Regulation of Synaptic Rhythmicity by Astrocytic Clock

认知缺陷，如学习和记忆障碍，在患有慢性精神分裂症的人中很常见 昼夜节律紊乱由于倒班工作、旅行或生物钟的遗传失调而造成的昼夜节律的紊乱 流行病学研究显示，认知障碍与昼夜节律紊乱共病的全球发病率上升。 如抑郁症和阿尔茨海默病，强调需要确定两者之间的因果关系 这些现象。然而，将昼夜节律周期和认知表现联系起来的分子机制 健康和疾病方面的问题在很大程度上仍未得到解决。神经元突触是学习和学习的细胞基础 记忆过程。突触数量、活性和突触蛋白的表达水平显示出节律性的时间- 昼夜变化，然而这些变化是如何被生物钟调节的却知之甚少。一个 越来越多的工作支持了神经胶质细胞、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 重要的突触调节器，是建立和维持记忆和学习的关键。然而，如何 星形细胞时钟调节突触节律性和相关的认知表现还不彻底 检查过了。必须解决知识中的这一关键差距，以便不仅要理解 星形细胞时钟的功能，但也表征了控制昼夜节律的调节机制 突触水平的变化。这一应用将定义星形细胞时钟在调节突触中的作用 三个目标的节奏性和随后的学习记忆行为。目标1调查星形细胞如何 在负责认知过程的大脑区域(例如，皮质和海马体；在 中枢时钟位于视交叉上核(SCN)，影响突触的时间依赖性变化 和认知能力。目的2研究星形细胞时钟是如何由钙活动调节的 影响突触节律性。在目标3中，我们测试了星形胶质细胞衍生的突触调节因子的假设 是有节奏地产生的，以促进突触的时间依赖的调制。成功完成 这些目的将揭示星形细胞时钟在调节突触和认知节奏中的作用，并揭示 未来通过星形胶质细胞靶向操纵突触节律性以恢复时钟相关的策略 认知缺陷普遍存在于神经性疾病中。

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.