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住院的首要原因和照顾者负担的原因。痴呆症或阿尔茨海默病患者通常会出现“日落综合症”，这是一系列症状，包括下午晚些时候/傍晚多动、躁动、神志不清和攻击性，以及核心体温和活动节律失调。这些症状表明昼夜节律网络失调，这通常允许对日常反复发生的环境事件进行预期和准备，包括认知功能中特定时间段的变异性。识别潜在的环钙蛋白失调的分子异常将允许开发恢复节律性和相关行为的有针对性的策略。这个项目将测试这样一个假设，即糖原合成酶激酶3为内在兴奋性提供了一种特定时间的门控机制，并且这种酶在特定大脑区域的磷酸化状态平衡的中断和每天变化导致了神经退行性疾病的昼夜节律和认知异常。具体地说，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的认知和昼夜行为异常是通过失去每日糖原合成酶激酶3磷酸化周期和失调的神经活动节律来调节的。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(目标1)以及病理条件下(目标2)在视交叉上核和海马区检验这一假说。这些实验的成功完成将确立糖原合成酶激酶3在膜特性和突触生理的昼夜变化中的关键作用，这对适当的认知功能和休息/活动模式是至关重要的。他们还将为旨在针对痴呆症和神经疾病的适当治疗时机的这一机制的转译研究奠定基础。

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.