Regulation of Synaptic Rhythmicity by Astrocytic Clock

星形细胞钟对突触节律的调节

• 批准号: 10715728
• 负责人: Isabella Farhy
• 金额: $ 29.47万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715728
• 关键词: AMPA Receptors; ARNTL gene; Address; Affect; Alzheimer' s Disease; Area; Astrocytes; Behavior; Brain; Brain region; Calcium; Calcium Signaling; Chronic; Circadian Dysregulation; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Data; Disease; Eating; Exhibits; Functional disorder; Future; Genes; Genetic; Glutamates; Glypican; Harvest; Health; Hippocampus; Human; Hypothalamic structure; ITPR1 gene; Impaired cognition; Investigation; Knockout Mice; Knowledge; Learning; Life Style; Light; Link; Maintenance; Mass Spectrum Analysis; Mediating; Memory; Memory impairment; Mental Depression; Modernization; Molecular; Mus; Nature; Neuroglia; Neurons; Periodicity; Persons; Population; Prevalence; Process; Production; Prosencephalon; Protein Secretion; Proteins; Proteome; Publishing; Regulation; Research; Role; Sleep; Sleep disturbances; Stress; Synapses; Testing; Time; Travel; Work; cell type; chordin; circadian; circadian pacemaker; cognitive function; cognitive performance; cognitive process; comorbidity; differential expression; epidemiology study; experimental study; in vivo; memory process; molecular clock; nervous system disorder; novel; receptor expression; shift work; sleep pattern; suprachiasmatic nucleus; synaptic function

Cognitive deficits such as learning and memory impairments are common in people subjected to chronic disturbance of the circadian cycle due to shift work, travel, or genetic dysregulation of the circadian clock. Epidemiological studies have revealed a global rise in cognitive disorders with circadian disruptions comorbidity such as depression, and Alzheimer’s disease, stressing the need to identify the causal relationship between these phenomena. However, the molecular mechanisms linking the circadian cycle and cognitive performance in health and disease remain largely unresolved. Neuronal synapses are the cellular basis for learning and memory processes. Synapse number, activity, and expression levels of synaptic proteins show rhythmic time- of-day-dependent changes, yet how these changes are regulated by the circadian clock is poorly understood. A growing body of work supports a critical role for the glial cells, astrocytes in normal clock function. Astrocytes are important synaptic regulators, and key for establishment and maintenance of memory and learning. Yet, how the astrocytic clock regulates synaptic rhythmicity and related cognitive performance has not been thoroughly examined. This critical gap in knowledge must be addressed in order to understand not only the fundamental functions of the astrocytic clock, but also to characterize the regulatory mechanisms that control circadian changes in synaptic levels. This application will define the role of astrocytic clocks in regulating synaptic rhythmicity and subsequent learning and memory behaviors in three aims. Aim 1 investigates how the astrocytic clock expressed in brain regions responsible for cognitive processes (e.g., cortex, and hippocampus; outside the central clock located in the suprachiasmatic nucleus (SCN)), affects time-of-day-dependent changes in synapses and cognitive performance. Aim 2 investigates how the astrocytic clock is regulated by calcium activity to influence synaptic rhythmicity. In Aim 3, we test the hypothesis that astrocyte-derived synapse-regulating factors are rhythmically produced to facilitate time-of-day-dependent modulation of synapses. Successful completion of these aims will uncover the role of astrocytic clock in regulating synaptic and cognitive rhythms, and reveal strategies for future manipulation of synaptic rhythmicity through astrocyte-targeting, to restore clock-associated cognitive deficits prevalent in neurological disorders.

学习和记忆障碍等认知缺陷在遭受慢性病的人中很常见 由于轮班工作、旅行或生物钟的遗传失调而引起的生物钟周期紊乱。 流行病学研究显示，全球认知障碍的发病率上升， 如抑郁症和阿尔茨海默病，强调需要确定 这些现象。然而，联系昼夜节律周期和认知表现的分子机制 在健康和疾病方面仍然基本上没有得到解决。神经元突触是学习的细胞基础， 记忆过程突触数量、活动和突触蛋白的表达水平显示出节律性的时间- 依赖于一天的变化，但这些变化是如何调节的生物钟是知之甚少。一 越来越多的工作机构支持神经胶质细胞，星形胶质细胞在正常的时钟功能的关键作用。星形胶质细胞是 重要的突触调节器，是建立和维持记忆和学习的关键。然而， 星形胶质细胞生物钟调节突触节律和相关的认知表现还没有被彻底地 考察必须解决这一关键的知识差距，以便不仅了解基本的 功能的星形细胞时钟，而且还表征调控机制，控制昼夜节律 突触水平的变化。这个应用程序将定义星形胶质细胞时钟在调节突触中的作用。 节律性和随后的学习和记忆行为的三个目标。Aim 1研究了星形胶质细胞 在负责认知过程的大脑区域中表达的时钟（例如，皮质和海马体; 位于视交叉上核（SCN）的中央时钟），影响突触的时间依赖性变化 和认知能力。目的2研究星形胶质细胞生物钟如何受钙活性调节， 影响突触节律性。在目标3中，我们验证了星形胶质细胞源性突触调节因子 有节奏地产生以促进突触的时间依赖性调节。成功完成 这些目标将揭示星形细胞时钟在调节突触和认知节律中的作用，并揭示 未来通过星形胶质细胞靶向操纵突触节律的策略， 神经系统疾病中普遍存在的认知缺陷。