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 个人电子和沟通增加了睡眠剥夺和整个年龄的睡眠障碍 组。睡眠剥夺会不利地影响个人健康，疾病发病率增加并减少 认知功能导致医疗服务增加，职业和交通事故。这 可以在物种中观察到睡眠剥夺对记忆的负面影响，表明睡眠 剥夺可能会改变高度保守的分子和细胞机制来影响记忆。这 海马是研究睡眠剥夺的神经影响的绝佳模型 活动对于空间记忆是必需的，这种类型的记忆特别容易剥夺睡眠。 当前的证据表明，睡眠损失会损害细胞水平的记忆的形成和稳定性 通过变化单个神经元的突触。但是，剥夺睡眠方式的具体基础 对记忆的不利影响以及如何使大脑对这些影响的韧性保持较差 理解。定义细胞，分子和网络机制至关重要 剥夺不仅会影响神经功能，不仅是睡眠剥夺的发生率上升，而且还会影响 睡眠丧失对许多神经精神病，神经和神经退行性疾病的加剧影响。我们的 先前的研究已经确定了第二信使信号传导下降，蛋白质合成的抑制和 神经元树突结构的变化是睡眠剥夺会影响记忆的途径。然而， 尚不清楚睡眠剥夺是否分别影响这些途径中的每一种或 睡眠剥夺是通过中央分子节点介导的。该提议的目的是确定 睡眠损失损害突触可塑性和记忆的分子和神经元机制 通过关注分子，细胞和网络机制来形成，通过这些机制的弹性 可能会发生剥夺。在特定目标1中，我们使用一种新型的转基因方法，我们开发了空间和 在时间上操纵第二个使者信号通路。这将使我们能够研究分子 神经元弹性的机制对睡眠损失的有害影响。在特定的目标2中，我们 研究在神经元水平的睡眠剥夺目标的几种类型的海马突触可塑性 确定哪些与弹性有关。在特定目标3中，我们确定网络和电路属性 使用来自大型神经元种群的体内记录受睡眠剥夺影响的神经元。结果 从我们在行为，生化，分子和 电生理水平将为促进弹性的分子特征提供重要的见解 睡眠剥夺对记忆的负面影响。因此，我们的工作可能会导致 开发干预措施以克服睡眠剥夺对认知的有害影响。