Prefrontal ensemble dynamics during response execution and inhibition

项目总结/摘要 响应执行和响应抑制之间的平衡（即，去与不去或停止）扮演一个 它在调节正常行为中起着重要作用，在许多精神疾病中被破坏， 包括多动症强迫症精神分裂症和药物滥用动作控制由一个 大脑结构的数量，前额叶皮层（PFC）在塑造go vs. no中起着特别突出的作用。 去或停的决定。然而，PFC神经元如何控制这种响应执行的机制与 抑制平衡目前是未知。本提案中的项目将通过测试 与PFC神经元集合在行为控制中的动态性质相关的假设数量。的 要检验的首要假设是，分布在多个区域的单独PFC神经元集合， PFC子区域由1）与下游目标的发散连接性， 以及2）在动作启动或动作抑制期间具有精确的时间动态的选择性激活。 我们将研究大鼠执行一项新的Go/NoGo任务时PFC的整体贡献， 提取与行动决策相关的信息。在目标1中，我们将使用新的钙整合工具来识别 任务激活的神经元集合，绘制它们的传出连接，并光遗传学地操纵它们， 从而证明了由时间共激活解剖学定义的神经元群体的因果作用， 具有调节动作控制的特点。在目标2中，我们将确定特定动作的特定时间动态。 通过大规模的细胞神经生理学记录在PFC合奏，并将确定如何 使用光遗传学配对的系综 神经生理学这些研究的结果将提供支持或反驳 假设PFC神经元集合，通过时间相关的活动和解剖结构排列成组， 连接，调节决定启动或抑制行为。这些研究的结果也将 为将来的工作提供一个发射台，研究更多的解剖学，分子和遗传特性， 与反应选择相关的神经系综，包括PFC和其他相关结构。在 除了大大推进我们对执行控制的理解，这些和未来的研究将确定 涉及冲动性和其他方面的干扰反应选择的精神疾病的新疗法 基于电路、分子身份和生理学的交叉。

PROJECT SUMMARY/ABSTRACT The balance between response execution and response inhibition (i.e., going vs. not-going or stopping) plays a fundamental role in regulating normal behavior, and it is disrupted in many psychiatric diseases associated with impulsivity, including ADHD, OCD, schizophrenia, and substance abuse. Action control is regulated by a number of brain structures, and prefrontal cortex (PFC) plays a particularly prominent role in shaping go vs. no- go or stop decisions. However, the mechanisms of how PFC neurons control this response execution vs. inhibition balance are currently unknown. The projects in this proposal will address this issue by testing a number of hypotheses related to the dynamic nature of PFC neuron ensembles in behavior control. The overarching hypothesis to be tested is that separate ensembles of PFC neurons, distributed across multiple PFC subregions are defined by the intersection between 1) diverging connectivity with downstream targets, and 2) selective activation with precise temporal dynamics during either action initiation or action suppression. We will study PFC ensemble contributions in rats performing a novel Go/NoGo task designed to specifically extract information related to action decisions. In Aim 1 we will use new calcium integrator tools to identify task-activated ensembles of neurons, map their efferent connectivity, and optogenetically manipulate them, thereby demonstrating a causal role for neuron populations defined by temporal co-activation anatomical features in regulating action control. In Aim 2, we will identify the specific temporal dynamics of action-specific ensembles through large-scale cellular neurophysiological recording across the PFC and will identify how anatomically-defined ensembles are differentially activated using optogenetics-paired ensemble neurophysiology. The results from these studies will provide key evidence supporting or refuting the hypothesis that PFC neuron ensembles, aligned into groups via temporally correlated activity and anatomical connectivity, regulate decisions to initiate or withhold behaviors. The results from these studies will also provide a launchpad for future work investigating additional anatomical, molecular, and genetic identities of neural ensembles related to response selection, both within PFC and in other associated structures. In addition to significantly advancing our understanding of executive control, these and future studies will identify novel treatments for mental diseases involving impulsivity and other aspects of disrupted response selection based on the intersection of circuitry, molecular identity, and physiology.