Circadian rhythms are approximately 24-hour cycles in behavioral and physiological processes, such as sleep/wake cycles and cognition. In mammals, these rhythms are endogenously generated and entrained to the external light cycle by the primary circadian pacemaker, the suprachiasmatic nucleus (SCN). A hallmark characteristic of SCN neurons is the daily rhythm in the spontaneous action potential frequency, with high activity during the day and low activity at night. These SCN firing rate patterns are critical for maintaining robust, consolidated behavioral rhythms, and persistent changes in SCN neuronal activity are involved light-induced behavioral shifts. Many of the ionic components underlying daily and light-responsive changes in SCN physiology have been described;however, the mechanism controlling expression of these currents is not known. Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that is an emerging regulator of mammalian circadian rhythms and has been implicated in a variety of neurological, neurodegenerative, and psychiatric disorders. In the SCN, GSK3 exhibits daily rhythms in activity. Our recent work has shown that chronic GSK3 activation eliminates the typical day/night differences in SCN activity, with high, """"""""day""""""""-like activity at night, highlighting GSK3 a a previously unexplored regulator of SCN neurophysiology. The overall goal of this proposal is to examine the role of GSK3 activity in regulating SCN neuronal excitability and photic (light) entrainment of the circadian system, using circadian behavioral analysis, immunohistochemistry, real-time bioluminescence, and whole-cell electrophysiology in the presence of chronic GSK3 activation and following pharmacological inhibition of GSK3.
The specific aims will test the hypotheses that: 1) GSK3 activity regulates SCN neurophysiological excitability through modulation of the persistent sodium current and 2) GSK3 mediates light- induced SCN excitability and phase-resetting. The results of the studies proposed here will expand upon the current understanding of GSK3's involvement in the circadian system, and provide novel insight into the mechanism controlling SCN membrane physiology. Furthermore, Because GSK3 has been implicated in numerous clinical disorders which also exhibit circadian disruption, a better understanding of the role of GSK3 in circadian regulation could lead to new treatment strategies for these disorders in the future.

Public Health Relevance

The purpose of this research is to determine the role of glycogen synthase kinase 3 (GSK3) in modulating the excitability of the suprachiasmatic nucleus, the master clock of the body that controls circadian function and entrainment to light stimuli. This study will provide insight into why patients with dysregulation of GSK3 activity, suc as in neurodegenerative disorders and Fragile X syndrome, exhibit sleep and circadian disruption.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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He, Janet
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University of Alabama Birmingham
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United States
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Paul, Jodi R; Munir, Hira A; van Groen, Thomas et al. (2018) Behavioral and SCN neurophysiological disruption in the Tg-SwDI mouse model of Alzheimer's disease. Neurobiol Dis 114:194-200
Besing, Rachel C; Rogers, Courtney O; Paul, Jodi R et al. (2017) GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity. Hippocampus 27:890-898
Paul, Jodi R; McKeown, Alex S; Davis, Jennifer A et al. (2017) Glycogen synthase kinase 3 regulates photic signaling in the suprachiasmatic nucleus. Eur J Neurosci 45:1102-1110
Paul, Jodi R; DeWoskin, Daniel; McMeekin, Laura J et al. (2016) Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability. Nat Commun 7:13470
Besing, Rachel C; Paul, Jodi R; Hablitz, Lauren M et al. (2015) Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. J Biol Rhythms 30:155-60