GSK3 regulation of suprachiasmatic neuronal excitability and light entrainment

描述(申请人提供)：昼夜节律是行为和生理过程中大约24小时的周期，如睡眠/清醒周期和认知。在哺乳动物中，这些节律是由内源性产生的，并由主要的昼夜节律起搏器-视交叉上核(SCN)引入外部光周期。SCN神经元的一个显著特征是自发动作电位频率的昼夜节律，白天高活动，夜间低活动。这些SCN的放电频率模式对于维持强健、巩固的行为节律至关重要，而SCN神经元活动的持续变化涉及光诱导的行为变化。SCN生理中的许多日常和光响应变化背后的离子成分已经被描述；然而，控制这些电流表达的机制尚不清楚。糖原合成酶激酶3(GSK3)是一种丝氨酸-苏氨酸激酶，是哺乳动物昼夜节律的新调节者，与多种神经、神经退行性疾病和精神疾病有关。在SCN中，GSK3表现出每日的活动节律。我们最近的工作表明，慢性GSK3的激活消除了SCN活动的典型昼夜差异，在夜间具有高的“白天”样活动，突显了GSK3是一种以前未被探索的SCN神经生理学调节因子。这项建议的总体目标是利用昼夜行为分析、免疫组织化学、实时生物发光和全细胞电生理学，在存在慢性GSK3激活和GSK3的药物抑制之后，研究GSK3活性在调节SCN神经元兴奋性和光(光)携带昼夜节律系统中的作用。这些特定的目的将检验以下假设：1)GSK3活性通过调节持续钠电流来调节SCN的神经生理性兴奋性；2)GSK3介导光诱导的SCN兴奋性和相位重置。本文的研究结果将扩展目前对GSK3的S参与昼夜节律系统的理解，并为调控SCN膜生理的机制提供新的见解。此外，由于GSK3与许多临床疾病有关，这些疾病也表现出昼夜节律紊乱，因此更好地了解GSK3在昼夜节律调节中的作用可能会导致未来这些疾病的新治疗策略。

DESCRIPTION (provided by applicant): 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.