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: 10284664
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284664
• 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; Genes; 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; Regulator Genes; 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; 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.

项目摘要 有效权衡行动选择的成本和收益的能力是生存的必要条件。许多环境 内部因素影响在面对能量消耗等成本时追求奖励的决策。这 一种称为“努力评估”的决策类型允许个人在以下情况下导航： 努力和回报的偶然性变化，并最大限度地提高行动的效用。努力价值往往受损 在患有包括抑郁症和精神分裂症在内的动机障碍的个体中， 认为预期的努力成本超过预期回报的价值。大脑前部的信号中断 扣带皮层（ACC）是已知的损害努力评价和偏见的个人向次优行为 然而，离散ACC回路在编码奖励和努力相关的精确功能 信息和启用这种行为仍然是未知的。我们将在体内整合双光子钙成像 (Aim 1）和光遗传学（目的2），以描绘两个投影定义的ACC亚型的作用-皮质纹状体 和皮质岛叶神经元-在编码任务的特点，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（脑桥核和岛叶皮质） 分别在驱动目标导向行为和监控内部状态方面发挥重要作用， 可以支持不同方面的努力评价。为了促进这些实验，我们开发并 验证了一个与想象兼容的努力评估任务，该任务能够测量动机（预期） 以及在低努力和高努力条件下的享乐（完美）奖励寻求行为。通过这项任务，我们将 确定慢性心理社会压力（抑郁症状的风险因素）对努力奖励的影响 搜索和电路功能（目标3）。重要的是，只有一小部分经历压力的人会发展成 抑郁症，而许多人仍然'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是重要的。在独立 阶段，我们将探索这些差异，通过单细胞转录询问皮质纹状体和 皮质岛神经元在压力敏感和抵抗动物，希望发现新的分子 途径候选人，以告知治疗目标。在电路解剖和个人和群体方面的培训- 水平神经活动数据分析将由主要导师Liston博士提供，并由 维克托和拉贾斯坦邦利用他们在威尔康奈尔医学和洛克菲勒的实验室的所有可用资源 大学作为共同导师，Macosko博士（哈佛医学院）将培训候选人的单细胞RNA- Anrather博士的本地支持下的测序方法。Nestler博士（Mt.西奈半岛）将提供额外的指导 压力的动物模型。候选人的导师和外部咨询委员会将帮助她 过渡到一个独立的研究计划，重点是健康的动机行为的电路机制 和疾病状态，通过实施结构化和全面的培训计划。