Prefrontal somatostatin interneurons in action valuation processing and motivational anhedonia

前额生长抑素中间神经元在行动评估处理和动机快感缺乏中的作用

• 批准号: 9469644
• 负责人: Robert N Fetcho
• 金额: $ 4.54万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469644
• 关键词: Acute; Affect; Anhedonia; Animals; Anterior; Attention; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Chronic; Chronic stress; Consumption; Corticosterone; Cost-Benefit Analysis; D Cells; Decision Making; Dendrites; Diagnosis; Diagnostic; Exposure to; Failure; Feedback; Fiber; Functional disorder; Glutamates; Hyperactive behavior; Impairment; Implant; Individual; Interneuron function; Interneurons; Investigation; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mental disorders; Messenger RNA; Methods; Modality; Modeling; Mood Disorders; Morphology; Motivation; Mus; Neurosecretory Systems; Outcome; Pathologic; Patients; Performance; Phenotype; Photometry; Play; Population; Prefrontal Cortex; Process; Psychological reinforcement; Pyramidal Cells; Recruitment Activity; Retrieval; Rewards; Role; Signal Transduction; Somatosensory Cortex; Somatostatin; Stress; Symptoms; Synapses; System; Techniques; Testing; Vertebral column; Work; awake; base; behavior test; behavioral impairment; behavioral response; brain circuitry; cingulate cortex; density; depressive symptoms; experience; gamma-Aminobutyric Acid; glutamatergic signaling; improved; indexing; interest; novel; novel diagnostics; novel therapeutics; optical fiber; optogenetics; pleasure; postsynaptic; response; reward processing; sensor; tool

PROJECT SUMMARY Major depressive disorder (MDD) is a highly prevalent and debilitating mood disorder that is diagnosed based on a mixture of symptoms, but anhedonia—decreased interest in rewarding activities—is a core feature. Anhedonia can be caused by an inability to experience pleasure or by a lack of motivation to work towards obtaining a reward. Every decision to exert effort to obtain a reward involves action valuation computations— essentially a cost-benefit analysis of whether the positive value of the expected outcome of an action outweighs the negative value of the expected effort associated with that action. The anterior cingulate cortex (ACC), a stress-sensitive region of prefrontal cortex (PFC), has been consistently implicated in action valuation computations across species. Whether and how dysfunctional action valuation computations drive anhedonic symptoms in stress-related psychiatric disease is unclear. While extensive, groundbreaking work has characterized the effects of stress on PFC glutamatergic circuitry, less is known about the role of local inhibitory circuitry in stress-induced depressive-like behaviors, despite substantial evidence for changes in the inhibitory system in MDD patients. This work will investigate the role of one cellular subtype, somatostatin (SST)-expressing interneurons, in driving both healthy reward-seeking and chronic stress-induced anhedonic behavior. Our hypothesis is that SST interneurons facilitate action valuation computations by dynamically regulating synaptic inputs to the ACC and that hyperactivity in SST cells disrupts this process in chronic stress states. To test this, we will record the activity of the ACC SST interneuron population through a chronically implanted optical fiber (fiber photometry) in awake, freely behaving mice performing an effortful reward-seeking task under normal and chronically stressed conditions. We will then optogenetically manipulate the activity of these cells to identify specific causal roles for SST interneurons in driving healthy and pathological reward processing. This investigation will fill a substantial gap in our understanding of stress-induced anhedonic behavior by focusing on a sparse but essential cell population that is understudied in the context of stress and depression. !

项目总结 严重抑郁障碍(MDD)是一种高度流行和衰弱的情绪障碍，被诊断为 基于一系列症状，但快感缺乏--对有回报的活动兴趣降低--是一个核心特征。 快感缺失可能是由于无法体验快乐或缺乏努力追求的动力所致 获得奖励。每一项努力获得奖励的决定都涉及到行动估值计算- 本质上是对一项行动的预期结果的正值是否具有成本效益分析 大于与该操作相关联的预期工作量的负值。前扣带回皮质 前额叶皮质(PFC)的应激敏感区(ACC)一直与动作评估有关 跨物种的计算。功能失调的行为估值计算是否以及如何驱动非享乐主义 与压力相关的精神疾病的症状尚不清楚。虽然广泛的、开创性的工作 以应激对PFC谷氨酸能回路的影响为特征，对局部的作用知之甚少 应激诱导的抑郁样行为中的抑制回路，尽管有大量证据表明 MDD患者的抑制系统。这项工作将研究细胞亚型生长抑素的作用 (SST)表达的中间神经元，在驱动健康的奖赏寻求和慢性应激诱导的快感缺失中 行为。我们的假设是SST中间神经元通过动态地促进动作估值计算 调节ACC的突触输入和SST细胞的过度活动破坏了慢性应激的这一过程 各州。为了测试这一点，我们将记录ACC SST中间神经元群体的活动通过长期 植入光纤(光纤光度法)在清醒、自由行为的小鼠中进行费力的奖赏寻求 在正常和长期紧张的条件下完成任务。然后我们将从光遗传学的角度操纵 这些细胞以确定SST中间神经元在驱动健康和病理奖励中的特定因果作用 正在处理。这项研究将填补我们对应激诱导快感缺乏症的理解的一个重大空白。 通过关注稀少但基本的细胞群体的行为，这一群体在压力和 抑郁症。 好了！