The role of mTOR signaling in the cognitive impact of sleep deprivation

mTOR 信号传导在睡眠剥夺认知影响中的作用

基本信息

批准号：
8717169
负责人：
Jennifer Choi Tudor
金额：
$ 5.78万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717169
关键词：
Affect Alzheimer&apos s Disease Animals Attenuated Behavioral Paradigm Brain Brain region Cognition Cognitive Cognitive deficits Complex Development Extramural Activities Gene Expression Gene Proteins Genetic Health Hippocampus (Brain)Hour Impairment Lead Learning Maintenance Mediating Memory Memory impairment Mental Depression Mental disorders Mentors Molecular Neurodegenerative Disorders Neurons Pathway interactions Personal Satisfaction Phosphorylation Play Preparation Protein Biosynthesis Proteins Public Health Publishing Quality of life Research Ribosomal Protein S6 Kinase Role Schizophrenia Signal Pathway Signal Transduction Sleep Sleep Deprivation Societies Synaptic plasticity Techniques Testing Time Training Translation Initiation Translations Viral Work base career career development cell type mTOR protein mutant novel novel therapeutic intervention public health relevance research study tool

项目摘要

DESCRIPTION (provided by applicant): Sleep loss produces deficits in hippocampal synaptic plasticity and hippocampus-dependent memory storage. However, the molecular and cellular mechanisms that underlie these effects of sleep deprivation remain unclear. Several studies have suggested that protein synthesis pathways are altered during sleep and after periods of sleep deprivation. None however have previously described in mechanistic detail how protein synthesis is altered with sleep or sleep deprivation, nor how these alterations regulate memory formation. In this proposal, we will explore the protein synthesis regulatory role of mammalian target of rapamycin (mTOR) signaling during sleep and sleep-mediated memory consolidation. The experiments proposed will develop tools to analyze mTOR signaling in the brain and will provide direct evidence for a novel role of mTOR signaling in sleep-dependent memory consolidation. In this application, two Specific Aims are proposed that use novel genetic approaches to study how sleep deprivation affects the mTOR signaling pathway that results in reduced translation. To directly test the role of mTOR signaling - and the role of 4E-BP activity in particular - in sleep deprivation-induced impairments, we will use a viral-expression approach in Specific Aim 1 to determine if expressing wild-type 4E-BP in the hippocampus is sufficient to restore memory and plasticity deficits induced by sleep deprivation. This approach will allow for carefully timed and cell type- and brain region-specific expression of 4E-BP with sleep deprivation. Finally, in Specific Aim 2 we will use a viral approach to determine if expressing phosphorylation-defective 4E-BP in the hippocampus will mimic the effects of sleep deprivation. Importantly, these experiments will allow us to determine if mTOR signaling plays a functional role in the memory and plasticity deficits observed with sleep loss.

描述（由申请人提供）：睡眠损失会导致海马突触可塑性和海马依赖性记忆存储的缺陷。然而，基于睡眠剥夺影响的分子和细胞机制尚不清楚。几项研究表明，蛋白质合成途径在睡眠期间和睡眠不足之后发生了变化。然而，没有在机械详细信息中描述过的蛋白质合成如何随着睡眠或睡眠剥夺而改变，或者这些改变如何调节记忆形成。在此提案中，我们将探讨乳腺霉素（MTOR）信号在睡眠和睡眠介导的记忆巩固过程中哺乳动物靶标的蛋白质合成调节作用。提出的实验将开发用于分析大脑中MTOR信号传导的工具，并将为MTOR信号在睡眠依赖性记忆巩固中的新作用提供直接证据。在此应用中，提出了两个具体的目的，它使用新型遗传方法研究睡眠剥夺如何影响MTOR信号传导途径，从而减少了翻译。为了直接测试MTOR信号传导的作用 - 尤其是4E-BP活性在睡眠剥夺引起的损伤中的作用，我们将在特定目标1中使用病毒表达方法1来确定在海马中表达野生型4e-bp是否足以恢复睡眠的记忆力和可塑性，导致睡眠不足。这种方法将允许在睡眠剥夺中精心定时和细胞类型和大脑区域特异性表达。最后，在特定的目标2中，我们将使用病毒方法来确定海马中表达磷酸化缺陷的4e-bp是否会模仿睡眠不足的影响。重要的是，这些实验将使我们能够确定MTOR信号是否在记忆和可塑性缺陷中起着功能作用。