Linking interneuron-mediated circuit regulation with sleep-dependent plasticity and memory storage in the hippocampus

将中间神经元介导的回路调节与海马体的睡眠依赖性可塑性和记忆存储联系起来

• 批准号: 10053374
• 负责人: SARA J ATON
• 金额: $ 136.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053374
• 关键词: Address; Affect; Affinity Chromatography; Anatomy; Animal Model; Architecture; Behavioral; Behavioral Paradigm; Biochemical; Biological Models; Brain; Cells; Cellular biology; Cognition; Data; Dementia; Genetic; Genetic Transcription; Hippocampus (Brain); Hour; Impaired cognition; Information Storage; Interneurons; Intervention; Label; Lead; Learning; Link; Measures; Mediating; Memory; Mental Depression; Mental disorders; Messenger RNA; Morphology; Mus; Neurons; Parvalbumins; Pattern; Pharmacogenetics; Phosphorylation; Population; Process; Proteins; Pyramidal Cells; Regulation; Reporting; Ribosomes; Role; Schizophrenia; Sleep; Sleep Deprivation; Sleep disturbances; Somatostatin; Structure; Synapses; Synaptic plasticity; Testing; Translating; Translations; Work; autism spectrum disorder; cell type; cognitive process; conditioned fear; experience; experimental study; fear memory; human subject; insight; long term memory; memory consolidation; memory process; neuronal circuitry; non rapid eye movement; novel; optogenetics; rapid eye movement; tool

Project summary: Synaptic plasticity in brain structures like the hippocampus has been hypothesized to underlie an essential brain function - consolidating transient experiences into long-lasting memories. The importance of sleep for promoting long-term memory storage, and the disruptive effect of sleep deprivation on memory, have been appreciated for nearly a century. However, it remains unclear how sleep-associated changes in the activity of specific brain circuits contribute to synaptic plasticity in the hippocampus and other structures. The studies proposed here will test a novel hypothesis – that sleep and sleep loss differentially affect memory consolidation through their differential effects on separate subpopulations of hippocampal interneurons. We will use a simple behavioral paradigm for studying sleep-dependent memory consolidation in mice (contextual fear memory; CFM) in combination with state-targeted pharmacogenetic and optogenetic manipulations of parvalbumin-expressing (PV+) and somatostatin-expressing (SOM+) hippocampal interneurons. In the context of these experimental manipulations, we will measure downstream effects on sleep- associated CFM consolidation, hippocampal network activity, microcircuit-level changes in neuronal structure, and biochemical changes in genetically-defined cell populations. We will first assess the effects of learning itself (contextual fear conditioning; CFC) and subsequent sleep or sleep deprivation (SD) on neuronal morphology using cell type-specific Brainbow labeling, and intracellular processes using cell type-specific translating ribosome affinity purification (TRAP). We will then determine how state-specific manipulations of hippocampal PV+ interneuron activity (which disrupt of rescue sleep-dependent CFM consolidation) affect these sleep- dependent processes. Finally, we will test the hypothesis that SD disrupts CFM consolidation by selectively activating SOM+ interneurons in the hippocampus, leading to suppression of activity in neighboring neurons. We will test whether pharmacogenetic activation of these neurons (mimicking effects of SD) disrupts CFM consolidation in freely-sleeping mice, and whether inhibition of these neurons during SD (mimicking effects of sleep) rescues CFM consolidation. We will then assess the effects of changing SOM+ interneuron activity levels on post-CFC changes in hippocampal network activity patterns, neuronal morphology, and cell biology. Together, these studies will test the necessity and sufficiency of state-dependent activity in defined hippocampal neuron populations for long-term storage of new memories.

项目概要：海马体等大脑结构中的突触可塑性被假设为 是大脑一项基本功能的基础--将短暂的经历巩固为持久的记忆。的 睡眠对促进长期记忆储存的重要性，以及睡眠剥夺对 近世纪来，然而，目前尚不清楚睡眠与 特定脑回路活动的变化有助于海马和其他神经元中的突触可塑性。 结构.这里提出的研究将测试一个新的假设-睡眠和睡眠不足不同地影响 通过对海马中间神经元的不同亚群的不同作用来巩固记忆。 我们将使用一个简单的行为模式来研究小鼠的睡眠依赖性记忆巩固 （背景恐惧记忆; CFM）与状态靶向药物遗传学和光遗传学相结合 小清蛋白表达（PV+）和生长抑素表达（SOM+）的海马 中间神经元在这些实验操作的背景下，我们将测量对睡眠的下游影响- 相关的CFM巩固，海马网络活动，神经元结构的微电路水平变化， 和生化变化的基因定义的细胞群体。我们将首先评估学习本身的效果 （背景恐惧条件反射; CFC）和随后的睡眠或睡眠剥夺（SD）对神经元形态的影响 使用细胞类型特异性Brainbow标记，和使用细胞类型特异性翻译的细胞内过程， 核糖体亲和纯化（TRAP）。然后，我们将确定海马神经元的状态特异性操作 PV+中间神经元活动（破坏救援睡眠依赖性CFM巩固）影响这些睡眠- 依赖过程。最后，我们将检验SD通过选择性地破坏CFM整合的假设。 激活海马中的SOM+中间神经元，导致抑制邻近神经元的活动。我们 将测试这些神经元的药物遗传学激活（模拟SD的作用）是否会破坏CFM 在自由睡眠的小鼠中进行巩固，以及在SD期间是否抑制这些神经元（模拟 睡眠）挽救CFM巩固。然后，我们将评估改变SOM+中间神经元活动水平的影响 对CFC后海马网络活动模式、神经元形态和细胞生物学的变化。我们一起努力， 这些研究将检验海马神经元状态依赖性活动的必要性和充分性。 长期储存新的记忆。