Prefontal Microcircuits Underlying Cognitive Flexibility

Prefontal 微电路是认知灵活性的基础

• 批准号: 10536984
• 负责人: Timothy Spellman
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536984
• 关键词: Address; Affect; Alzheimer' s Disease; Anatomy; Animal Model; Attention; Award; Behavior; Behavioral; Calcium; Calcium Signaling; Characteristics; Chronic; Chronic stress; Code; Cognitive; Cognitive deficits; Connecticut; Cues; Disease; Environment; Fluorescence; Glutamates; Goals; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Institution; Intervention; Investigation; Laser Scanning Microscopy; Light; Link; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mentors; Microscopy; Modeling; Mus; Nature; Neurodegenerative Disorders; Neurons; Output; Pathogenicity; Pathway interactions; Patients; Pharmacogenetics; Phase; Population; Prefrontal Cortex; Presynaptic Terminals; Probability; Property; Protocols documentation; Public Health; Publishing; Regulation; Research; Risk; Rodent; Role; Sampling; Scanning; Schizophrenia; Secure; Signal Transduction; Specific qualifier value; Speed; Stimulus; Stress; Surveys; Synapses; Task Performances; Testing; Therapeutic Intervention; Time; Universities; Vertebral column; Work; anxiety symptoms; behavioral response; cognitive performance; density; depressive symptoms; experimental study; flexibility; follow-up; glutamatergic signaling; in vivo imaging; information processing; medical schools; member; neural circuit; neuroregulation; rapid detection; response; social defeat; targeted treatment; temporal measurement; tenure track; two-photon

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.

项目摘要 这个项目是在最初的K99申请中提出的工作的继续。在康涅狄格大学医学院获得终身教职助理教授职位后，剩下的工作将在该机构进行。这里提出的目标与最初为奖项独立阶段提出的目标基本不变。灵活适应不断变化的环境的能力对于驾驭世界至关重要。为了有效地利用来自环境的线索来指导选择和指导决策，不相关的线索必须被有效地忽略，而且在一种情况下的适当反应往往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移，代表了一种认知灵活性。慢性压力会削弱定势转换的能力，可能与定势转换的障碍有关，后者伴随着精神分裂症和抑郁症等精神疾病，以及阿尔茨海默病等神经退行性疾病。在人类和翻译动物模型中的大量研究已经确立了前额叶皮质(PFC)在维持认知灵活性方面的关键作用。然而，使这种行为发生的PFC内神经回路的精确解剖和信息处理特征仍然未知。在这里，我建议利用强大的成像技术来调查执行定势转移任务的小鼠特定群体前额叶神经元的活动。首先，实验室成员将通过检查遭受慢性应激的小鼠投射特定神经元群体的与任务相关的编码特性，来跟进慢性应激导致认知灵活性下降的初步发现。这个项目的目标将是确定压力对前额叶神经元之间行为相关信息编码的影响。其次，实验室成员将通过测试前额叶投射神经元中谷氨酸能信号的药物遗传激活是否可以拯救这种缺陷，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，实验室成员将进一步研究压力对前额叶活动的影响，通过使用高速成像来检查压力对快速、网络级别的状态转换的影响。总之，这些实验将促进我们对前额叶皮质在支持与认知灵活性相关的行为方面的作用，以及压力可能损害精神疾病相关认知缺陷的认知灵活性的电路水平机制的理解。