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: 10700761
• 负责人: SARA J ATON
• 金额: $ 47.02万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700761
• 关键词: Linking; interneuron; mediated; circuit; regulation; Linking; interneuron; mediated; circuit; regulation

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：假设海马等大脑结构中的突触可塑性已被认为 是基本的大脑功能 - 将瞬态体验整合到持久的记忆中。这 睡眠对于促进长期记忆存储的重要性以及睡眠剥夺的破坏性影响 记忆，近一个世纪以来一直受到赞赏。但是，目前尚不清楚与睡眠相关 特定脑电路活性的变化有助于海马和其他 结构。这里提出的研究将检验一个新的假设 - 睡眠和睡眠损失会差异影响 记忆通过对海马中间神经元单独亚群的不同影响通过其不同的影响。 我们将使用简单的行为范式来研究小鼠的睡眠依赖性记忆巩固 （上下文恐惧记忆； CFM）与靶向状态的药物遗传学和光遗传学结合 表达白蛋白的（PV+）和表达生长抑素的（SOM+）海马的操纵 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合并，海马网络活性，神经元结构的微电路级变化， 以及一般定义的细胞群体的生化变化。我们将首先评估学习的影响 （上下文恐惧条件； CFC）以及随后的睡眠或睡眠剥夺（SD）（SD） 使用细胞类型特异性的Brainbow标记和使用细胞类型特异性翻译的细胞内过程 核糖体亲和力纯化（陷阱）。然后，我们将确定如何对海马的特定国家操纵 PV+中间神经元活动（破坏救助睡眠依赖性CFM巩固）会影响这些睡眠 依赖过程。最后，我们将测试SD通过选择性地破坏CFM巩固的假设 激活海马中的SOM+中间神经元，从而抑制相邻神经元的活性。我们 将测试这些神经元的药物遗传激活（模仿SD的效应）是否会破坏CFM 自由放血小鼠的巩固，以及在SD期间抑制这些神经元（模仿 睡眠）营救CFM合并。然后，我们将评估改变SOM+中间神经元活动水平的影响 关于海马网络活性模式，神经元形态和细胞生物学的CFC后CFC变化。一起， 这些研究将测试定义的海马神经元中国家依赖活性的必要和充分性 长期存储新记忆的种群。