Molecular, Cellular and Circuit Effects of Sleep Deprivation on Hippocampal Function

项目摘要。现代社会的需求，职业压力，以及技术进步， 个人电子产品和通信增加了不同年龄段的睡眠剥夺和睡眠障碍 组睡眠不足会对个人健康产生不利影响， 认知功能，导致医疗保健增加，以及职业和交通事故。的 睡眠剥夺对记忆的负面影响可以在不同物种中观察到，这表明睡眠 剥夺可以改变高度保守的分子和细胞机制，从而影响记忆。的 海马是研究睡眠剥夺对神经系统影响的理想模型， 活动对于空间记忆是必要的，并且这种类型的记忆特别容易受到睡眠剥夺的影响。 目前的证据表明，睡眠不足会在细胞水平上损害记忆的形成和稳定性 通过单个神经元突触的变化。然而，睡眠剥夺的具体依据是什么？ 对记忆力有负面影响，如何使大脑对这些影响具有弹性仍然很差 明白确定睡眠的细胞、分子和网络机制至关重要， 剥夺睡眠不仅会影响神经功能， 睡眠不足对许多神经精神、神经和神经退行性疾病的影响加剧。我们 以前的研究已经确定了第二信使信号的减少，蛋白质合成的抑制， 神经元树突结构的变化是睡眠剥夺影响记忆的途径。然而，在这方面， 目前尚不清楚睡眠剥夺是否会单独影响这些途径中的每一个目标， 睡眠剥夺是通过一个中心分子节点来介导。本建议的目的是确定 睡眠不足损害突触可塑性和记忆的分子和神经机制 通过关注分子，细胞和网络机制， 剥夺是可能发生的。在具体目标1中，我们使用了一种新的转基因方法，我们开发了空间和 暂时操纵第二信使信号通路。这将使我们能够研究分子 神经元对睡眠不足的有害影响的恢复机制。在具体目标2中， 在神经元水平上研究睡眠剥夺对海马突触可塑性的影响 来确定哪些与恢复力有关。在具体目标3中，我们确定了网络和电路特性 使用来自大型神经元群体的体内记录来研究受睡眠剥夺影响的神经元。结果 从我们在行为、生物化学、分子和 电生理水平将为促进恢复力的分子特征提供重要的见解 睡眠不足对记忆力的负面影响。因此，我们的工作可能会导致 制定干预措施，克服睡眠剥夺对认知的不利影响。

Project Summary. The demands of modern society, career pressures, and technological advances in personal electronics and communication have increased sleep deprivation and sleep disorders across age groups. Sleep deprivation adversely impacts individual health with increased disease incidence and decreased cognitive function resulting in increased medical care, as well as occupational and traffic accidents. The negative impact of sleep deprivation on memory can be observed across species suggesting that the sleep deprivation may alter highly conserved molecular and cellular mechanisms to impact memory. The hippocampus is an excellent model to investigate the neural impacts of sleep deprivation as hippocampal activity is necessary for spatial memory and this type of memory is particularly susceptible to sleep deprivation. Current evidence indicates that sleep loss impairs the formation and stability of memories at the cellular level through changes in the synapses of individual neurons. However, the specific basis of how sleep deprivation adversely affects memory and how the brain can be rendered resilient to these effects remains poorly understood. It is critical to define the cellular, molecular and network mechanisms through which sleep deprivation impacts neural function given not only the rising incidence of sleep deprivation but also the aggravating impact of sleep loss on many neuropsychiatric, neurological and neurodegenerative disorders. Our previous research has identified decreased second messenger signaling, suppression of protein synthesis and changes in neuron dendritic structure as pathways through which sleep deprivation affects memory. However, it remains unknown if sleep deprivation separately impacts targets in each of these pathways or if the effects of sleep deprivation are mediated through a central molecular node. The objective of this proposal is to identify the molecular and neuronal mechanisms through which sleep loss impairs synaptic plasticity and memory formation by focusing on the molecular, cellular and network mechanisms through which resilience to sleep deprivation can occur. In Specific Aim 1, we use a novel transgenic approach we developed to spatially and temporally manipulate a second messenger signaling pathway. This will allow us to investigate the molecular mechanisms which underlie neuronal resilience to the detrimental effects of sleep loss. In Specific Aim 2, we investigate several types of hippocampal synaptic plasticity targeted by sleep deprivation at the neuronal level to identify which is associated with resilience. In Specific Aim 3, we identify the network and circuit properties of neurons affected by sleep deprivation using in vivo recordings from large neuronal populations. The results from our comprehensive experimental approach at the behavioral, biochemical, molecular, and electrophysiological levels will provide significant insights into the molecular signature that promotes resilience to the negative impact of sleep deprivation on memory. As such, our work may potentially lead to the development of interventions to overcome the detrimental effects of sleep deprivation on cognition.