Prefrontal ensemble dynamics during response execution and inhibition

项目摘要/摘要 反应执行和反应抑制之间的平衡(即，去与不去或停止)起到了作用 在调节正常行为方面的基本作用，它在许多相关的精神疾病中被破坏 有冲动，包括多动症、强迫症、精神分裂症和药物滥用。操作控制由 大脑结构的数量，而前额叶皮质(PFC)在决定GO与NO- 做决定还是不做决定。然而，PFC神经元如何控制这一反应执行与. 抑制平衡目前尚不清楚。本提案中的项目将通过测试 与行为控制中PFC神经元集合的动态性质相关的假设的数量。这个 有待检验的最重要的假设是，分布在多个 PFC子区域由1)与下游目标的发散连通性之间的交集定义， 2)在动作启动或动作抑制过程中，具有精确的时间动力学的选择性激活。 我们将研究在执行新的GO/NOGO任务的大鼠中PFC集合的贡献，该任务旨在特定地 提取与行动决策相关的信息。在目标1中，我们将使用新的钙集成器工具来识别 任务激活的神经元集合，绘制它们的传出连接，并对它们进行光遗传操作， 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 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力学 通过跨PFC的大规模细胞神经生理记录进行组合，并将确定如何 解剖学定义的合奏使用光遗传学配对合奏以不同的方式激活 神经生理学。这些研究的结果将提供关键证据，支持或驳斥 假设PFC神经元集合，通过时间相关的活动和解剖学排列成组 连通性，规范发起或保留行为的决策。这些研究的结果也将 为未来研究更多的解剖学、分子和遗传学身份提供了一个发射台 与反应选择相关的神经群，在PFC和其他相关结构中都是如此。在……里面 除了显著促进我们对执行控制的理解外，这些和未来的研究将确定 治疗精神疾病的新疗法，涉及冲动和反应中断选择的其他方面 基于电路、分子同一性和生理学的交叉。

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.