Prefontal Microcircuits Underlying Cognitive Flexibility

项目摘要 该项目是原K99申请中提出的工作的延续。在获得了康涅狄格大学医学院终身助理教授职位后，剩下的工作将在该机构进行。这里提出的目标与最初为独立阶段的奖项提出的目标基本相同。灵活适应不断变化的环境的能力对于在世界上航行至关重要。为了有效地利用来自环境的线索来告知选择和指导决策，必须有效地忽略不相关的线索，并且通常在一种情况下适当的反应在另一种情况下变得不适当。这种类型的行为，被称为定势转换，代表了一种认知灵活性。慢性压力会损害设定转换的能力，并且可能与伴随精神疾病（如精神分裂症和抑郁症）以及神经退行性疾病（如阿尔茨海默病）的设定转换障碍有关。在人类和翻译动物模型中进行的大量研究已经确立了前额叶皮层（PFC）在维持认知灵活性方面的关键作用。然而，PFC内的神经回路的精确解剖和信息处理特征使这种行为仍然未知。在这里，我建议利用强大的成像技术来调查特定群体的前额叶神经元在小鼠执行集转移任务的活动。首先，实验室成员将通过检查经历慢性压力的小鼠中投射特异性神经元群体的任务相关编码特性，来跟进慢性压力导致认知灵活性缺陷的初步发现。这个项目的目标是确定压力对前额叶神经元中行为相关信息编码的影响。其次，实验室成员将通过测试是否可以通过药物遗传学激活前额叶投射神经元中的谷氨酸能信号来挽救这种缺陷，来研究前额叶谷氨酸释放对应激诱导的认知灵活性缺陷的影响。第三，实验室成员将通过使用高速成像来研究压力对快速网络级状态转换的影响，从而扩展对压力对前额叶活动影响的研究。总之，这些实验将推进我们对前额叶皮层在支持与认知灵活性相关的行为中的作用的理解，以及对压力可能损害精神疾病相关认知缺陷中的认知灵活性的回路水平机制的理解。

Project Summary This project is a continuation of the work proposed in the original K99 application. Having secured a tenure- track assistant professorship at the University of Connecticut School of Medicine, the remaining work will be carried out at that institution. The aims proposed here are substantively unchanged from those originally proposed for the independent phase of the award. The ability to flexibly adapt to changing circumstance is critical for navigating through the world. In order to effectively use cues from the environment to inform choices and guide decisions, irrelevant cues must be effectively ignored, and often an appropriate response in one situation becomes inappropriate in another. This type of behavior, referred to as set-shifting, represents a form of cognitive flexibility. Chronic stress can impair the ability to set-shift and may be related to the impairments in set-shifting that accompany psychiatric disorders such as schizophrenia and depression, as well as neurodegenerative disorders such as Alzheimer’s disease. An extensive body of research in humans and in translational animal models has established a critical role for the prefrontal cortex (PFC) in maintaining cognitive flexibility. However, the precise anatomical and information processing characteristics of the neural circuits within the PFC that enable this behavior remain unknown. Here I propose to leverage powerful imaging techniques to survey the activity of specific populations of prefrontal neurons in a mouse performing a set-shifting task. First, lab members will follow up on preliminary findings that chronic stress results in a deficit in cognitive flexibility by examining the task-related coding properties of projection-specific neuronal populations in mice undergoing chronic stress. The goal of this project will be to determine the effect of stress on behaviorally relevant information coding among prefrontal neurons. Second, lab members will examine the effects of prefrontal glutamate release on stress-induced deficits in cognitive flexibility by testing whether this deficit can be rescued by pharmacogenetic activation of glutamatergic signaling in prefrontal projection neurons. Third, lab members will extend the investigation of the effects of stress on prefrontal activity by using high-speed imaging to examine the effects of stress on rapid, network-level state transitions. Together, these experiments will advance our understanding of the role of the prefrontal cortex in supporting behavior related to cognitive flexibility and of the circuit-level mechanisms by which stress may impair cognitive flexibility in psychiatric illness-related cognitive deficits.