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

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。在一起， 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。

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.