Circadian dysfunction and GSK3 in neurodegenerative disease

描述（申请人提供）：痴呆症患者的行为障碍和昼夜节律紊乱是入院的首要原因，也是护理人员负担的主要原因。痴呆症或阿尔茨海默病患者经常表现出“日落综合症”，这是一系列症状，包括下午晚些时候/晚上多动、烦躁不安、精神错乱和攻击性，以及核心体温和活动节奏失调。这些症状表明昼夜节律网络失调，该网络通常允许对日常反复发生的环境事件进行预测和准备，包括一天中特定时间的认知功能变异性。确定昼夜节律素失调的分子异常将有助于制定恢复节律性和相关行为的有针对性的策略。该项目将测试糖原合成酶激酶3为内在兴奋性提供了一种特定时间的门控机制，并且在特定大脑区域内这种酶的磷酸化状态平衡的日常变化的破坏有助于神经退行性疾病的昼夜节律和认知异常。具体来说，该项目将确定糖原合成酶激酶3磷酸化的昼夜变化是否调节时钟基因表达和生理的振荡，以及神经退行性疾病中的认知和昼夜行为异常是由糖原合成酶激酶3磷酸化周期的丧失和神经活动节律失调介导的。拟议的研究将利用神经退行性疾病的动物模型，在正常生理条件下（目的1）以及病理条件下（目的2）在视交叉上核和海马中检验这一假设。这些实验的成功完成将确定糖原合成酶激酶3在膜特性和突触生理学的昼夜变化中起关键作用，这对于适当的定时认知功能和休息/活动模式至关重要。他们还将为转化研究奠定基础，这些研究旨在针对这种机制，为痴呆和神经系统疾病提供适当的治疗时机。

DESCRIPTION (provided by applicant): Behavioral disturbance and day-night rhythm disruption of dementia patients are top reasons for institutionalization and cause of caregiver burden. Patients with dementia or Alzheimer's disease often exhibit "sundowning syndrome," a constellation of symptoms including late afternoon/evening hyperactivity, restlessness, confusion, and aggression, along with misaligned core body temperature and activity rhythms. These symptoms suggest a dysregulated circadian network, which normally allows anticipation of and preparation for daily recurring environmental events, including time-of-day-specific variability in cognitive function. Identification of the molecular abnormalities underlying circadin dysregulation would allow for the development of targeted strategies for reinstating rhythmicity and associated behaviors. This project will test the hypothesis that glycogen synthase kinase 3 provides a time-of-day-specific gating mechanism for intrinsic excitability, and that disruptions i daily changes in the phosphorylation state balance of this enzyme within specific brain regions contribute to circadian and cognitive abnormalities of neurodegenerative disease. Specifically, this project will determine whether day-night changes in phosphorylation of glycogen synthase kinase 3 regulate oscillations of clock gene expression and physiology and that cognition and circadian behavioral abnormalities in neurodegenerative disease are mediated by loss of daily glycogen synthase kinase 3 phosphorylation cycles and dysregulated neural activity rhythms. Proposed studies will examine this hypothesis in the suprachiasmatic nucleus and hippocampus under normal physiologic conditions (Aim 1) as well as under pathological conditions (Aim 2) utilizing animal models of neurodegenerative disease. Successful completion of these experiments will establish glycogen synthase kinase 3 as a key player in day-night variation of membrane properties and synaptic physiology, which are critical for appropriately timed cognitive function and rest/activity patterns. They will also lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing in dementia and neurological disease.