are qualitatively similar to the real EEG recorded in vivo during the experiments. We conclude that changes in the synaptic weight function in our model, which affects excitatory synapses organization and reproduces the changes in cortical map connectivity can be understood as the main mechanism to explain the transitions of the EEG from the normal to the epileptic regime in the auditory cortex.
• Chang, E. F., Bao, S., Imaizumi, K., Schreiner, C. E., & Merzenich, M. M. (2005). Development of spectral and temporal response selectivity in the auditory cortex. Proceedings of the National Academy of Sciences of the United States of America, 102(45), 16460-5.
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  The mechanisms by which hearing selectivity is elaborated and refined in early development are very incompletely determined. In this study, we documented contributions of progressively maturing inhibitory influences on the refinement of spectral and temporal response properties in the primary auditory cortex. Inhibitory receptive fields (IRFs) of infant rat auditory cortical neurons were spectrally far broader and had extended over far longer duration than did those of adults. The selective refinement of IRFs was delayed relative to that of excitatory receptive fields by an approximately 2-week period that corresponded to the critical period for plasticity. Local application of a GABA(A) receptor antagonist revealed that intracortical inhibition contributes to this progressive receptive field maturation for response selectivity in frequency. Conversely, it had no effect on the duration of IRFs or successive-signal cortical response recovery times. The importance of exposure to patterned acoustic inputs was suggested when both spectral and temporal IRF maturation were disrupted in rat pups reared in continuous, moderate-intensity noise. They were subsequently renormalized when animals were returned to standard housing conditions as adults.
• Bao, S., Chang, E. F., Woods, J., & Merzenich, M. M. (2004). Temporal plasticity in the primary auditory cortex induced by operant perceptual learning. Nature neuroscience, 7(9), 974-81.
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  Processing of rapidly successive acoustic stimuli can be markedly improved by sensory training. To investigate the cortical mechanisms underlying such temporal plasticity, we trained rats in a 'sound maze' in which navigation using only auditory cues led to a target location paired with food reward. In this task, the repetition rate of noise pulses increased as the distance between the rat and target location decreased. After training in the sound maze, neurons in the primary auditory cortex (A1) showed greater responses to high-rate noise pulses and stronger phase-locking of responses to the stimuli; they also showed shorter post-stimulation suppression and stronger rebound activation. These improved temporal dynamics transferred to trains of pure-tone pips. Control animals that received identical sound stimulation but were given free access to food showed the same results as naive rats. We conclude that this auditory perceptual learning results in improvements in temporal processing, which may be mediated by enhanced cortical response dynamics.
• Bao, S., Chan, V. T., Zhang, L. I., & Merzenich, M. M. (2003). Suppression of cortical representation through backward conditioning. Proceedings of the National Academy of Sciences of the United States of America, 100(3), 1405-8.
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  Temporal stimulus reinforcement sequences have been shown to determine the directions of synaptic plasticity and behavioral learning. Here, we examined whether they also control the direction of cortical reorganization. Pairing ventral tegmental area stimulation with a sound in a backward conditioning paradigm specifically reduced representations of the paired sound in the primary auditory cortex (AI). This temporal sequence-dependent bidirectional cortical plasticity modulated by dopamine release hypothetically serves to prevent the over-representation of frequently occurring stimuli resulting from their random pairing with unrelated rewards.
• Bao, S., Chang, E. F., Davis, J. D., Gobeske, K. T., & Merzenich, M. M. (2003). Progressive degradation and subsequent refinement of acoustic representations in the adult auditory cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 23(34), 10765-75.
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  Correlated neuronal activity is believed to play an important role in refining and maintaining cortical circuitry during early development. Here we provide evidence that globally and locally correlated activity mediate different forms of adult plasticity. Pulses of broad-spectrum noise were used to activate time-locked responses across large areas of the rat auditory cortex, globally synchronizing cortical activity. Brief tone pips were used to activate relatively small groups of neurons, generating locally correlated activity. Pairing pulsed noises with nucleus basalis (NB) stimulation in awake rats for 4 weeks broadened spectral tuning, disrupted tonotopic maps, and reduced spontaneous discharge correlation in the primary auditory cortex (AI), as examined under anesthesia. Those effects caused AI neurons to appear qualitatively similar to neurons in nonprimary auditory fields of naive animals. Subsequent pairing of tone pips with NB stimulation for a period of 4 weeks completely reversed these effects induced by previous noise-NB pairing. These findings further demonstrate that the adult auditory cortex retains a substantial capacity for receptive field plasticity and tonotopic map reorganization and that locally correlated activity plays an important role in plasticity in the adult, as in the developing cortex.
• Bao, S., Chen, L., Kim, J. J., & Thompson, R. F. (2002). Cerebellar cortical inhibition and classical eyeblink conditioning. Proceedings of the National Academy of Sciences of the United States of America, 99(3), 1592-7.
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  The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.
• Sahani, M., Orduna, I., Merzenich, M. M., Mercado, E., Linden, J. F., Gluck, M. A., & Bao, S. (2002). Experience‐dependent cortical processing of complex sounds by rats. Journal of the Acoustical Society of America, 112(5), 2314-2314. doi:10.1121/1.4779329
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  Auditory cortex is thought to play a critical role in the processing of species‐specific vocalizations and other acoustically complex sounds. Although evolutionary processes strongly constrain cortical sensitivities to sound, cortical processing is not fixed by biology, but rather is shaped by the auditory experiences of each individual. Auditory cortical neurons in adult rats respond selectively to spectrotemporal features of complex sounds. These selective responses are predictive of rats’ behaviorally measured perceptual sensitivities. With extensive training, the abilities of rats to discriminate frequency‐modulated sounds improve. Recordings from cortical neurons in trained rats show increased sensitivities to features of the sounds used in training. These results demonstrate that discrimination training with biologically irrelevant complex sounds can change how cortical neurons process those sounds. Changes in cortical processing of complex sounds can also be induced by controlling activity in neuro...
• Zhang, L. I., Bao, S., & Merzenich, M. M. (2002). Disruption of primary auditory cortex by synchronous auditory inputs during a critical period. Proceedings of the National Academy of Sciences of the United States of America, 99(4), 2309-14.
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  In the primary auditory cortex (AI), the development of tone frequency selectivity and tonotopic organization is influenced by patterns of neural activity. Introduction of synchronous inputs into the auditory pathway achieved by exposing rat pups to pulsed white noise at a moderate intensity during P9-P28 resulted in a disrupted tonotopicity and degraded frequency-response selectivity for neurons in the adult AI. The latter was manifested by broader-than-normal tuning curves, multipeaks, and discontinuous, tone-evoked responses within AI-receptive fields. These effects correlated with the severe impairment of normal, developmental sharpening, and refinement of receptive fields and tonotopicity. In addition, paradoxically weaker than normal temporal correlations between the discharges of nearby AI neurons were recorded in exposed rats. In contrast, noise exposure of rats older than P30 did not cause significant change of auditory cortical maps. Thus, patterned auditory inputs appear to play a crucial role in shaping neuronal processing/decoding circuits in the primary auditory cortex during a critical period.
• Bao, S., Chan, V. T., & Merzenich, M. M. (2001). Cortical remodelling induced by activity of ventral tegmental dopamine neurons. Nature, 412(6842), 79-83.
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  Representations of sensory stimuli in the cerebral cortex can undergo progressive remodelling according to the behavioural importance of the stimuli. The cortex receives widespread projections from dopamine neurons in the ventral tegmental area (VTA), which are activated by new stimuli or unpredicted rewards, and are believed to provide a reinforcement signal for such learning-related cortical reorganization. In the primary auditory cortex (AI) dopamine release has been observed during auditory learning that remodels the sound-frequency representations. Furthermore, dopamine modulates long-term potentiation, a putative cellular mechanism underlying plasticity. Here we show that stimulating the VTA together with an auditory stimulus of a particular tone increases the cortical area and selectivity of the neural responses to that sound stimulus in AI. Conversely, the AI representations of nearby sound frequencies are selectively decreased. Strong, sharply tuned responses to the paired tones also emerge in a second cortical area, whereas the same stimuli evoke only poor or non-selective responses in this second cortical field in naive animals. In addition, we found that strong long-range coherence of neuronal discharge emerges between AI and this secondary auditory cortical area.
• Mercado, E., Bao, S., Orduña, I., Gluck, M. A., & Merzenich, M. M. (2001). Basal forebrain stimulation changes cortical sensitivities to complex sound. Neuroreport, 12(10), 2283-7.
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  Experience affects how brains respond to sound. Here, we examined how the sensitivity and selectivity of auditory cortical neuronal responses were affected in adult rats by the repeated presentation of a complex sound that was paired with basal forebrain stimulation. The auditory cortical region that was responsive to complex sound was 2-5 five times greater in area in paired-stimulation rats than in naive rats. Magnitudes of neuronal responses evoked by complex sounds were also greatly increased by associative pairing, as were the percentages of neurons that responded selectively to the specific spectrotemporal features that were paired with stimulation. These findings demonstrate that feature selectivity within the auditory cortex can be flexibly altered in adult mammals through appropriate intensive training.
• Zhang, L. I., Bao, S., & Merzenich, M. M. (2001). Persistent and specific influences of early acoustic environments on primary auditory cortex. Nature neuroscience, 4(11), 1123-30.
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  This study demonstrates that the adult form of 'tonotopic maps' of sound frequency in the rat primary auditory cortex (A1) arises from parallel developmental processes involving two cortical zones: the progressive differentiation and refinement of selectively tone-responsive receptive fields within an initially broadly-tuned posterior zone, and the progressive loss of tone-evoked, short-latency response over an initially large, very broadly tuned anterior zone. The formation of tonotopic maps in A1 was specifically influenced by a rat pup's early acoustic environments. Exposure to pulsed tones resulted in accelerated emergence and an expansion of A1 representations of those specific tone frequencies, as well as a deteriorated tonotopicity and broader-than-normal receptive fields. Thus, auditory experiences during early postnatal development are important in shaping the functional development of auditory cortical representations of specific acoustic environments.
• Bao, S., Chen, L., & Thompson, R. F. (2000). Learning- and cerebellum-dependent neuronal activity in the lateral pontine nucleus. Behavioral neuroscience, 114(2), 254-61.
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  The effects of inactivation of cerebellar deep nuclei and the lateral pontine nucleus on classical eyeblink conditioning with tone or lateral reticular nucleus (LRN) stimulation as conditioned stimuli (CSs) were examined. Inactivation of cerebellar deep nuclei abolished eyeblink conditioned responses (CRs) when the CS was either a tone or LRN stimulation. Inactivation of the lateral pontine nucleus prevented only the acquisition and retention of tone-evoked eyeblink CRs. Multiple-unit recording demonstrated that when LRN stimulation was used as the CS, inactivation of the interpositus nucleus abolished learning-related neuronal activity in the lateral pontine nucleus, whereas inactivation of pontine nucleus had little effect on similar activity in the interpositus nucleus. Thus, the learning-induced neuronal activity in the lateral pontine nucleus was most likely driven by the cerebellar interpositus nucleus.
• Bao, S., Chen, L., Qiao, X., & Thompson, R. F. (1999). Transgenic brain-derived neurotrophic factor modulates a developing cerebellar inhibitory synapse. Learning & memory (Cold Spring Harbor, N.Y.), 6(3), 276-83.
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  Brain-derived neurotrophic factor (BDNF) has been shown to promote synapse formation and maturation in neurons of many brain regions, including inhibitory synapses. In the cerebellum, the Golgi cell-granule cell GABAergic synaptic responses undergo developmental transition from slow-decaying to fast-decaying kinetics, which parallels a developmental increase of GABA(A) receptor alpha6 subunit expression in the cerebellar granule cells. In culture, BDNF accelerates the expression of GABA(A) receptor alpha6 subunit expression in granule cells. Here we examined synaptic GABA(A) response kinetics in BDNF transgenic mice. The mutant mouse, which carries a BDNF transgene driven by a beta-actin promoter, overexpresses BDNF (two- to fivefold increase compared with wild types) in all brain regions. Recordings of the spontaneous GABA(A) responses indicate that the decay time constant of the GABAergic responses decreases during early postnatal development; this transition is accelerated in the BDNF transgenic mouse. The amplitude of the spontaneous GABA(A) responses was also larger in the transgenic mouse than in the wild-type mouse. However, the frequency of the spontaneous GABA(A) responses were not different between the two groups. Our results suggest that BDNF may modulate GABAergic synapse maturation in the cerebellum.
• Chen, L., Bao, S., & Thompson, R. F. (1999). Bilateral lesions of the interpositus nucleus completely prevent eyeblink conditioning in Purkinje cell-degeneration mutant mice. Behavioral neuroscience, 113(1), 204-10.
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  The authors have previously demonstrated that Purkinje cell-degeneration (pcd) mutant mice are impaired in eyeblink conditioning (L. Chen et al., 1996a). The present study addresses the following 3 questions: (a) whether pcd mice perceive the conditioned and unconditioned stimuli as well as the wild-type mice, (b) whether pcd mice have a normal sensitization level, and (c) whether the residual learning in pcd mice is cerebellum-dependent. Results indicated that the pcd mice exhibited normal tone-induced responses in the cochlear nucleus and normal sensitivity to heat-induced pain. They showed a similar level of sensitization as the wild-type mice and were completely unable to learn conditioned eyeblinks after bilateral lesions aimed at the anterior interpositus nucleus. Thus, pcd mice are partially impaired in eyeblink conditioning because of a deficiency in learning mechanisms, and the residual learning in the pcd mice is mediated by the cerebellar nuclei.
• Chen, L., Bao, S., Qiao, X., & Thompson, R. F. (1999). Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proceedings of the National Academy of Sciences of the United States of America, 96(21), 12132-7.
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  The waggler, a neurological mutant mouse with a disrupted putative neuronal Ca(2+) channel gamma subunit, exhibits a cerebellar granule cell-specific brain-derived neurotrophic factor deficit, severe ataxia, and impaired eyeblink conditioning. Here, we show that multiple synapses of waggler cerebellar granule cells are arrested at an immature stage during development. Synaptic transmission is reduced at parallel fiber-Purkinje cell synapses. The Golgi cell-granule cell synaptic currents show immature kinetics associated with reduced gamma-aminobutyric acid type A receptor alpha6 subunit expression in granule cells. In addition, the mossy fiber-granule cell synapses exhibit N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs), but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs. Our results suggest that voltage-dependent Ca(2+) channels are involved in synapse maturation. This deficient synaptic transmission in the waggler cerebellum may account for their behavioral deficits.
• Bao, S., Chen, L., & Thompson, R. F. (1998). Classical eyeblink conditioning in two strains of mice: conditioned responses, sensitization, and spontaneous eyeblinks. Behavioral neuroscience, 112(3), 714-8.
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  Conditioned eyeblink responses (CRs), sensitization, and spontaneous eyeblinks were studied in C57BL/6J and BALB/c mice. Both strains of mice acquired CRs during 10 days of classical delay eyeblink conditioning. The BALB/c mice reached a higher asymptotic CR level than the C57BL/6J mice. The CRs were extinguished and recovered in both strains following conditioned stimulus-alone and paired conditioned stimulus-unconditioned stimulus training. During 10 days of explicitly unpaired training, the control groups showed no signs of sensitization and low incidence of spontaneous eyeblinks. When switched to paired training, the unpaired groups exhibited significant conditioned inhibition. These results suggest that strain differences must be considered in experimental design and data interpretation for these basic aspects of associative learning and memory.
• Bao, S., Chen, L., Qiao, X., Knusel, B., & Thompson, R. F. (1998). Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency. Learning & memory (Cold Spring Harbor, N.Y.), 5(4-5), 355-64.
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  In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.
• Qiao, X., Chen, L., Gao, H., Bao, S., Hefti, F., Thompson, R. F., & Knusel, B. (1998). Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 18(17), 6990-9.
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  In the spontaneous ataxic mutant mouse stargazer, there is a selective reduction of brain-derived neurotrophic factor (BDNF) mRNA expression in the cerebellum. BDNF protein levels in the cerebellum are reduced by 70%. Despite normal levels of full-length and truncated TrkB receptor, constitutive and neurotrophin-4/5-induced tyrosine phosphorylation was significantly reduced in several signal transduction molecules, including phospholipase-Cgamma1, erk1, and erk2. Morphological examination revealed an increased number of external granule cells at postnatal day 15 and the presence of abnormal neurons resembling immature granule cells in the adult. These abnormalities are associated with a severe impairment in the acquisition of classical eyeblink conditioning, indicating cerebellar malfunction. Our data suggest that normal BDNF expression and TrkB signal transduction in the cerebellum are necessary for learning and plasticity in this model.
• Kim, J. J., Shih, J. C., Chen, K., Chen, L., Bao, S., Maren, S., Anagnostaras, S. G., Fanselow, M. S., De Maeyer, E., Seif, I., & Thompson, R. F. (1997). Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 94(11), 5929-33.
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  Mice deficient in monoamine oxidase A (MAOA), an enzyme that metabolizes monoamines such as norepinephrine and serotonin, have elevated norepinephrine and serotonin levels in the frontal cortex, hippocampus, and cerebellum, compared with normal wild-type mice. Since monoamines in these areas are critically involved in a variety of behaviors, we examined learning and memory (using emotional and motor tasks) in MAOA mutant mice. The MAOA-deficient mice exhibited significantly enhanced classical fear conditioning (freezing to both tone and contextual stimuli) and step-down inhibitory avoidance learning. In contrast, eyeblink conditioning was normal in these mutant mice. The female MAOA-deficient mice also displayed normal species-typical maternal behaviors (nesting, nursing, and pup retrieval). These results suggest that chronic elevations of monoamines, due to a deletion of the gene encoding MAOA, lead to selective alterations in emotional behavior.
• Thompson, R. F., Bao, S., Chen, L., Cipriano, B. D., Grethe, J. S., Kim, J. J., Thompson, J. K., Tracy, J. A., Weninger, M. S., & Krupa, D. J. (1997). Associative learning. International review of neurobiology, 41, 151-89.
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  This chapter reviews evidence demonstrating the essential role of the cerebellum and its associated circuitry in the learning and memory of classical conditioning of discrete behavioral responses (e.g., eyeblink, limb flexion, head turn). It now seems conclusive that the memory traces for this basic category of associative learning are formed and stored in the cerebellum. Lesion, neuronal recording, electrical microstimulation, and anatomical procedures have been used to identify the essential conditioned stimulus (CS) circuit, including the pontine mossy fiber projections to the cerebellum; the essential unconditioned stimulus (US) reinforcing or teaching circuit, including neurons in the inferior olive (dorsal accessory olive) projecting to the cerebellum as climbing fibers; and the essential conditioned response (CR) circuit, including the interpositus nucleus, its projection via the superior cerebellar peduncle to the magnocellular red nucleus, and rubral projections to premotor and motor nuclei. Each major component of the eyeblink CR circuit was reversibly inactivated both in trained animals and over the course of training. In all cases in trained animals, inactivation abolished the CR (and the UR as well when motor nuclei were inactivated). When animals were trained during inactivation (and not exhibiting CRs) and then tested without inactivation, animals with inactivation of the motor nuclei, red nucleus, and superior peduncle had fully learned, whereas animals with inactivation of a very localized region of the cerebellum (anterior interpositus and overlying cortex) had not learned at all. Consequently, the memory traces are formed and stored in the cerebellum. Several alternative possibilities are considered and ruled out. Both the cerebellar cortex and the interpositus nucleus are involved in the memory storage process, suggesting that a phenomenon-like long-term depression (LTD) is involved in the cerebellar cortex and long-term potentiation (LTP) is involved in the interpositus. The experimental findings reviewed in this chapter provide perhaps the first conclusive evidence for the localization of a basic form of memory storage to a particular brain region, namely the cerebellum, and indicate that the cerebellum is indeed a cognitive machine.
• Chen, L., Bao, S., Lockard, J. M., Kim, J. K., & Thompson, R. F. (1996). Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 16(8), 2829-38.
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  Converging lines of evidence from rabbits, rats, and humans argue for the crucial involvement of the cerebellum in classical conditioning of the eyeblink/nictitating membrane response in mammals. For example, selective lesions (permanent or reversible) of the cerebellum block both acquisition and retention of eyeblink conditioning. Correspondingly, electrophysiological and brain-imaging studies indicate learning-related plasticity in the cerebellum. The involvement of the cerebellum in eyeblink conditioning is also supported by stimulation studies showing that direct stimulation of the two major afferents to the cerebellum (the mossy fibers emanating from the pontine nucleus and climbing fibers originating from the inferior olive) can substitute for the peripheral conditioned stimulus (CS) and unconditioned stimulus (US), respectively, to yield normal behavioral learning. In the present study, we examined the relative contribution of the cerebellar cortex versus deep nuclei (specifically the interpositus nucleus) in eyeblink learning by using mutant mice deficient of Purkinje cells, the exclusive output neurons of the cerebellar cortex. We report that Purkinje cell degeneration (pcd) mice exhibit a profound impairment in the acquisition of delay eyeblink conditioning in comparison with their wild-type littermates. Nevertheless, the pcd animals did acquire a subnormal level of conditioned eyeblink responses. In contrast, wild-type mice with lesions of the interpositus nucleus were completely unable to learn the conditioned eyeblink response. These results suggest that both cerebellar cortex and deep nuclei are important for normal eyeblink conditioning.
• Shibuki, K., Gomi, H., Chen, L., Bao, S., Kim, J. J., Wakatsuki, H., Fujisaki, T., Fujimoto, K., Katoh, A., Ikeda, T., Chen, C., Thompson, R. F., & Itohara, S. (1996). Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron, 16(3), 587-99.
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  Mice devoid of glial fibrillary acidic protein (GFAP), an intermediate filament protein specifically expressed in astrocytes, develop normally and do not show any detectable abnormalities in the anatomy of the brain. In the cerebellum, excitatory synaptic transmission from parallel fibers (PFs) or climbing fibers (CFs) to Purkinje cells is unaltered, and these synapses display normal short-term synaptic plasticity to paired stimuli in GFAP mutant mice. In contrast, long-term depression (LTD) at PF-Purkinje cell synapses is clearly deficient. Furthermore, GFAP mutant mice exhibited a significant impairment of eyeblink conditioning without any detectable deficits in motor coordination tasks. These results suggest that GFAP is required for communications between Bergmann glia and Purkinje cells during LTD induction and maintenance. The data support the notion that cerebellar LTD is a cellular mechanism closely associated with eyeblink conditioning, but is not essential for motor coordination tasks tested.
• Chen, C., Kano, M., Abeliovich, A., Chen, L., Bao, S., Kim, J. J., Hashimoto, K., Thompson, R. F., & Tonegawa, S. (1995). Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. Cell, 83(7), 1233-42.
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  It is generally believed that a smooth execution of a compound movement, or motor coordination, requires learning of component movements as well as experience-based refinement of the motor program as a whole. PKC gamma mutant mice display impaired motor coordination but intact eyeblink conditioning, a form of component movement learning. Cerebellar long-term depression, a putative cellular mechanism for component motor learning, is also unimpaired. Thus, PKC gamma mutant mice are defective in refinement of the motor program. In the accompanying paper, we demonstrate that innervation of multiple climbing fibers onto Purkinje cells persists in adulthood in these mutant mice. We propose that this defective elimination of surplus climbing fibers underlies motor discoordination.

Presentations

• Bao, S. (2019, Feb). Role of cortical PV+ interneuron in auditory processing and perception. Winter Conference on Brain Research. Snowmass, Colorado.
• Bao, S. (2019, Nov). Mechanisms of Hearing Loss-Induced Plasticity and Pathologies. Sensory Neuroscience Forum. Chongqing, China.
• Bao, S. (2018, June). Mechanisms of Hearing Loss-Induced Plasticity and Pathologies. Gordon Research Conference—Neuroplasticity and Maladaptation of Sensory Systems. Hong Kong.
• Bao, S. (2018, June). Neuroinflammation and Neural Plasticity in Traumatic Brain Injury. Suzhou Institute of Systems Medicine. Suzhou, China: Suzhou Institute of Systems Medicine.
• Bao, S. (2018, June). Neuroinflammation in Traumatic Brain Injury, Hearing Loss and Hypoxia. Guangzhou Medical University. Guangzhou Medical University: Guangzhou Medical University.
• Bao, S. (2016, December). Mechanisms of phantom sound perception. Invited seminar, City University of Hong Kong. City University of Hong Kong, Hong Kong: Department of Biomedical Sciences.
• Bao, S. (2016, March). Optogenetic approaches to understanding CNS auditory processing. MENDEL DAY 2016/NEUROGENETICS DATABLITZ. University of Arizona, Tucson: Department of Neuroscience, School of Mind, Brain & Behavior.
• Bao, S. (2016, September). Neural Mechanisms Underlying Phantom Sound Perception. Invited seminar, University of Michigan. University of Michigan Medical School: Department of Otolaryngology – Head & Neck Surgery.

Poster Presentations

• Schwartz, B., Wang, W., & Bao, S. (2019, October). Epigenetic modulation of auditory cortical critical period plasticity. Society for Neuroscience Annual Meeting. Chicago, Illinoi: Society for Neuroscience.
• Wang, W., Zhang, L., Zinsmaier, A. K., Patterson, G., Leptich, E., Shoemaker, S., Yatskievych, T., Zhang, j., Yang, S., Pace, E., & Bao, S. (2019, Feb.). Neuroinflammation Mediates Noise-Induced Synaptic Imbalance and Tinnitus in Rodent Models. Association for Research in Otolaryngology 42nd Midwinter Meeting. Baltimore, Maryland.
• Masri, S., Luo, H., Pace, E., Zhang, J., & Bao, S. (2016, November). Distortion of tonotopic maps in auditory cortex of rats following blast exposure. Society for Neuroscience Annual Meeting. San Diego, California: Society for Neuroscience.