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.

项目摘要：海马体等大脑结构的突触可塑性已被捕获 它是大脑一项重要功能的基础——将短暂的经历整合成持久的记忆。 睡眠对于促进长期记忆储存的重要性，以及睡眠不足对记忆的破坏性影响 近一个世纪以来，记忆力一直受到人们的重视，然而，睡眠与记忆有何关联仍不清楚。 特定脑回路活动的变化有助于海马体和其他区域的突触可塑性 这里提出的研究将检验一个新的假设——睡眠和睡眠不足会产生不同的影响。 通过对海马中间神经元不同亚群的不同影响来巩固记忆。 我们将使用一个简单的行为范例来研究小鼠的睡眠依赖性记忆巩固 （情境恐惧记忆；CFM）与状态靶向药物遗传学和光遗传学相结合 表达小白蛋白（PV+）和表达生长抑素（SOM+）海马的操作 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、神经结构的微电路水平变化、 我们将首先评估学习本身的影响。 （情境恐惧调节；CFC）以及随后的睡眠或睡眠剥夺（SD）对神经形态的影响 使用细胞类型特异性 Brainbow 标记，以及使用细胞类型特异性翻译的细胞内过程 然后我们将确定如何对海马进行状态特异性操作。 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- 最后，我们将检验 SD 有选择地破坏 CFM 整合的假设。 激活海马体中的 SOM+ 中间神经元，从而抑制邻近神经元的活动。 将测试这些神经元的药物遗传学激活（模拟 SD 的效果）是否会破坏 CFM 自由睡眠小鼠的巩固，以及 SD 期间是否抑制这些神经元（模仿 然后，我们将评估改变 SOM+ 中间神经元活动水平的影响。 CFC 后海马网络活动模式、神经形态和细胞生物学的变化。 这些研究将测试特定海马神经元状态依赖性活动的必要性和充分性 长期储存新记忆的人群。