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

睡眠剥夺对海马功能的分子、细胞和回路影响

• 批准号: 10431989
• 负责人: EDWIN TED G. ABEL
• 金额: $ 46.97万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431989
• 关键词: Affect; Alzheimer' s Disease; Attenuated; Behavioral; Biochemical; Brain; Caring; Cell Signaling Process; Cell physiology; Cognition; Cognitive deficits; Communication; Coupled; Cyclic AMP; Development; Disease; Drosophila garnet protein; Electrodes; Electronics; Electrophysiology (science); Future; Goals; Health; Hippocampus (Brain); Impairment; Incidence; Individual; Lead; Link; Long-Term Potentiation; Mediating; Mediator of activation protein; Medical; Memory; Memory Disorders; Memory impairment; Mental Depression; Mental disorders; Modeling; Modernization; Molecular; Molecular Profiling; Monitor; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Occupational Accidents; Pathway interactions; Pattern; Persons; Population; Process; Property; Protein Biosynthesis; Protocols documentation; Public Health; Quality of life; Rattus; Research; Role; Running; Schizophrenia; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; Sleep; Sleep Deprivation; Sleep Disorders; Sleeplessness; Societies; Specificity; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Traffic accidents; Transgenic Organisms; United States; Vertebral column; Viral; Virus; Work; age group; autism spectrum disorder; base; behavioral study; career; cognitive function; density; excitatory neuron; experience; experimental study; improved; in vivo; insight; memory consolidation; memory recognition; nervous system disorder; neuronal circuitry; neuropsychiatric disorder; novel; novel therapeutic intervention; object recognition; octopamine receptor; pressure; prevent; relating to nervous system; resilience; spatial memory; synaptic function; therapy development

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.

项目摘要。现代社会的需求、职业压力和技术进步 个人电子产品和通讯增加了睡眠不足和睡眠障碍的年龄 组。睡眠不足对个人健康造成不利影响，疾病发病率增加，发病率下降 认知功能导致更多的医疗护理，以及职业和交通事故。这个 睡眠剥夺对记忆的负面影响可以跨物种观察到，这表明睡眠 剥夺可能会改变高度保守的分子和细胞机制，从而影响记忆。这个 海马区是研究睡眠剥夺对神经影响的一个很好的模型 活动对于空间记忆是必要的，而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损害记忆的形成和稳定性 通过改变单个神经元的突触。然而，睡眠剥夺的具体依据是 对记忆有负面影响，大脑如何对这些影响恢复能力仍然很差。 明白了。定义睡眠的细胞、分子和网络机制是至关重要的 剥夺不仅影响神经功能，因为睡眠剥夺的发生率上升，而且 睡眠不足加重了许多神经精神、神经和神经退行性疾病的影响。我们的 先前的研究发现，第二信使信号减少，蛋白质合成受到抑制， 作为睡眠剥夺影响记忆的通路的神经元树突结构的变化。然而， 目前尚不清楚睡眠剥夺是否会单独影响这些通路中的每一个靶点，或者 睡眠剥夺是通过一个中央分子节点调节的。这项提案的目标是确定 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、细胞和网络机制形成对睡眠的弹性 剥夺是可能发生的。在特定的目标1中，我们使用了我们开发的一种新的转基因方法来空间和 在时间上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，我们 在神经元水平上研究睡眠剥夺靶向的几种类型的海马突触可塑性 以确定哪一项与韧性有关。在具体目标3中，我们确定了网络和电路属性 使用大量神经元群体的活体记录，研究受睡眠剥夺影响的神经元。结果是 从我们在行为、生化、分子和 电生理水平将提供对促进弹性的分子签名的重要见解 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 制定干预措施以克服睡眠剥夺对认知的有害影响。