All ETDs from UAB

Advisory Committee Chair

Karen L Gamble

Advisory Committee Members

Frank Amthor

Burel Goodin

John Hablitz

Robert Sorge

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

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. This dissertation examines 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. In the main chapters we show that: 1) loss of rhythmic GSK3 inactivation disrupts behavioral and neurophysiological rhythms in the SCN, 2) GSK3 mediates light-induced SCN excitability and phase-resetting, and 3) GSK3 activity regulates SCN neurophysiological excitability through modulation of the persistent sodium current. The results presented here expand upon the current understanding of GSK3’s involvement in the circadian system, and provide novel insight into the mechanism controlling SCN membrane physiology. 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.

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