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.

认知缺陷，如学习和记忆障碍，在慢性糖尿病患者中很常见