Prefrontal Microcircuits Underlying Cognitive Flexibility (K99 Administrative Supplement)

项目摘要 灵活适应不断变化的环境的能力对于驾驭世界至关重要。在……里面 为了有效地利用来自环境的线索来通知选择和指导决策，无关的线索 必须有效地忽略，并且通常在一种情况下的适当响应在 又一个。这种类型的行为被称为定势转移，代表了一种认知灵活性。慢性 应激可损害定势转换能力，可能与随之而来的定势转换障碍有关 精神障碍，如精神分裂症或抑郁症。在人类和人类中进行的大量研究 翻译动物模型已经确立了前额叶皮质(PFC)在维持 认知灵活性。然而，神经的精确解剖和信息处理特征 PFC内启用此行为的电路仍然未知。 通过三个不同的目标，我们建议利用强大的成像技术来调查 在执行定势转换任务的小鼠中，特定群体的前额叶神经元的活动。在目标1中，我们 将使用先进的计算方法来识别编码不同任务特征和 绘制它们的功能连接图，揭示专门编码特定基因的神经元的子网络 环境和动物行为的特征。在目标2中，我们将在这些发现的基础上，通过 检测小鼠投射特定神经元群体的任务相关编码特性 慢性应激，以考察应激对行为相关信息编码的影响。在《目标3》中， 将在资助期的独立阶段完成，我们将延长调查 应激对前额叶活动的影响通过高速成像检查应激对前额叶活动的影响 快速的网络级别状态。综合起来，这些目标将促进我们对前额叶作用的理解 大脑皮层支持与认知灵活性相关的行为，以及通过这种机制 压力可能会损害精神疾病相关认知缺陷的认知灵活性。 通过解决这些问题并执行拟议的工作，候选人将建立这两个 技术和专业技能，将为未来的独立职业生涯奠定坚实的基础 研究员。共同导师Liston博士和Fusi博士将在正式方面监督候选人 通过定期会议的实验方法和计算生物学(见培训计划)以及 在获得教员职位、建立独立实验室、 以及获得初始资金。咨询小组由Nestler博士、Paninski博士和Grosenick博士组成， 对研究战略中概述的方法有丰富的经验，将就以下问题提供咨询 无论是研究的进行和解释，还是对早期职业前景的导航- 在学术环境中进行阶段性研究。

Project Summary 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 or depression. 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. Through three distinct aims, we propose to leverage powerful imaging techniques to survey the activity of specific populations of prefrontal neurons in a mouse performing a set-shifting task. In Aim 1, we will use advanced computational methods to identify neural populations encoding distinct task features and map their functional connectivity, revealing subnetworks of neurons specialized for encoding particular features of the environment and of the animal's behavior. In Aim 2, we will build upon these findings by examining the task-related coding properties of projection-specific neuronal populations in mice undergoing chronic stress in order to examine the effect of stress on behaviorally relevant information coding. In Aim 3, which will be completed during the Independent Phase of the funding period, we will extend our 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. Together, these aims 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. By addressing these questions and carrying out the proposed work, the candidate will build both technical and professional skills that will provide a solid foundation for a future career as an independent researcher. The co-mentors, Drs. Liston and Fusi, will supervise the candidate in formal aspects of the experimental methods and the computational biology through regular meetings (see Training Plan) and also advise and support the candidate in the process of securing a faculty position, setting up an independent lab, and securing initial funding. The Advisory Panel, which consists of Drs. Nestler, Paninski and Grosenick, who have extensive experience with the methods outlined in the Research Strategy, will provide consultation on both the conduct and interpretation of the research and on navigating the professional landscape of early- stage research in an academic setting.