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: 9768577
• 负责人: Robert N Fetcho
• 金额: $ 5万
• 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/9768577
• 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; 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; recruit; response; reward processing; sensor; stress state; 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. !

项目摘要 重度抑郁症（MDD）是一种高度流行和衰弱的情绪障碍， 基于症状的混合，但快感缺乏--对奖励活动的兴趣降低--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的动力而引起的。 获得奖励。每一个努力获得奖励的决定都涉及到行动价值的计算- 基本上是一个成本效益分析是否积极价值的预期结果的行动 超过了与该操作相关的预期工作量的负值。前扣带皮层 (ACC)前额叶皮层（PFC）的压力敏感区域一直与行动评估有关 跨物种的计算功能失调的行动评估计算是否以及如何驱动享乐缺失 与压力有关的精神疾病的症状尚不清楚。虽然广泛的，开创性的工作， 特征的影响，压力对PFC神经元能电路，少是已知的作用， 抑制电路在压力诱导的抑郁样行为，尽管有大量的证据表明， 抑郁症患者的抑制系统。这项工作将调查的作用，一种细胞亚型，生长抑素 （SST）表达的中间神经元，在驱动健康的奖励寻求和慢性应激诱导的快感缺失中的作用 行为我们的假设是，SST中间神经元通过动态地促进动作评估计算， 调节ACC的突触输入，SST细胞的过度活跃破坏了慢性应激中的这一过程 states.为了验证这一点，我们将通过长期的实验记录ACC SST中间神经元群的活性。 在清醒的、行为自由的小鼠体内植入光纤（光纤光度测定法）， 在正常和慢性应激条件下完成任务。然后，我们将光遗传学操纵的活动， 这些细胞来确定SST中间神经元在驱动健康和病理性奖励中的特定因果作用 处理.这项研究将填补我们对压力引起的快感缺失的理解中的一个实质性空白 通过关注在压力背景下研究不足的稀疏但必不可少的细胞群， 萧条 !