Interrogation of network-wide neuronal dynamics during fear memory in mouse default mode network

项目摘要 认知症状是许多精神障碍的临床重要组成部分， 影响复杂的领域，如长时记忆，通过协调的相互作用 全脑网络中的活动。重要的是，特定的神经元动力学和 集成网络功能的基础机制还不完全了解，即使在 健康。这项建议的目标是了解在一个人的大脑中 临床上重要的记忆相关网络，默认模式网络(DMN)，有助于 使用鼠标模型进行内存处理。中心假设是关联度低的 跨DMN的频率活动在与以下各项相关的短时间段内发生 在网络结构之间传播与记忆相关的活动。该提案正在调查 将光遗传学与一种新的光学技术--多光纤相结合的DMN功能 光度法(MFP)，它直接测量跨DMN的神经元动力学 区域。我对MFP的初步研究显示兴奋性神经元的慢相关动力学 在小鼠的DMN(但不是对照区域)上的种群。我现在可以直接探测真正的- 与相关DMN相关的时间全网络神经元活动和相互作用 记忆过程中的动态变化。目标1将确定经典的theta，3-10赫兹活动的可靠性 与内存相关联，以其相关状态通过DMN传播。目标2将 考察记忆(恐惧条件反射)诱导的DMN动态变化及其与回忆的关系 (上下文召回)。AIM 3将通过光遗传学演示记忆过程中DMN的相互作用 抑制记忆加工过程中的个别区域和测量结果网络 动力学。这些目标代表了对神经元动力学的首次深入剖析 内存中的DMN。他们利用一种创新的方法，利用新颖和可推广的 方法在小鼠模型中产生对DMN功能的基本了解 术语记忆与人类神经影像表现和临床症状的相关性。在 过程中，我将精通探测分布式网络的全光方法， 全网活动分析和集成行为测试。我会和一位专家合作 咨询委员会(Deisseroth博士、Blair博士、Wiltgen博士、Etkin博士、O‘Hara博士) 在这些方法中指导学员的经验。这个尖端系统的培训 神经科学，将极大地补充我的分子和细胞神经科学背景， 让我以独立调查员的身份开始了我的职业生涯 神经回路整合和调节它们的功能，以产生对健康和疾病的认知。

Project Abstract Cognitive symptoms are a clinically important component of many psychiatric disorders, affecting complex domains, like long-term memory, mediated by coordinated interaction of activity across brain-wide networks. Importantly, the specific neuronal dynamics and mechanisms underlying integrated network function are incompletely understood, even in health. The objective of this proposal is to understand how correlated neuronal dynamics in a clinically important memory-related network, the default mode network (DMN), contribute to memory processing using a mouse model. The central hypothesis is that correlated low- frequency activity across the DMN occurs in short periods of time associated with propagation of memory-related activity between network structures. The proposal probes DMN function by combining optogenetics with a novel optical technique, multifiber photometry (MFP), which directly measures neuronal dynamics simultaneously across DMN areas. My preliminary studies using MFP show slow correlated dynamics in excitatory neuron populations across DMN (but not a control area) in mouse. I can now directly probe the real- time network-wide neuronal activity and interactions associated with correlated DMN dynamics during memory. Aim 1 will determine how reliably theta, 3-10Hz activity classically associated with memory, propagates through the DMN in its correlated state. Aim 2 will examine DMN dynamics induced by memory (fear conditioning), and their relationship to recall (context recall). Aim 3 will demonstrate DMN interactions during memory by optogenetically inhibiting individual areas during memory processing and measuring resulting network dynamics. These aims represent the first in-depth dissection of neuronal dynamics across the DMN during memory. They utilize an innovative approach, leveraging novel and generalizable methods in a mouse model to generate fundamental insight into DMN function during long- term memory, with relevance to human neuroimaging findings and clinical symptoms. In the process, I will become proficient in all-optical approaches to probing distributed networks, analysis of network-wide activity, and integrated behavioral testing. I will work with an expert advisory committee (Dr. Deisseroth, Dr. Blair, Dr. Wiltgen, Dr. Etkin, Dr. O’Hara) with pioneering experience mentoring trainees in these methods. This training in cutting-edge systems neuroscience, will critically supplement my molecular and cellular neuroscience background, allowing me to launch a career as an independent investigator examining how distributed neural circuits integrate and regulate their function to generate cognition in health and disease.