- Assistant Professor, Psychology
- Assistant Professor, Neurology
- Assistant Professor, Evelyn F Mcknight Brain Institute
- Assistant Professor, Neuroscience - GIDP
- Assistant Professor, BIO5 Institute
- Member of the Graduate Faculty
Fabian Fernandez, Ph.D., is an Assistant Professor of Psychology and Neurology, and a Fellow with the BIO5 Institute at the University of Arizona (UA). Dr. Fernandez earned his B.S. in a self-tailored interdisciplinary program in Neurobiological Science from the University of Florida, Gainesville, in 2002, and a Ph.D. in Neurosciences from Stanford University in 2008. While at Stanford, he devised the first hypothesis based pharmacological treatment for intellectual disabilities accompanying Down syndrome and worked with a collaborative team to define the memory problems associated with chronic circadian dysrhythmia. Fabian held positions in industry and at Johns Hopkins University as a research affiliate before joining the UA faculty in 2015.
- Ph.D. Neurosciences
- Stanford University, Palo Alto, California, United States
- Pharmacotherapy for Intellectual Disabilities Associated with Down Syndrome: Work in a Mouse Model
- B.S. IDS - Neurobiological Sciences
- University of Florida, Gainesville, Florida, United States
- Nociceptin/orphanin FQ increases anxiety-related behavior and circulating levels of corticosterone during neophobic tests of anxiety.
- BIO5 Fellow
- University of Arizona, BIO5 Institute, Fall 2015
- Bisgrove Scholar
- Science Foundation Arizona, Fall 2015
- Postdoctoral Fellowship
- La Fondation Jerome-Lejeune, Fall 2007
- Ruth L. Kirschstein NRSA Research Service Award
- National Institutes of Health, Spring 2007
- NSF Predoctoral Fellowship
- National Science Foundation, Fall 2003
As a UA faculty, Dr. Fernandez’s work focuses on circadian timekeeping, an ability that allows us to maintain a close relationship between the inner workings of our mind to the natural schedule of day and night produced by the earth's rotation about its axis. The eye uses a photoreceptor system to process circadian time that is independent of the one it uses for image perception. This system extends from the back of the retina directly to where the brain’s internal clock is located and reacts to the appearance of light presented at different points during the evening. How the brain’s clock ticks in response to illumination of the eye is not well understood. Dr. Fernandez’s research is determining what characteristics of light most influence the brain’s timekeeping ability. With data he is systematically collecting, he will develop the world’s first programming language for how to strategically deliver photic information to normalize the clock's operation when it has weakened. His ultimate goal will be to embody this programming language in a small medical device that can be activated to strengthen circadian rhythms and cognition when a person is asleep. Memory loss occurs during normal aging, is one of the earliest features of cognitive, age- related disease, and is itself presaged by fragmentation of a person’s daily schedule of activity. By augmenting circadian rhythmicity with the medical device—by orienting an individual's cadence so that they are awake during the day and at rest during the evening—Dr. Fernandez hopes to prolong the time the people of Arizona can thrive as they enter the mature stages of life.
Honors ThesisPSY 498H (Fall 2022)
Sleep + Sleep DisordersPSY 478 (Fall 2022)
Sleep + Sleep DisordersPSY 578 (Fall 2022)
Directed ResearchPSYS 492 (Spring 2022)
DissertationNRSC 920 (Spring 2022)
DissertationPSY 920 (Spring 2022)
Honors ThesisPSY 498H (Spring 2022)
ResearchPSY 900 (Spring 2022)
DissertationNRSC 920 (Fall 2021)
DissertationPSY 920 (Fall 2021)
Honors ThesisPSIO 498H (Fall 2021)
Honors ThesisPSY 498H (Fall 2021)
ResearchPSY 900 (Fall 2021)
DissertationNRSC 920 (Spring 2021)
Honors ThesisPSIO 498H (Spring 2021)
PreceptorshipPSY 391 (Spring 2021)
ResearchPSY 900 (Spring 2021)
Sleep + Sleep DisordersPSY 478 (Spring 2021)
Directed ResearchPSYS 492 (Fall 2020)
DissertationNRSC 920 (Fall 2020)
ResearchPSY 900 (Fall 2020)
Directed ResearchPSYS 492 (Summer I 2020)
Master's ReportPSY 909 (Spring 2020)
ResearchNRSC 900 (Spring 2020)
ResearchPSY 900 (Spring 2020)
Sleep + Sleep DisordersPSY 478 (Spring 2020)
Sleep + Sleep DisordersPSY 578 (Spring 2020)
Master's ReportPSY 909 (Fall 2019)
ResearchNRSC 900 (Fall 2019)
Cognitive PsychologyPSY 596F (Spring 2019)
Honors ThesisNSCS 498H (Spring 2019)
Independent StudyPSIO 499 (Spring 2019)
ResearchNRSC 900 (Spring 2019)
Directed ResearchPSIO 492 (Fall 2018)
Honors ThesisNSCS 498H (Fall 2018)
Independent StudyPSY 499 (Fall 2018)
ResearchNRSC 900 (Fall 2018)
ResearchPSY 900 (Fall 2018)
Directed ResearchPSIO 492 (Spring 2018)
Honors ThesisNSCS 498H (Spring 2018)
ResearchNRSC 900 (Spring 2018)
Sleep + Sleep DisordersPSY 478 (Spring 2018)
Sleep + Sleep DisordersPSY 578 (Spring 2018)
Directed ResearchPSIO 492 (Fall 2017)
Honors ThesisNSCS 498H (Fall 2017)
ResearchNRSC 900 (Fall 2017)
Sleep + Sleep DisordersPSY 478 (Spring 2017)
Sleep + Sleep DisordersPSY 578 (Spring 2017)
Directed ResearchPSIO 492 (Summer I 2016)
Honors ThesisNSCS 498H (Spring 2016)
Intro to BiopsychologyPSY 302 (Spring 2016)
- Fernandez, F. X. (2022). Current Insights into Optimal Lighting for Promoting Sleep and Circadian Health: Brighter Days and the Importance of Sunlight in the Built Environment. Nature and Science of Sleep, 14, 25-39.More infoThis perspective considers the possibility that daytime's intrusion into night made possible by electric lighting may not be as pernicious to sleep and circadian health as the encroachment of nighttime into day wrought by 20th century architectural practices that have left many people estranged from sunlight.
- Kaladchibachi, S., Negelspach, D. C., Zeitzer, J. M., & Fernandez, F. X. (2022). Investigation of the aging clock's intermittent-light responses uncovers selective deficits to green millisecond flashes. Journal of Photochemistry and Photobiology B: Biology, 228, 112389.More infoThe central pacemaker of flies, rodents, and humans generates less robust circadian output signals across normative aging. It is not well understood how changes in light sensitivity might contribute to this phenomenon. In the present study, we summarize results from an extended data series (n = 5681) showing that the locomotor activity rhythm of aged Drosophila can phase-shift normally to intermittently spaced episodes of bright polychromatic light exposure (600 lx) but that deficits emerge in response to 8, 16, and 120-millisecond flashes of narrowband blue (λ, 452 nm) and green (λ, 525 nm) LED light. For blue, phase-resetting of the activity rhythm of older flies is not as energy efficient as it is in younger flies at the fastest flash-exposures tested (8 milliseconds), suggesting there might be different floors of light duration necessary to incur photohabituation in each age group. For green, the responses of older flies are universally crippled relative to those of younger flies across the slate of protocols we tested. The difference in green flash photosensitivity is one of the most salient age-related phenotypes that has been documented in the circadian phase-shifting literature thus far. These data provide further impetus for investigations on pacemaker aging and how it might relate to changes in the circadian system's responses to particular sequences of light exposure tuned for wavelength, intensity, duration, and tempo.
- Mason, B. J., Tubbs, A. S., Fernandez, F. X., & Grandner, M. A. (2022). Spectrophotometric properties of commercially available blue blockers across multiple lighting conditions. Chronobiology International, 1-12.More infoLenses that filter short-wavelength ("blue") light are commercially marketed to improve sleep and circadian health. Despite their widespread use, minimal data are available regarding their comparative efficacy in curtailing blue light exposure while maintaining visibility. Fifty commercial lenses were evaluated using five light sources: a blue LED array, a computer tablet display, an incandescent lamp, a fluorescent overhead luminaire, and sunlight. Absolute irradiance was measured at baseline and for each lens across the visual spectrum (380-780 nm), which allowed calculation of percent transmission. Transmission specificity was also calculated to determine whether light transmission was predominantly circadian-proficient (455-560 nm) or non-proficient (380-454 nm and 561-780 nm). Lenses were grouped by tint and metrics were compared between groups. Red-tinted lenses exhibited the lowest transmission of circadian-proficient light, while reflective blue lenses had the highest transmission. Orange-tinted lenses transmitted similar circadian-proficient light as red-tinted lenses but transmitted more non-circadian-proficient light, resulting in higher transmission specificity. Orange-tinted lenses had the highest transmission specificity while limiting biologically active light exposure in ordinary lighting conditions. Glasses incorporating these lenses currently have the greatest potential to support circadian sleep-wake rhythms.
- Negelspach, D. C., Kaladchibachi, S., Dollish, H. K., & Fernandez, F. X. (2022). Sleep Deprivation Does Not Influence Photic Resetting of Circadian Activity Rhythms in Drosophila. Clocks & Sleep, 4(1), 202-207.More infoPrevious investigations in humans and rodent animal models have assessed the interplay of sleep in the circadian system's phase responses to nighttime light exposure. The resulting data have been mixed, but generally support a modulatory role for sleep in circadian photic resetting (not an absolute requirement). have been historically used to provide important insights in the sleep and circadian sciences. However, no experiments to date have evaluated how immediate sleep need or recent sleep history affects their pacemaker's phase readjustments to light. We did so in the current study by (1) forcing separate groups of animals to stay awake for 1 or 4 h after they were shown a broadspectrum pulse (15 min during the first half of the night, 950 lux), or (2) placing them on a restricted sleep schedule for a week before light presentation without any subsequent sleep disruption. Forced sleep restriction, whether acute or chronic, did not alter the size of light-induced phase shifts. These data are consistent with observations made in other diurnal animals and raise the possibility, more broadly, that phototherapies applied during sleep-such as may be necessary during the winter months-may still be efficacious in individuals experiencing sleep-continuity problems such as insomnia.
- Tubbs, A. S., Fernandez, F. X., Grandner, M. A., & Perlis, M. L. (2022). Emerging evidence for sleep instability as a risk mechanism for non-suicidal self-injury. Sleep.
- Tubbs, A. S., Fernandez, F., Grandner, M. A., Perlis, M. L., & Klerman, E. B. (2022). The mind after midnight: Nocturnal wakefulness, behavioral dysregulation, and psychopathology. Frontiers in Network Physiology, 1, 830338. doi:https://doi.org/10.3389/fnetp.2021.830338
- Tubbs, A. S., Ghani, S. B., Valencia, D., Jean-Louis, G., Killgore, W. D., Fernandez, F., & Grandner, M. A. (2022). Racial/ethnic minorities have greater declines in sleep duration with higher risk of cardiometabolic disease: an analysis of the U.S. National Health Interview Survey. Sleep Epidemiology, 2, 100022. doi:10.1016/j.sleepe.2022.100022
- Tubbs, A. S., Hendershot, S., Ghani, S. B., Nadorff, M. R., Drapeau, C. W., Fernandez, F. X., Perlis, M. L., & Grandner, M. A. (2022). Social Jetlag and Other Aspects of Sleep Are Linked to Non-Suicidal Self-Injury Among College Students. Archives of Suicide Research : official journal of the International Academy for Suicide Research, 1-18.More infoDisrupted sleep is associated with non-suicidal self-injury (NSSI) in young adults, but many specific features of sleep continuity and timing have yet to be examined. Additionally, the psychological mechanisms linking sleep to NSSI are unclear. The present study evaluated 14 sleep variables as classifiers of lifetime or recent NSSI and examined potential confounding and mediating factors.
- Dollish, H. K., Kaladchibachi, S., Negelspach, D. C., & Fernandez, F. X. (2021). The Drosophila Circadian Phase Response Curve to Light: Conservation across Seasonally Relevant Photoperiods and Anchorage to Sunset. Physiology & Behavior, 113691.More infoPhotic history, including the relative duration of day versus night in a 24-hour cycle, is known to influence subsequent circadian responses to light in mammals. Whether such modulation is present in Drosophila is currently unknown. To date, all photic phase-response curves (PRCs) generated from Drosophila have done so with animals housed under seasonally agnostic equatorial photoperiods with alternating 12-hour segments of light and darkness. However, the genus contains thousands of species, some of which populate high and low-latitude habitats (20-50° north or south of the Equator) where seasonal variations in the light-dark schedule are pronounced. Here, we address this disconnect by constructing the first high-resolution Drosophila seasonal atlas for light-induced circadian phase-resetting. Testing the light responses of over 4, 000 Drosophila at 120 timepoints across 5 seasonally-relevant rectangular photoperiods (i.e., LD 8:16, 10:14, 12:12, 14:10, and 16:8; 24 hourly intervals surveyed in each), we determined that many aspects of the fly circadian PRC waveform are conserved with increasing daylength. Surprisingly though, irrespective of LD schedule, the start of the PRCs always remained anchored to the timing of subjective sunset, creating a differential overlap of the advance zone with the morning hours after subjective sunrise that was maximized under summer photoperiods and minimized under winter photoperiods. These data suggest that there may be differences in flies versus mammals as to how the photoperiod modulates the waveform and amplitude of the circadian PRC to light. On the other hand, they support the possibility that the lights-off transition determines the phase-positioning of photic PRCs across seasons and across species. More work is necessary to test this claim and whether it might factor into the timing of seasonal light responses in humans.
- Fernandez, F. X., Kaladchibachi, S., & Negelspach, D. C. (2021). Resilience in the suprachiasmatic nucleus: Implications for aging and Alzheimer's disease. Experimental Gerontology, 147, 111258.More infoMany believe that the circadian impairments associated with aging and Alzheimer's disease are, simply enough, a byproduct of tissue degeneration within the central pacemaker, the suprachiasmatic nucleus (SCN). However, the findings that have accumulated to date examining the SCNs obtained postmortem from the brains of older individuals, or those diagnosed with Alzheimer's disease upon autopsy, suggest only limited atrophy. We review this literature as well as a complementary one concerning fetal-donor SCN transplant, which established that many circadian timekeeping functions can be maintained with rudimentary (structurally limited) representations of the SCN. Together, these corpora of data suggest that the SCN is a resilient brain region that cannot be directly (or solely) implicated in the behavioral manifestations of circadian disorganization often witnessed during aging as well as early and late progression of Alzheimer's disease. We complete our review by suggesting future directions of research that may bridge this conceptual divide and briefly discuss the implications of it for improving health outcomes in later adulthood.
- Gao, F. J., Klinedinst, D., Fernandez, F. X., Cheng, B., Savonenko, A., Devenney, B., Li, Y., Wu, D., Pomper, M. G., & Reeves, R. H. (2021). Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates. Acta Neuropathologica Communications, 9(1), 137.More infoDown syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model "Ts65Dn" shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice "Camk2a-tTA;TRE-hShh" and "Pcp2-tTA;TRE-hShh" induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.
- Grandner, M. A., & Fernandez, F. X. (2021). The translational neuroscience of sleep: A contextual framework. Science (New York, N.Y.), 374(6567), 568-573.More info[Figure: see text].
- Lee, R., McGee, A., & Fernandez, F. X. (2021). Systematic review of drugs that modify the circadian system's phase-shifting responses to light exposure. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.More infoWe searched PubMed for primary research quantifying drug modification of light-induced circadian phase-shifting in rodents. This search, conducted for work published between 1960 and 2018, yielded a total of 146 papers reporting results from 901 studies. Relevant articles were those with any extractable data on phase resetting in wildtype (non-trait selected) rodents administered a drug, alongside a vehicle/control group, near or at the time of exposure. Most circadian pharmacology experiments were done using drugs thought to act directly on either the brain's central pacemaker, the suprachiasmatic nucleus (SCN), the SCN's primary relay, the retinohypothalamic tract, secondary pathways originating from the medial/dorsal raphe nuclei and intergeniculate leaflet, or the brain's sleep-arousal centers. While the neurotransmitter systems underlying these circuits were of particular interest, including those involving glutamate, gamma-aminobutyric acid, serotonin, and acetylcholine, other signaling modalities have also been assessed, including agonists and antagonists of receptors linked to dopamine, histamine, endocannabinoids, adenosine, opioids, and second-messenger pathways downstream of glutamate receptor activation. In an effort to identify drugs that unduly influence circadian responses to light, we quantified the net effects of each drug class by ratioing the size of the phase-shift observed after administration to that observed with vehicle in a given experiment. This allowed us to organize data across the literature, compare the relative efficacy of one mechanism versus another, and clarify which drugs might best suppress or potentiate phase resetting. Aggregation of the available data in this manner suggested that several candidates might be clinically relevant as auxiliary treatments to suppress ectopic light responses during shiftwork or amplify the circadian effects of timed bright light therapy. Future empirical research will be necessary to validate these possibilities.
- Lee, R., Tapia, A., Kaladchibachi, S., Grandner, M. A., & Fernandez, F. X. (2021). Meta-analysis of light and circadian timekeeping in rodents. Neuroscience and Biobehavioral Reviews, 123, 215-229.More infoWe conducted a meta-analysis of papers published over the past half-century (1964-2017) that quantified the phase-shifting effects of timed light exposure on rodent locomotor rhythms. Descriptive statistics were tabulated in order to explore the extent to which these studies were generalizable across species, sex, age, circadian timing, and light sources. Attempts at understanding photic resetting were primarily targeted at younger male animals, with particular emphases placed on characterizing the pacemaker systems of C57BL/6 mice and Syrian hamsters during the parts of their subjective night most sensitive to delivery of white-fluorescent light. With subsequent analyses restricted to these rodent models, we then assessed the relationship between luminous exposure (via broadspectrum emission) and phase-shifting through a series of linear regressions. Monotonically increasing illuminance-response functions were noted at most circadian times surveyed. In the aggregate, our results show that previous research conducted on light's regulation of circadian timekeeping has been skewed in design with respect to several important biological variables. This bias might limit translation of phototherapy-relevant data to women and older individuals.
- Rahman, S. A., Fernandez, F. X., & Spitschan, M. (2021). Editorial: Translation and Processing of Light by the Non-image Forming Visual System-Context, Mechanisms and Applications. Frontiers in Neurology, 12, 727849.
- Tubbs, A. S., Fernandez, F. X., Ghani, S. B., Karp, J. F., Patel, S. I., Parthasarathy, S., & Grandner, M. A. (2021). Prescription medications for insomnia are associated with suicidal thoughts and behaviors in two nationally representative samples. Journal of Clinical Sleep Medicine : official publication of the American Academy of Sleep Medicine.More infoZ-drugs (eszopiclone, zolpidem, and zaleplon) are commonly used for insomnia, but are also associated with suicide risk. However, it is unclear if this association is unique to Z-drugs. Therefore, the present study estimated the associations between multiple prescription insomnia medications and suicidal thoughts and behaviors.
- Tubbs, A. S., Fernandez, F. X., Johnson, D. A., Perlis, M. L., & Grandner, M. A. (2021). Nocturnal and Morning Wakefulness Are Differentially Associated With Suicidal Ideation in a Nationally Representative Sample. The Journal of Clinical Psychiatry, 82(6).More infoPrior studies indicate nocturnal wakefulness is associated with suicide, while morning wakefulness is linked to reduced suicidal ideation. These relationships, however, may be confounded by sociodemographic factors. Therefore, this study investigated whether timing of wakefulness was associated with suicidal ideation in a nationally representative sample.
- Tubbs, A. S., Fernandez, F. X., Perlis, M. L., Hale, L., Branas, C. C., Barrett, M., Chakravorty, S., Khader, W., & Grandner, M. A. (2021). Suicidal ideation is associated with nighttime wakefulness in a community sample. Sleep, 44(1).More infoNocturnal wakefulness is a risk factor for suicide and suicidal ideation in clinical populations. However, these results have not been demonstrated in general community samples or compared to sleep duration or sleep quality. The present study explored how the timing of wakefulness was associated with suicidal ideation for weekdays and weekends.
- Wills, C., Ghani, S., Tubbs, A., Fernandez, F. X., Athey, A., Turner, R., Robbins, R., Patterson, F., Warlick, C., Alfonso-Miller, P., Killgore, W. D., & Grandner, M. A. (2021). Chronotype and social support among student athletes: impact on depressive symptoms. Chronobiology International, 38(9), 1319-1329.More infoPrevious studies have shown individuals with evening chronotype to have a greater likelihood for depression (self-reported and clinical ratings), especially in young adults. However, the mechanisms for this relationship remain unknown. Low levels of social support may be a plausible mechanism: young adults with evening chronotypes are awake when others are sleeping, which may lead to feelings of isolation or low support. This study examined links between chronotype, depression, and social support in relationship subtypes within a group of university student athletes. Data were obtained from 189 NCAA Division-I student athletes across all sports. Chronotype was assessed with the Circadian Energy Scale and ranged from -2 (definitely morning type) to +2 (definitely evening type). Depressive symptoms were assessed with Center for Epidemiological Studies Depression scale. Social support was assessed with the Multidimensional Scale of Perceived Social Support, which included subscales for Family, Friends, and Significant Other. A subscale for Team was created using the items from the Friends subscale (changing the word "friends" to "teammates"). Regression analyses adjusted for age, sex, and minority status. More evening chronotype was associated with higher reported depressive symptoms ( = .018), lower overall perceived social support ( = .001), and lower perceived social support specifically provided by family (
- Wong, K. Y., & Fernandez, F. (2021). Circadian responses to light-flash exposure: Conceptualization and new data guiding future directions. Frontiers in Neurology, 12, 627550. doi:https://doi.org/10.3389/fneur.2021.627550
- Fernandez, F. X., Flygare, J., & Grandner, M. A. (2020). Narcolepsy and COVID-19: sleeping on an opportunity?. Journal of Clinical Sleep Medicine : official publication of the American Academy of Sleep Medicine, 16(8), 1415.
- Giordano, K. R., Denman, C. R., Dollish, H. K., Fernandez, F., Lifshitz, J., Akhter, M., & Rowe, R. K. (2020). Intracerebral hemorrhage in the mouse altered sleep-wake patterns and activated microglia. Experimental Neurology, 327, 113242.More infoSleep-wake disturbances are both a risk factor and reported morbidity for intracerebral hemorrhage (ICH). ICH begins with a ruptured blood vessel and blood leakage into the parenchyma. In response to initial damage, pathophysiological processes ensue that both exacerbate and repair damage. Inflammation is a hallmark process of ICH, which includes microglia activation and increased cytokine signaling. Due to the dual role of cytokines as inflammatory signaling proteins and sleep regulatory substances (SRSs), we hypothesized that ICH would activate microglia, increase SRSs, and alter sleep-wake patterns following an experimental model of ICH in the mouse. Male mice were randomized to receive an injection of collagenase (ICH; n = 8) or saline (sham; n = 11) in the striatum of the right hemisphere. Sleep-wake activity was recorded for 6 full days after ICH via noninvasive sleep cages. Blood and tissue were collected at 7 days after ICH to quantify pro-inflammatory cytokines/SRSs (IL-1β, TNF-α, IL-6) and microglia deramification by skeleton analysis. There was an overall injury effect on sleep in mice subjected to ICH at the transition from dark (wake) to light (sleep) at 2, 3, 4, 5, and 6 days after ICH compared with shams. Further analysis confirmed that ICH mice had significantly earlier wake offsets at the dark/light transition and more robust circadian patterns of wake behavior than saline control mice. Spatiotemporal skeleton analysis indicated an increase in microglial cell number with a decrease in endpoints per cell (decreased ramification) for the ipsilateral ICH perihematomal region compared with saline control. There were no changes to plasma cytokine levels at 7 days after ICH when comparing each condition. This is the first known study to show changes in sleep-wake patterns after experimental ICH. Elucidation of mechanisms that link sleep, inflammation, and ICH offers new pharmacological opportunities and rehabilitative strategies to improve recovery in stroke patients.
- Khader, W. S., Fernandez, F. X., Seixas, A., Knowlden, A., Ellis, J., Williams, N., Hale, L., Branas, C., Perlis, M., Jean-Louis, G., Killgore, W. D., Alfonso-Miller, P., & Grandner, M. A. (2020). What makes people want to make changes to their sleep? Assessment of perceived risks of insufficient sleep as a predictor of intent to improve sleep. Sleep Health.More infoThe objective of the present study is to identify which underlying beliefs about the impact of sleep on health may motivate change in sleep behavior.
- Khader, W. S., Tubbs, A. S., Haghighi, A., Athey, A. B., Killgore, W. D., Hale, L., Perlis, M. L., Gehrels, J. A., Alfonso-Miller, P., Fernandez, F. X., & Grandner, M. A. (2020). Onset insomnia and insufficient sleep duration are associated with suicide ideation in university students and athletes. Journal of Affective Disorders, 274, 1161-1164.More infoPrevious work has shown that poor sleep is a prospective risk factor for suicide in clinical populations and might contribute to risk in the general population. The present study evaluated whether sleep distress, onset insomnia, and insufficient sleep are associated with suicide ideation in university students and athletes participating in the 2011-2014 National College Health Assessment (NCHA; n = 113,185).
- Killgore, W. D., Cloonan, S. A., Taylor, E. C., Fernandez, F., Grandner, M. A., & Dailey, N. S. (2020). Suicidal ideation during the COVID-19 pandemic: The role of insomnia. Psychiatry Research, 290, 113134.More infoThere is growing concern over the potential for increased suicide risk in vulnerable populations as the COVID-19 pandemic unfolds. To contextualize this risk during the first weeks of the nationwide lockdown efforts, we had 1,013 U.S. adults complete questionnaires assessing worries over COVID-19, insomnia severity, and suicidal ideation. Anxiety about COVID-19 correlated positively with insomnia severity and suicidal ideation. Analysis revealed that the statistical association between pandemic fears and suicidal thinking was fully accounted for by insomnia severity, suggesting that interventions aimed at improving sleep may be useful in reducing suicide risk during the current pandemic.
- Snyder, H. M., Bain, L. J., Brickman, A. M., Carrillo, M. C., Esbensen, A. J., Espinosa, J. M., Fernandez, F., Fortea, J., Hartley, S. L., Head, E., Hendrix, J., Kishnani, P. S., Lai, F., Lao, P., Lemere, C., Mobley, W., Mufson, E. J., Potter, H., Zaman, S. H., , Granholm, A. C., et al. (2020). Further understanding the connection between Alzheimer's disease and Down syndrome. Alzheimer's & Dementia : the journal of the Alzheimer's Association, 16(7), 1065-1077.More infoImproved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.
- Tubbs, A. S., Harrison-Monroe, P., Fernandez, F. X., Perlis, M. L., & Grandner, M. A. (2020). When reason sleeps: attempted suicide during the circadian night. Journal of Clinical Sleep Medicine : official publication of the American Academy of Sleep Medicine, 16(10), 1809-1810.More infoDisrupted sleep and nocturnal wakefulness are evidence-based risk factors for suicidal thoughts and behaviors. We present a suicide attempt following a rapid increase in nocturnal wakefulness. This case illustrates how nocturnal wakefulness may drive suicide risk through circadian misalignment.
- Tubbs, A. S., Khader, W., Fernandez, F., & Grandner, M. A. (2020). The common denominators of sleep, obesity, and psychopathology. Current Opinion in Psychology, 34, 84-88.More infoSleep is an important contributor to mental and physical health. Insomnia, nightmares, and other sleep disturbances are closely linked to depression, anxiety, weight gain, diabetes, and progression of cardiometabolic disease. The high comorbidity between sleep problems, obesity, and mental illness suggest that common mechanisms are at work between them. This review discusses the presence of bivariate relations between sleep, obesity, and psychopathology, as well as the limited evidence suggesting interactions among all three. While the review identifies obstructive sleep apnea, food intake, and inflammation as potential linking mechanisms, the dearth of current literature limits strong conclusions. More data is needed to evaluate the potential moderating/mediating influences between sleep, obesity, and mental health.
- Tubbs, A. S., Perlis, M. L., Basner, M., Chakravorty, S., Khader, W., Fernandez, F., & Grandner, M. A. (2020). Relationship of Nocturnal Wakefulness to Suicide Risk Across Months and Methods of Suicide. The Journal of Clinical Psychiatry, 81(2).More infoInsomnia is a risk factor for suicide, and the risk of suicide after accounting for population wakefulness is disproportionately highest at night. This study investigated whether this risk varied across months and/or methods of suicide.
- Fernandez, F. (2019). Circadian Responses to Fragmented Light: Research Synopsis in Humans. The Yale Journal of Biology and Medicine, 92(2), 337-348.More infoLight is the chief signal used by the human circadian pacemaker to maintain precise biological timekeeping. Though it has been historically assumed that light resets the pacemaker's rhythm in a dose-dependent fashion, a number of studies report enhanced circadian photosensitivity to the initial moments of light exposure, such that there are quickly diminishing returns on phase-shifting the longer the light is shown. In the current review, we summarize findings from a family of experiments conducted over two decades in the research wing of the Brigham and Women's Hospital that examined the human pacemaker's responses to standardized changes in light patterns generated from an overhead fluorescent ballast. Across several hundred days of laboratory recording, the research group observed phase-shifts in the body temperature and melatonin rhythms that scaled with illuminance. However, as suspected, phase resetting was optimized when exposure occurred as a series of minute-long episodes separated by periods of intervening darkness. These observations set the stage for a more recent program of study at Stanford University that evaluated whether the human pacemaker was capable of integrating fragmented bursts of light in much the same way it perceived steady luminance. The results here suggest that ultra-short durations of light-lasting just 1-2 seconds in total-can elicit pacemaker responses rivaling those created by continuous hour-long stimulation if those few seconds of light are evenly distributed across the hour as discreet 2-millisecond pulses. We conclude our review with a brief discussion of these findings and their potential application in future phototherapy techniques.
- Grandner, M. A., Khader, W. S., Warlick, C. D., & Fernandez, F. (2019). Acculturation and sleep: implications for sleep and health disparities. Sleep, 42(3).
- Kaladchibachi, S., Negelspach, D. C., & Fernandez, F. (2019). Responses to Intermittent Light Stimulation Late in the Night Phase Before Dawn. Clocks & Sleep, 1(1), 26-41.More infoThe circadian clock is comprised of two oscillators that independently track sunset (evening) and sunrise (morning), though little is known about how light responses differ in each. Here, we quantified the morning oscillator's responses to 19 separate pulse trains, collecting observations from over 1300 at ZT23. Our results show that the advances in activity onset produced by these protocols depended on the tempo of light administration even when total exposure was conserved across a 15-min window. Moreover, patterns of stimulation previously shown to optimize the evening oscillator's delay resetting at ZT13 (an hour after dusk) were equally effective for the M oscillator at ZT23 (an hour before dawn), though the morning oscillator was by comparison more photosensitive and could benefit from a greater number of fractionation strategies that better converted light into phase-shifting drive. These data continue to build the case that the reading frames for the pacemaker's time-of-day estimates at dusk and dawn are not uniform and suggest that the "photologic" for the evening versus morning oscillator's resetting might be dissociable.
- Kaladchibachi, S., Negelspach, D. C., Zeitzer, J. M., & Fernandez, F. (2019). Optimization of circadian responses with shorter and shorter millisecond flashes. Biology Letters (Royal Society Publishing), 15(8), 20190371.More infoRecent work suggests that the circadian pacemaker responds optimally to millisecond flashes of light, not continuous light exposure as has been historically believed. It is unclear whether these responses are influenced by the physical characteristics of the pulsing. In the present study, Drosophila (n = 2199) were stimulated with 8, 16 or 120 ms flashes. For each duration, the energy content of the exposure was systematically varied by changing the pulse irradiance and the number of stimuli delivered over a fixed 15 min administration window (64 protocols surveyed in all). Results showed that per microjoule invested, 8 ms flashes were more effective at resetting the circadian activity rhythm than 16- and 120 ms flashes (i.e. left shift of the dose-response curve, as well as a higher estimated maximal response). These data suggest that the circadian pacemaker's photosensitivity declines within milliseconds of light contact. Further introduction of light beyond a floor of (at least) 8 ms leads to diminishing returns on phase-shifting.
- Kaladchibachi, S., Secor, M. A., Negelspach, D. C., & Fernandez, F. (2019). Longitudinal study of sleep and diurnal rhythms in Drosophila ananassae. Experimental Gerontology, 116, 74-79.More infoMistiming of circadian rhythms impairs quality of life. The sleep fragmentation that results can lead to fatigue, mood alteration, and short-term memory problems. Unfortunately, this suite occurs in humans as we age. In the current study, we used high-resolution monitors to track how circadian patterns of locomotor activity change in female Drosophila ananassae as they enter mid-to-late life. This equipment is a more recent addition to the fly circadian field and has not been previously used for long-term activity tracking. At 2-3 days post-eclosion, D. ananassae were placed into climate-controlled vivariums for 60 days. Daily actograms were generated for each animal, along with a time series of activity across the observational period. Consistent with findings from older rodents and humans, older D. ananassae exhibited degraded patterns of wake and sleep that were fragmented-but still rhythmic-across the 24-h cycle. Overall levels of daily activity declined with age, with particular loss of circadian arousal in the wake-maintenance zone a few hours before bedtime. Interestingly, our high-resolution monitoring strategy was also able to document a sleep correlation previously associated with human aging in flies: displacement of sleep timing arising from possible changes in circadian and homeostatic regulation. Future experiments may determine whether the age-related impairments seen in the sleep-circadian system of D. ananassae can be mitigated through precision light treatment.
- Tubbs, A. S., Dollish, H. K., Fernandez, F., & Grandner, M. A. (2019). The basics of sleep physiology and behavior. In Sleep and Health, 3-10. doi:https://doi.org/10.1016/B978-0-12-815373-4.00001-0
- Kaladchibachi, S., & Fernandez, F. (2018). Precision Light for the Treatment of Psychiatric Disorders. Neural Plasticity, 2018, 5868570.More infoCircadian timekeeping can be reset by brief flashes of light using stimulation protocols thousands of times shorter than those previously assumed to be necessary for traditional phototherapy. These observations point to a future where flexible architectures of nanosecond-, microsecond-, and millisecond-scale light pulses are compiled to reprogram the brain's internal clock when it has been altered by psychiatric illness or advanced age. In the current review, we present a chronology of seminal experiments that established the synchronizing influence of light on the human circadian system and the efficacy of prolonged bright-light exposure for reducing symptoms associated with seasonal affective disorder. We conclude with a discussion of the different ways that precision flashes could be parlayed during sleep to effect neuroadaptive changes in brain function. This article is a contribution to a special issue on curated by editors Shimon Amir, Karen Gamble, Oliver Stork, and Harry Pantazopoulos.
- Kaladchibachi, S., Negelspach, D. C., & Fernandez, F. (2018). Circadian phase-shifting by light: Beyond photons. Neurobiology of Sleep and Circadian Rhythms, 5, 8-14.More infoCircadian entrainment to the solar light:dark schedule is thought to be maintained by a simple photon counting method. According to this hypothesis, the pacemaker adjusts the phase of the body's endogenous rhythms in accordance to the intensity and duration with which it encounters a perceived twilight signal. While previous data have generally supported the hypothesis, more recent analysis has codified other factors besides irradiance that influence the magnitude of resetting responses to light delivered within the same phase of the circadian cycle. In particular, the frequency with which light is alternated with darkness, or whether it's packaged in millisecond flashes versus continuous blocks, can significantly alter the dose-response relationship. Here, we used a drosophilid model to test whether circadian photon-counting trends can be broken with light administration protocols spanning just 15 minutes. In the early part of the delay zone, a 15-min continuous light pulse was fragmented until it could no longer produce a full-magnitude shift of the flies' locomotor activity rhythms. The remaining exposure was then reorganized along various fractionation schemes that employed pulses with different widths and interstimulus intervals. Our results suggest that the pacemaker integrates the phase-shifting effects of equiluminous light differently depending on the stimulus pattern with which light is made available. For example, despite having fewer photons, certain ratios of light and darkness could be optimized on a timescale of seconds and minutes so as to achieve pacemaker resetting close to par with steady luminance. These data provide further evidence that the circadian pacemaker's responses to light entail more than photon counting and motivate continued discussion on how phototherapy can be best optimized in clinical practice to improve conditions linked to circadian impairment.
- Maple, A. M., Rowe, R. K., Lifshitz, J., Fernandez, F., & Gallitano, A. L. (2018). Influence of Schizophrenia-Associated Gene Egr3 on Sleep Behavior and Circadian Rhythms in Mice. Journal of Biological Rhythms, 33(6), 662-670.More infoUp to 80% of people meeting DSM-IV definitions for schizophrenia will exhibit difficulties with sleep, along with a breakdown in circadian entrainment and rhythmicity. The changes to the sleep and circadian systems in this population are thought to be interdependent, as evidenced by the frequent use of the combined term "sleep and circadian rhythm disruption" or "SCRD" to describe their occurrence. To understand links between sleep and circadian problems in the schizophrenia population, we analyzed the duration and rhythmicity of sleep behavior in mice lacking function of the immediate early gene early growth response 3 ( Egr3). EGR3 has been associated with schizophrenia risk in humans, and Egr3-deficient (-/-) mice display various features of schizophrenia that are responsive to antipsychotic treatment. While Egr3-/- mice slept less than their wildtype (WT) littermates, they showed no evidence of circadian disorganization; in fact, circadian rhythms of activity were more robust in these mice compared with WT, as measured by time series analysis and the relative amplitude index of Van Someren's suite of non-parametric circadian rhythm analyses. Differences in circadian robustness were maintained when the animals were transferred to several weeks of housing under constant darkness or constant light. Together, our results suggest that Egr3-/- mice retain control over the circadian timekeeping of sleep and wake, while showing impaired sleep. The findings are compatible with those from a surprising array of mouse models of schizophrenia and raise the possibility that SCRD may be 2 separate disorders in the schizophrenia population requiring different treatment strategies.
- Negelspach, D. C., Kaladchibachi, S., & Fernandez, F. (2018). The circadian activity rhythm is reset by nanowatt pulses of ultraviolet light. Proceedings of the Royal Society of London B: Biological Sciences, 285(1884).More infoThe circadian pacemaker synchronizes to the Earth's rotation by tracking step-by-step changes in illumination that occur as the sun passes the horizon. While twilight progressions of irradiance and colour are considered important stimuli in this process, comparably less thought has been given to the possibility that ultraviolet A (UVA) radiation might actually play a more formative role given its evolutionary significance in shaping 24 h timekeeping. Here, we show that activity rhythms can be phase-shifted by UVA light at an energy range seated well below that of the visible spectrum. Because the energy threshold for this resetting matches the incident amount of UVA on the human retina at twilight, our results suggest that UVA light has the potential to function as a similar time cue in people.
- Clark, C. A., Fernandez, F., Sakhon, S., Spanò, G., & Edgin, J. O. (2017). The medial temporal memory system in Down syndrome: Translating animal models of hippocampal compromise. Hippocampus, 27(6), 683-691.More infoRecent studies have highlighted the dentate gyrus as a region of increased vulnerability in mouse models of Down syndrome (DS). It is unclear to what extent these findings are reflected in the memory profile of people with the condition. We developed a series of novel tasks to probe distinct medial temporal functions in children and young adults with DS, including object, spatial, and temporal order memory. Relative to mental age-matched controls (n = 45), individuals with DS (n = 28) were unimpaired on subtests involving short-term object or configural recall that was divorced from spatial or temporal contexts. By contrast, the DS group had difficulty recalling spatial locations when contextual information was salient and recalling the order in which objects were serially presented. Results are consistent with dysfunction of spatial and temporal contextual pattern separation abilities in individuals with DS, mediated by the hippocampus, including the dentate gyrus. Amidst increasing calls to bridge human and animal work, the memory profile demonstrated here in humans with DS is strikingly similar to that of the Ts65Dn mouse model of DS. The study highlights the trisynaptic circuit as a potentially fruitful intervention target to mitigate cognitive impairments associated with DS.
- Fernandez, F., Nyhuis, C. C., Anand, P., Demara, B. I., Ruby, N. F., Spanò, G., Clark, C., & Edgin, J. O. (2017). Young children with Down syndrome show normal development of circadian rhythms, but poor sleep efficiency: a cross-sectional study across the first 60 months of life. Sleep Medicine, 33, 134-144.More infoTo evaluate sleep consolidation and circadian activity rhythms in infants and toddlers with Down syndrome (DS) under light and socially entrained conditions within a familiar setting. Given previous human and animal data suggesting intact circadian regulation of melatonin across the day and night, it was hypothesized that behavioral indices of circadian rhythmicity would likewise be intact in the sample with DS.
- Lewis, S. A., Negelspach, D. C., Kaladchibachi, S., Cowen, S. L., & Fernandez, F. (2017). Spontaneous alternation: A potential gateway to spatial working memory in Drosophila. Neurobiology of Learning and Memory, 142(Pt B), 230-235.More infoDespite their ubiquity in biomedical research, Drosophila have yet to be widely employed as model organisms in psychology. Many complex human-like behaviors are observed in Drosophila, which exhibit elaborate displays of inter-male aggression and female courtship, self-medication with alcohol in response to stress, and even cultural transmission of social information. Here, we asked whether Drosophila can demonstrate behavioral indices of spatial working memory in a Y-maze, a classic test of memory function and novelty-seeking in rodents. Our data show that Drosophila, like rodents, alternate their visits among the three arms of a Y-maze and spontaneously favor entry into arms they have explored less recently versus ones they have just seen. These findings suggest that Drosophila possess some of the information-seeking and working memory facilities mammals depend on to navigate through space and might be relevant models for understanding human psychological phenomena such as curiosity.
- Ruby, N. F., Fisher, N., Patton, D. F., Paul, M. J., Fernandez, F., & Heller, H. C. (2017). Scheduled feeding restores memory and modulates c-Fos expression in the suprachiasmatic nucleus and septohippocampal complex. Scientific Reports, 7(1), 6755.More infoDisruptions in circadian timing impair spatial memory in humans and rodents. Circadian-arrhythmic Siberian hamsters (Phodopus sungorus) exhibit substantial deficits in spatial working memory as assessed by a spontaneous alternation (SA) task. The present study found that daily scheduled feeding rescued spatial memory deficits in these arrhythmic animals. Improvements in memory persisted for at least 3 weeks after the arrhythmic hamsters were switched back to ad libitum feeding. During ad libitum feeding, locomotor activity resumed its arrhythmic state, but performance on the SA task varied across the day with a peak in daily performance that corresponded to the previous daily window of food anticipation. At the end of scheduled feeding, c-Fos brain mapping revealed differential gene expression in entrained versus arrhythmic hamsters in the suprachiasmatic nucleus (SCN) that paralleled changes in the medial septum and hippocampus, but not in other neural structures. These data show that scheduled feeding can improve cognitive performance when SCN timing has been compromised, possibly by coordinating activity in the SCN and septohippocampal pathway.
- Fernandez, F., & Edgin, J. O. (2016). Pharmacotherapy in Down's syndrome: which way forward?. The Lancet. Neurology, 15(8), 776-7.
- Fernandez, F., & Reeves, R. H. (2015). Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials. Handbook of Experimental Pharmacology, 228, 335-80.More infoExperimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized.
- Fernandez, F., Lu, D., Ha, P., Costacurta, P., Chavez, R., Heller, H. C., & Ruby, N. F. (2014). Circadian rhythm. Dysrhythmia in the suprachiasmatic nucleus inhibits memory processing. Science, 346(6211), 854-7.More infoChronic circadian dysfunction impairs declarative memory in humans but has little effect in common rodent models of arrhythmia caused by clock gene knockouts or surgical ablation of the suprachiasmatic nucleus (SCN). An important problem overlooked in these translational models is that human dysrhythmia occurs while SCN circuitry is genetically and neurologically intact. Siberian hamsters (Phodopus sungorus) are particularly well suited for translational studies because they can be made arrhythmic by a one-time photic treatment that severely impairs spatial and recognition memory. We found that once animals are made arrhythmic, subsequent SCN ablation completely rescues memory processing. These data suggest that the inhibitory effects of a malfunctioning SCN on cognition require preservation of circuitry between the SCN and downstream targets that are lost when these connections are severed.
- Zampieri, B. L., Fernandez, F., Pearson, J. N., Stasko, M. R., & Costa, A. C. (2014). Ultrasonic vocalizations during male-female interaction in the mouse model of Down syndrome Ts65Dn. Physiology & Behavior, 128, 119-25.More infoDown syndrome (DS) is the leading cause of genetically defined intellectual disability. Although speech and language impairments are salient features of this disorder, the nature of these phenotypes and the degree to which they are exacerbated by concomitant oromotor dysfunction and/or hearing deficit are poorly understood. Mouse models like Ts65Dn, the most extensively used DS animal model, have been critical to understanding the genetic and developmental mechanisms that contribute to intellectual disability. In the present study, we characterized the properties of the ultrasonic vocalizations (USVs) emitted by Ts65Dn males during courtship episodes with female partners. USVs emitted by mice in this setting have been proposed to have some basic correlation to human speech. Data were collected and analyzed from 22 Ts65Dn mice and 22 of their euploid littermates. We found that both the minimum and maximum peak frequencies of Ts65Dn calls were lower than those produced by euploid mice, whereas the mean individual duration of "down" and "complex" syllable types was significantly longer. Peak, minimal and maximal, and the fundamental frequencies of short syllables generated by Ts65Dn mice were lower compared to those by euploid mice. Finally, Ts65Dn males made fewer multiple jumps calls during courtship and the mean total duration of their "arc", "u", and "complex" syllables was longer. We discuss the human correlates to these findings, their translational potential, and the limitations of this approach. To our knowledge, this is the first characterization of differences between adult Ts65Dn and euploid control mice with respect to USVs.
- Fernandez, F., & Edgin, J. O. (2013). Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis. Journal of Alzheimer's Disease & Parkinsonism, 3(2), 124.More infoWe propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer's Disease & Parkinsonism.
- Ruby, N. F., Fernandez, F., Garrett, A., Klima, J., Zhang, P., Sapolsky, R., & Heller, H. C. (2013). Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole. PloS One, 8(8), e72433.More infoPerformance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.
- Fernandez, F., Torres, V., & Zamorano, P. (2010). An evolutionarily conserved mechanism for presynaptic trapping. Cellular and Molecular Life Sciences, 67(11), 1751-4.More infoPresynaptic differentiation takes place over three interrelated acts involving the biogenesis and trafficking of molecular complexes of active zone material, the "trapping" or stabilization of active zone sites, and the subsequent development of mature synapses. Although the identities of proteins involved with establishing presynaptic specializations have been increasingly delineated, the exact functional mechanisms by which the active zone is assembled remain poorly understood. Here, we discuss a theoretical model for how the trapping stage of presynaptic differentiation might occur in developing neurons. We suggest that subsets of active zone proteins containing polyglutamine domains undergo concentration-dependent prion-like conversions as they accumulate at the plasma membrane. This conversion might serve to aggregate the proteins into a singular structure, which is then able to recruit scaffolding agents necessary for regulated synaptic transmission. A brief informatics analysis in support of this 'Q' assembly hypothesis--across commonly used models of synaptogenesis--is presented.
- Ruby, N. F., Fernandez, F., Zhang, P., Klima, J., Heller, H. C., & Garner, C. C. (2010). Circadian locomotor rhythms are normal in Ts65Dn "Down syndrome" mice and unaffected by pentylenetetrazole. Journal of Biological Rhythms, 25(1), 63-6.More infoTs65Dn mice are used extensively as a model for Down syndrome. Recent studies have reported conflicting evidence as to whether these mice express circadian rhythms. The authors therefore recorded locomotor activity patterns from these animals while they were housed under a standard light-dark cycle, constant darkness (DD), and constant light (LL). Contrary to expectations, Ts65Dn mice had more robust circadian rhythms with slightly shorter periods compared with their wild-type littermates. They also exhibited increased rhythm period and marked activity suppression when moved from DD to LL (i.e., Aschoff's rule). Administration of the GABA(A) antagonist pentylenetetrazole did not influence any of these circadian parameters. Thus, locomotor activity is under strict circadian control in Ts65Dn mice, suggesting that their cognitive deficits and sleep disturbances are not due to dysfunctional circadian timing as proposed previously.
- Torres, V., Barra, L., Garcés, F., Ordenes, K., Leal-Ortiz, S., Garner, C. C., Fernandez, F., & Zamorano, P. (2010). A bicistronic lentiviral vector based on the 1D/2A sequence of foot-and-mouth disease virus expresses proteins stoichiometrically. Journal of Biotechnology, 146(3), 138-42.More infoClassic IRES sequences are notorious for exerting biased expression in favor of upstream coding regions when placed into polycistronic vectors. Here, we report the development of a bicistronic lentiviral system based on the 1D/2A sequence from the foot-and-mouth disease virus that is able to maintain tightly balanced control of upstream and downstream protein expression for several days at a stoichiometry very closely approaching 1.0. Our results suggest that the 1D/2A sequence can be optimized in an FUGW lentiviral setting to coordinate expression of multiple polypeptides, presenting a potentially valuable tool to signaling network researchers and to the gene therapy community.
- Fernandez, F., Trinidad, J. C., Blank, M., Feng, D., Burlingame, A. L., & Garner, C. C. (2009). Normal protein composition of synapses in Ts65Dn mice: a mouse model of Down syndrome. Journal of Neurochemistry, 110(1), 157-69.More infoDown syndrome (DS) is the most prevalent form of intellectual disability caused by the triplication of approximately 230 genes on chromosome 21. Recent data in Ts65Dn mice, the foremost mouse model of DS, strongly suggest that cognitive impairment in individuals with DS is a consequence of reduced synaptic plasticity because of chronic over-inhibition. It remains unclear however whether changes in plasticity are tied to global molecular changes at synapses, or are due to regional changes in the functional properties of synaptic circuits. One interesting framework for evaluating the activity state of the DS brain comes from in vitro studies showing that chronic pharmacological silencing of neuronal excitability orchestrates stereotyped changes in the protein composition of synaptic junctions. In the present study, we use proteomic strategies to evaluate whether synapses from the Ts65Dn cerebrum carry signatures characteristic of inactive cortical neurons. Our data reveal that synaptic junctions do not exhibit overt alterations in protein composition. Only modest changes in the levels of synaptic proteins and in their phosphorylation are observed. This suggests that subtle changes in the functional properties of specific synaptic circuits rather than large-scale homeostatic shifts in the expression of synaptic molecules contribute to cognitive impairment in people with DS.
- Fernandez, F., & Garner, C. C. (2008). Episodic-like memory in Ts65Dn, a mouse model of Down syndrome. Behavioural Brain Research, 188(1), 233-7.More infoTs65Dn mice, like individuals with Down syndrome (DS), demonstrate a functional dissociation between explicit and implicit forms of memory, showing selective impairment in explicit or declarative learning tasks. Here, we explored Ts65Dn explicit memory deficits further by evaluating the ability of these mice to assimilate the temporal and spatial contexts under which previously novel objects had been encountered. We found that Ts65Dn mice could in fact form contextual representations of objects over the course of a few hours, contrary to their inability to discriminate object novelty over a more prolonged period of 24h. These results suggest that Ts65Dn mice might have particular difficulties in declarative tasks requiring long-term memory, presenting an especially important putative therapeutic target for pre-clinical and clinical DS research.
- Ruby, N. F., Hwang, C. E., Wessells, C., Fernandez, F., Zhang, P., Sapolsky, R., & Heller, H. C. (2008). Hippocampal-dependent learning requires a functional circadian system. Proceedings of the National Academy of Sciences of the United States of America, 105(40), 15593-8.More infoDecades of studies have shown that eliminating circadian rhythms of mammals does not compromise their health or longevity in the laboratory in any obvious way. These observations have raised questions about the functional significance of the mammalian circadian system, but have been difficult to address for lack of an appropriate animal model. Surgical ablation of the suprachiasmatic nucleus (SCN) and clock gene knockouts eliminate rhythms, but also damage adjacent brain regions or cause developmental effects that may impair cognitive or other physiological functions. We developed a method that avoids these problems and eliminates rhythms by noninvasive means in Siberian hamsters (Phodopus sungorus). The present study evaluated cognitive function in arrhythmic animals by using a hippocampal-dependent learning task. Control hamsters exhibited normal circadian modulation of performance in a delayed novel-object recognition task. By contrast, arrhythmic animals could not discriminate a novel object from a familiar one only 20 or 60 min after training. Memory performance was not related to prior sleep history as sleep manipulations had no effect on performance. The GABA antagonist pentylenetetrazol restored learning without restoring circadian rhythms. We conclude that the circadian system is involved in memory function in a manner that is independent of sleep. Circadian influence on learning may be exerted via cyclic GABA output from the SCN to target sites involved in learning. Arrhythmic hamsters may have failed to perform this task because of chronic inhibitory signaling from the SCN that interfered with the plastic mechanisms that encode learning in the hippocampus.
- Fernandez, F., & Garner, C. C. (2007). Object recognition memory is conserved in Ts1Cje, a mouse model of Down syndrome. Neuroscience Letters, 421(2), 137-41.More infoTs1Cje and Ts65Dn are genetic mouse models of Down syndrome (DS). Like individuals with DS, these mice exhibit various hallmarks of hippocampal pathology, and deficits in hippocampal-based, declarative learning and memory tasks. Both spatial navigation and novel object recognition, two prototypical domains of declarative memory function, have been strongly characterized in the Ts65Dn DS model. Indeed, Ts65Dn mice show navigation problems in the Morris water maze, impaired alternation in a T-maze, and deficient working and reference memory in the radial arm maze task. They, likewise, show an inability to detect object novelty over time. In contrast to the Ts65Dn model, hippocampal-dependent cognition has been less well characterized in Ts1Cje. Although Ts1Cje mice have been found to exhibit spatial difficulties in the Morris water maze and reduced spontaneous alternation, their ability to process object-based information has never been examined. Here, we report that Ts1Cje mice perform normally in short-term and long-term novel object recognition tasks. The ability of Ts1Cje mice to detect object novelty, unlike Ts65Dn, may point to differences in the extent of hippocampal pathology in the two DS mouse models.
- Fernandez, F., & Garner, C. C. (2007). Over-inhibition: a model for developmental intellectual disability. Trends in Neurosciences, 30(10), 497-503.More infoDevelopmental intellectual disability (DID) is a daunting societal problem. Although tremendous progress has been made in defining the genetic causes of DID, therapeutic strategies remain limited. In particular, there is a marked absence of a unified approach to treating cognitive impairments associated with DID. Here, we suggest that the brain in many DID-related disorders is subject to a basic imbalance in neuronal activity, with an increased contribution of inhibition to neural circuits. This over-inhibition, in turn, is predicted to lead to deficits in synaptic plasticity and learning and memory. We further discuss possibilities for pharmacological intervention in DID, focusing on the concept of drug-induced 'therapeutic neuroadaptation' as a means of stably enhancing constitutive circuit excitability and cognition over time.
- Fernandez, F., Morishita, W., Zuniga, E., Nguyen, J., Blank, M., Malenka, R. C., & Garner, C. C. (2007). Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neuroscience, 10(4), 411-3.More infoTs65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.
- Fernandez, F., Misilmeri, M. A., Felger, J. C., & Devine, D. P. (2004). Nociceptin/orphanin FQ increases anxiety-related behavior and circulating levels of corticosterone during neophobic tests of anxiety. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 29(1), 59-71.More infoIntracranial administration of nociceptin/orphanin FQ (N/OFQ) increases circulating concentrations of adrenocorticotrophic hormone and corticosterone in unstressed rats, and elevates the responsiveness of these hormones during mild stress. Furthermore, N/OFQ and its cognate receptor are both abundant in a variety of limbic nuclei, and stress exposure decreases neuronal N/OFQ content in forebrain neurons. In light of these and other findings, we examined the potential involvement of N/OFQ in regulation of anxiety-related behaviors in rats. In the open field, elevated plus maze, and dark-light neophobic tests, intracerebroventricular N/OFQ (1.0 pmole-1.0 nmole) increased the expression of anxiety-related behaviors. Specifically, N/OFQ increased the latency to enter, decreased the number of entries into, and decreased the time spent in the exposed or brightly lit environments of all three tests. N/OFQ also enhanced thigmotactic responses in the open field test. The effects of diazepam and of the benzodiazepine inverse agonist FG 7142 were also assessed in independent groups of rats. In all three tests, the behavioral effects of N/OFQ resembled the anxiogenic actions of FG 7142, and contrasted with the anxiolytic actions of diazepam. N/OFQ administration also increased circulating concentrations of corticosterone during anxiety testing, in comparison with the concentrations in vehicle-treated controls. We conclude that N/OFQ administration is anxiogenic, and elevates responsiveness of the hypothalamic pituitary-adrenal axis during neophobic tests of anxiety. This supports the possibility that N/OFQ neurotransmission participates in processing of emotionally-salient and stressful stimuli, and suggests that normal functioning of the N/OFQ system may be important in physiological and psychological well-being.
- Fernandez, F. (2022, January). Daylight and Sleep. Behavioral Sleep Medicine Seminar Series (Invited Talk)UAHS, Psychiatry.
- Fernandez, F. (2022, May). Nocturnal Wakefulness and Sleep. Psychology Department Colloquium, California State University, Northridge (Invited Talk). Virtual: California State University, Northridge.
- Fernandez, F. (2021, Summer). Building of the Sleep and Circadian World by Animal Models. Translational Sleep Medicine Seminar (limited international series).
- Fernandez, F. (2020, Fall). Circadian Rhythms. Behavioral Sleep Medicine Seminar Series (Invited Talk). Tucson, Arizona.
- Fernandez, F. (2020, Spring). Circadian Timekeeping. Behavioral Sleep Medicine Seminar Series (Invited Talk). Tucson, Arizona.
- Fernandez, F. (2019, Fall). On Narcolepsy. Behavioral Sleep Medicine Seminar Series (Invited Talk). Tucson, Arizona.
- Fernandez, F. (2019, Fall). Sleep & Aging. Behavioral Sleep Medicine Seminar Series (Invited Talk). Tucson, Arizona.
- Fernandez, F. (2019, Spring). Chronobiology and circadian rhythms. Behavioral Sleep Medicine Seminar Series (Invited Talk). Tucson, Arizona.
- Fernandez, F. (2019, Spring). Impact of Sleep on Cognition and Alzheimer's disease in Down syndrome. National Institute on Aging – Alzheimer’s Association Workshop on Intersection of Down Syndrome and Alzheimer’s Disease (Invited National Talk). Bethesda, Maryland: NIH.
- Fernandez, F. (2019, Spring). Optimization of circadian responses with millisecond flashes of light. Neuroscience Community Datablitz, University of Arizona (Invited Talk). Tucson, Arizona: Neuroscience GIDP.
- Fernandez, F. (2016, April). Changes in time perception during aging can impair memory: Is no clock better than a bad clock?. Ninth Annual McKnight Inter-Institutional Meeting (Invited Talk). Tucson, Arizona: The McKnight Brain Research Foundation.
- Fernandez, F. (2016, Fall). Circadian Programming by Light. BIO5 Fellows Series, University of Arizona (Invited Talk)The BIO5 Institute, University of Arizona.
- Fernandez, F. (2016, January). Programming Circadian Rhythms. UA Sleep Research Conference, Inaugural Meeting (Invited Talk). Old Main, University of Arizona, Tucson: UA School of Mind, Brain, and Behavior.More infoDiscussed recent work in my lab concerned with the development of a smart lens to restore circadian health.
- Fernandez, F. (2016, July). Can Broken Clocks Lead to Broken Memories?. 24th Biennial Meeting of the ISSBD/APS (Invited International Talk). Vilnius, Lithuania: International Society for the Study of Behavioural Development and Association of Psychological Science (APS).More infoWill discuss recent findings from my laboratory suggesting circadian links between Down syndrome and Alzheimer's disease.
- Fernandez, F. (2016, May). Dysrhythmia in the SCN Produces Memory Impairment. Basic Medical Sciences Colloquium Series (Invited State Talk). UA Medical Campus, Phoenix, AZ: BMS Seminar Series, Steering Committee.
- Fernandez, F. (2015, June). Circadian Biomarkers of Pathology Progression in Down syndrome. Biennial Meeting, Trisomy 21 Research Society (Invited International Talk). Paris, France: Trisomy 21 Research Society.More infoDelivered an invited talk at the inaugural meeting of the T21 Research Society.
- Fernandez, F. (2015, October). A Vision for how Circadian Rhythms Shape Memory. Psychology Colloquium, University of Arizona (Invited Talk). UA Campus: Department of Psychology, University of Arizona, Tucson.More infoGave an overview of my laboratory's research goals over the next few decades.
- Fernandez, F. (2015, October). Drug Therapy for a Multigene Neurodevelopmental Disorder: Down syndrome as a Case Study. Genetics and Genomics Grand Rounds, University of Arizona (Invited Talk). University of Arizona Cancer Center, Tucson, AZ: UA Genetics Grand Rounds Committee.More infoLectured on the development of one of the first drug therapies for Down syndrome (DS).
- Fernandez, F. (2015, September). Dysrhythmia-related memory impairment: When no clock is better than a bad clock. Neuroscience Community Datablitz, University of Arizona (Invited Talk). Museum of Contemporary Art, Tucson, AZ: Neuroscience Graduate Interdisciplinary Program, Committee on Neuroscience.More infoDelivered a talk discussing my laboratory's latest work on the links between circadian rhythms and memory.
- Fernandez, F. (2014, September). Down Syndrome: Bridging the Animal-Human Divide. Universidad Nacional Autónoma de México, Congress on Intellectual Disabilities (Invited International Talk). Acapulco, México.: Universidad Nacional Autónoma de México and the government of Mexico.More infoDelivered the Closing Keynote of the conference.
- Fernandez, F. (2021, Summer). Blue Blockers’ Ability to Block Circadian-Active Light Emitted from a Tablet. SLEEP, #258. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). How Much Blue Do Blue-Blockers Block if Blue-Blockers Do Block Blue?, SLEEP, #257. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). Insomnia precedes suicidal ideation in a national longitudinal study of sleep continuity (NITES). SLEEP, #774. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). Perceived sleep control and nightmares distinguish college students with suicidal ideation from past attempters. SLEEP, #776. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). Sleep and non-suicidal self-injury in college students. SLEEP, #777. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). Spectrophotometric Properties of 31 Different Commercially Available Blue Blocking Glasses Under Electric Room Lighting. SLEEP, #256. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). Spectrophotometric Properties of Commercial Blue-Blocking Lenses in Sunlight. SLEEP, #255. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2021, Summer). The Relationship Between Sleep and Suicidal Ideation in College Students. SLEEP, #775. Sleep Research Society MeetingSleep Research Society.
- Fernandez, F. (2020, Summer). Community-Level Daytime Sleepiness and Substance Use: Implications of Sleep Time and Mental Health. SLEEP, #0243. Sleep Research Society Meeting. Virtual Event.
- Fernandez, F. (2020, Summer). Decline in Habitual Sleep Duration over 10 Years and Worsening Sleep Disparities: Data from NHIS (2006-2015). SLEEP, #374. Sleep Research Society Meeting. Virtual Event.
- Fernandez, F. (2020, Summer). Impact of Mental Health on 10-Year Trends in Habitual Sleep Duration. SLEEP, #0232. Sleep Research Society Meeting. Virtual Event.
- Fernandez, F. (2020, Summer). Morning Wakefulness is Associated with Reduced Suicidal Ideation in a Nationally-Representative Sample. SLEEP, #1096. Sleep Research Society Meeting. Virtual Event.
- Fernandez, F. (2019, Summer). Actigraphy-Based Measurement of Sleep and Diurnal Rhythms in Subjects with Age-Related Macular Degeneration. SLEEP, #0266. Sleep Research Society Meeting. San Antonio, Texas.
- Fernandez, F. (2019, Summer). What makes people want to make changes to their sleep? Assessment of perceived risks of insufficient sleep as a predictor of intent to improve sleep. SLEEP, #0188. Sleep Research Society Meeting. San Antonio, Texas.
- Fernandez, F. (2018, Spring). Inflammation and acute sleep disturbances following experimental intracerebral hemorrhage. The 3rd Joint Symposium of the International and National Neurotrauma Societies and AANA/CNS Section on Neurotrauma and Critical Care. Toronto, Canada.
- Fernandez, F. (2016, November). Influence of schizophrenia-associated gene Egr3 on circadian rhythms in mice. Society for Neuroscience Abstracts. San Diego, CA: Society for Neuroscience.
- Fernandez, F. (2014, August). The Truth About Down Syndrome. New York Times. http://www.nytimes.com/2014/08/29/opinion/the-truth-about-down-syndrome.html?_r=0