Corticostriatal and Corticoinsular Circuit Mechanisms Underlying Stress Effects on Effort-based Reward Processing

基于努力的奖励处理的压力影响下的皮质纹状体和皮质岛环路机制

• 批准号: 10472666
• 负责人: Puja Parekh
• 金额: $ 12.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472666
• 关键词: Address; Advisory Committees; Affect; Anhedonia; Animal Model; Animals; Anterior; Antidepressive Agents; Automobile Driving; Behavior; Behavior monitoring; Behavioral; Calcium; Cells; Chronic; Chronic stress; Clinical; Cognitive; Complement; Cost-Benefit Analysis; Costs and Benefits; Cues; Data Analyses; Decision Making; Dendritic Spines; Development; Disease; Dissection; Emotional; Energy Metabolism; Etiology; Expenditure; Gene Expression; Gene Expression Profile; Genetic; Goals; Head; Heterogeneity; Image; Impairment; Individual; Individual Differences; Ketamine; Learning; Maintenance; Measurement; Mediator of activation protein; Medicine; Mental Depression; Mental disorders; Mentors; Methods; Modality; Molecular; Mood Disorders; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Pathologic; Pathway interactions; Phase; Population; Predisposition; Prefrontal Cortex; Process; Psychological reinforcement; Psychosocial Stress; Recording of previous events; Research; Resistance; Resources; Rewards; Risk Factors; Role; Schizophrenia; Science; Signal Transduction; Stimulus; Stress; Structure; Techniques; Testing; Training; Universities; Viral; Work; base; behavioral impairment; behavioral response; calcium indicator; cingulate cortex; cost; depressive symptoms; expectation; experience; experimental study; gene network; gene regulatory network; hedonic; in vivo; in vivo imaging; interest; medical schools; motivated behavior; novel; optogenetics; pleasure; pre-clinical; programs; psychosocial; relating to nervous system; resilience; response; reward processing; single-cell RNA sequencing; social defeat; therapeutic target; tool; trait; transcriptomics; two-photon

Project Summary The ability to effectively weigh costs and benefits for action selection is integral to survival. Many environmental and internal factors influence the decision to pursue reward in the face of costs such as energy expenditure. This type of decision making, referred to as “effort valuation” allows individuals to navigate circumstances in which effort and reward contingencies change and to maximize the utility of actions. Effort valuation is often impaired in individuals suffering from disorders of motivation including depression and schizophrenia, whereby they may perceive the anticipated effort cost to outweigh the value of expected rewards. Disrupted signaling in the anterior cingulate cortex (ACC) is known to impair effort valuation and bias individuals toward suboptimal behavioral responses, however, the precise function of discrete ACC circuits in encoding reward- and effort-related information and enabling this behavior remains unknown. We will integrate in vivo 2-photon calcium imaging (Aim 1), and optogenetics (Aim 2) to delineate the roles of two projection-defined ACC subtypes - corticostriatal and corticoinsular neurons – in encoding of task features including reward- and effort-predictive cues. Clinical and preclinical evidence suggests that these subcortical structures (the nucleus accumbens and insular cortex) are critically involved in driving goal-directed behavior and monitoring internal state, respectively, processes that may support different aspects of effort valuation. To facilitate these experiments, we have developed and validated an imaging-compatible effort valuation task which enables measurement of motivational (anticipatory) and hedonic (consummatory) reward seeking behavior in low- and high-effort conditions. Using this task, we will determine the effects of chronic psychosocial stress, a risk factor for depressive symptoms, on effortful reward seeking and circuit function (Aim 3). Importantly, only a subset of individuals who experience stress develop depression while many remain `resilient.' Uncovering the neurobiological bases for individual differences in susceptibility to stress is important to understanding the etiology of psychiatric disorders. In the independent phase, we will explore these differences through single-cell transcriptomic interrogation of corticostriatal and corticoinsular neurons in stress-susceptible and resistant animals in the hope of uncovering novel molecular pathway candidates to inform therapeutic targets. Training in circuit dissection and individual and population- level neural activity data analysis will be provided by the primary mentor, Dr. Liston, and complemented by Drs. Victor and Rajasethupathy with all available resources in their labs at Weill Cornell Medicine and Rockefeller University. As co-mentor, Dr. Macosko (Harvard Medical School), will train the candidate in single-cell RNA- sequencing methods with local support from Dr. Anrather. Dr. Nestler (Mt. Sinai) will provide additional guidance on animal models of stress. The candidate's mentors and External Advisory Committee will facilitate her transition to an independent research program focused on circuit mechanisms of motivated behavior in healthy and disease states, through the implementation of a structured and comprehensive training plan.

项目概要 有效权衡行动选择的成本和收益的能力对于生存至关重要。许多环保 内部因素会影响在面临能源支出等成本时追求奖励的决定。这 称为“努力评估”的决策类型使个人能够应对以下情况： 努力和奖励会发生变化，并最大限度地提高行动的效用。努力的估价常常受到损害 在患有抑郁症和精神分裂症等动机障碍的个体中，他们可能会 认为预期的努力成本超过预期回报的价值。前部信号传导中断 众所周知，扣带皮层 (ACC) 会损害努力评估并使个人偏向次优行为 然而，离散 ACC 电路在编码与奖励和努力相关的过程中的精确功能 信息和启用此行为仍然未知。我们将整合体内 2 光子钙成像 （目标 1）和光遗传学（目标 2）描述两种投影定义的 ACC 亚型 - 皮质纹状体的作用 和皮质岛神经元 - 编码任务特征，包括奖励和努力预测线索。临床 临床前证据表明这些皮质下结构（伏隔核和岛叶皮质） 分别关键地参与驱动目标导向的行为和监控内部状态， 可以支持努力评估的不同方面。为了促进这些实验，我们开发并 验证了一种与成像兼容的努力评估任务，可以测量动机（预期） 以及在低努力和高努力条件下寻求享乐（圆满）奖励的行为。使用这个任务，我们将 确定慢性心理社会压力（抑郁症状的危险因素）对努力奖励的影响 寻道和电路功能（目标 3）。重要的是，只有一小部分经历过压力的人会发展为 抑郁症，而许多人仍然“有弹性”。揭示个体差异的神经生物学基础 对压力的敏感性对于理解精神疾病的病因很重要。在独立 阶段，我们将通过单细胞转录组学研究皮质纹状体和 研究压力敏感和抵抗动物的皮质岛神经元，希望发现新的分子 途径候选者以告知治疗目标。电路解剖以及个体和群体的培训- 水平神经活动数据分析将由主要导师 Liston 博士提供，并由 Dr. Liston 补充。 Victor 和 Rajasethupathy 拥有威尔康奈尔医学院和洛克菲勒实验室的所有可用资源 大学。作为联合导师，Macosko 博士（哈佛医学院）将对候选人进行单细胞 RNA 方面的培训 Anrather 博士的本地支持下的测序方法。 Nestler 博士（西奈山）将提供额外指导 压力动物模型。候选人的导师和外部咨询委员会将为她提供便利 过渡到一个独立的研究项目，重点关注健康人群动机行为的循环机制 和疾病状态，通过实施结构化和全面的培训计划。