Prefrontal Microcircuits Underlying Cognitive Flexibility (K99 Administrative Supplement)

认知灵活性的前额叶微电路（K99 行政补充）

• 批准号: 10226523
• 负责人: Timothy Spellman
• 金额: $ 10.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226523
• 关键词: Address; Administrative Supplement; Anatomy; Animal Behavior; Animal Model; Behavior; Behavioral; Characteristics; Chronic stress; Code; Cognitive; Cognitive deficits; Computational Biology; Computing Methodologies; Consultations; Cues; Disease; Environment; Faculty; Foundations; Funding; Future; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Intervention; Investigation; Link; Major Depressive Disorder; Maps; Mediating; Mental Depression; Mental disorders; Mentors; Methods; Mus; Neurons; Pathogenicity; Phase; Population; Positioning Attribute; Prefrontal Cortex; Process; Property; Public Health; Research; Research Personnel; Risk; Role; Schizophrenia; Secure; Solid; Speed; Stress; Supervision; Surveys; Task Performances; Training; Work; career; cognitive performance; experience; flexibility; information processing; meetings; neural circuit; neuroregulation; relating to nervous system; response; skills

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.

项目摘要 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。在 为了有效地利用来自环境的线索来告知选择和指导决策， 必须被有效地忽略，而且在一种情况下的适当反应往往变得不适当， 另这种类型的行为，被称为定势转换，代表了一种认知灵活性。慢性 压力会损害定势转换的能力，并可能与随之而来的定势转换障碍有关。 精神疾病，如精神分裂症或抑郁症。一个广泛的研究机构在人类和 翻译的动物模型已经建立了一个关键作用，前额叶皮层（PFC），在维持 认知灵活性然而，神经系统的精确解剖和信息处理特征 PFC中实现这种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 活动的特定群体的前额叶神经元在小鼠执行一套转移任务。目标1： 将使用先进的计算方法来识别编码不同任务特征的神经群体， 绘制它们的功能连接，揭示专门编码特定神经元的子网络。 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， 检查小鼠中投射特异性神经元群体的任务相关编码特性， 慢性应激，以研究应激对行为相关信息编码的影响。在目标3中， 这将是在独立阶段的资助期间完成，我们将延长我们的调查 通过使用高速成像来检查压力对前额叶活动的影响，以了解压力对前额叶活动的影响 快速的网络级状态。总之，这些目标将促进我们对前额叶作用的理解， 皮层支持与认知灵活性有关的行为，以及 压力可能会损害与精神疾病相关的认知缺陷的认知灵活性。 通过解决这些问题并执行建议的工作，候选人将建立两个 技术和专业技能，这将为未来的职业生涯作为一个独立的坚实基础 研究员共同导师，博士利斯顿和富西，将监督候选人在正式方面的 实验方法和计算生物学通过定期会议（见培训计划）， 建议和支持候选人在确保教师职位，建立一个独立的实验室， 并获得初始资金。咨询小组由Nestler、Paninski和Grosenick博士组成， 在研究战略中概述的方法方面有丰富的经验，将提供以下方面的咨询： 无论是研究的进行和解释，还是在早期的专业景观中导航， 在学术环境中进行阶段性研究。