Fabian Fernandez
Assistant Professor, BIO5 Institute
Assistant Professor, Evelyn F Mcknight Brain Institute
Assistant Professor, Neurology
Assistant Professor, Neuroscience - GIDP
Assistant Professor, Psychology
Primary Department
Department Affiliations
(520) 621-7447
Work Summary
Fabian-Xosé Fernandez's work includes a focus on parsing the logic used by the circadian pacemaker to interpret multidimensional light patterns, developing light-emitting diode (LED) photo-stimulation protocols to improve mental and physical health across the lifespan, and understanding the role that nocturnal wakefulness plays in suicide risk and developing countermeasures centered around light exposure.
Research Interest
Fabian-Xosé Fernandez, PhD, Departments of Psychology and Neurology, McKnight Brain InstituteCircadian timekeeping is fundamental to human health. Unfortunately, under many clinical circumstances, the temporal organization of our minds and bodies can stray slowly from the Universal Time (UT) that is set with the Earth’s rotation. This disorganization has been linked to progression of several age-related and psychiatric diseases. Non-invasive phototherapy has the potential to improve disease outcomes, but the information that the brain’s clock tracks in twilight (or any electric light signal) to assure that a person entrains their sleep-wake cycles to the outside world is not understood. The central theme of my research program is to fill in this blank and to usher in an era where therapeutically relevant “high-precision” light administration protocols are institutionalized at the level of the American Medical and Psychiatric Associations to change the standard of care for a wide variety of conditions that impair quality of life. Of the conditions my lab is currently studying, we are particularly interested in how chronic and quick, sequenced light exposure can be designed to: 1. promote normal healthy aging and 2. strengthen adaptive cognitive/emotional responses to being awake in the middle of the night (12-6AM), a key interval of the 24-h cycle that we have associated with increased suicidal ideation and mortality. Our circadian work on suicide is done in very close partnership with the University of Arizona Sleep Health and Research Program directed by Dr. Michael A. Grandner.

Publications

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.

Disruptions 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.

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.

Performance 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.

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.

Despite 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.

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.

Experimental 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., & Garner, C. C. (2007). Object recognition memory is conserved in Ts1Cje, a mouse model of Down syndrome. Neuroscience letters, 421(2), 137-41.

Ts1Cje 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.