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.

认知定义诸如学习和记忆力障碍之类的认知很常见在经历慢性的人中很常见 昼夜节律循环循环引起的昼夜节日循环的干扰。 流行病学研究表明，昼夜节律干扰的认知障碍全球增长 例如抑郁症和阿尔茨海默氏病，强调需要确定 这些现象。但是，连接昼夜节律和认知性能的分子机制 在健康和疾病中，在很大程度上仍未解决。神经元突触是学习和 内存过程。突触蛋白的突触数，活性和表达水平显示有节奏的时间 依赖日的变化，但是这些变化如何受到昼夜节律的调节。一个 不断增长的工作体系支持神经胶质细胞，星形胶质细胞在正常时钟功能中的关键作用。星形胶质细胞是 重要的突触调节器，以及建立和维护记忆和学习的关键。但是，如何 星形胶质时钟调节突触的节奏和相关的认知表现尚未彻底 检查。必须解决这个知识的关键差距，以便不仅了解基本 星形胶质细胞时钟的功能，但也表征控制昼夜节律的调节机制 突触水平的变化。该应用将定义星形胶质时钟在调节突触中的作用 节奏性和随后的学习和记忆行为三个目标。 AIM 1研究星形胶质细胞如何 时钟在负责认知过程的大脑区域（例如皮层和海马； 位于上核（SCN）中的中央时钟会影响突触的时间依赖时间变化 和认知表现。 AIM 2调查了如何通过钙活性调节星形胶质时钟 影响突触节奏。在AIM 3中，我们检验了星形胶质细胞衍生的突触调节因素的假设 在逻辑上生产以促进突触的日期依赖性调制。成功完成 这些目标将揭示星形胶质时钟在确定突触和认知节奏中的作用，并揭示 通过符合星形胶质细胞的未来操纵突触节奏的策略，以恢复与时钟相关的 认知缺陷在神经系统疾病中普遍存在。