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 有效的体重成本和行动选择收益的能力对于生存而言是不可或缺的。许多环境 内部因素会影响面对诸如能源支出等成本的决定。这 决策类型，称为“努力价值” 努力和奖励意外事件发生了变化，并最大程度地提高了行动的效用。努力价值通常会受到损害 在患有抑郁症和精神分裂症在内的动机障碍的人中，他们可能 认为预期的努力大于预期奖励的价值。前部的信号传导 已知扣带回皮层（ACC）会损害努力价值，而偏向于次优行为的偏见 但是，响应在编码奖励和努力有关 信息和实现此行为仍然未知。我们将集成在体内2-光子钙成像中 （AIM 1）和光遗传学（AIM 2）来描述两个投影定义的ACC亚型的作用 - 皮质纹状体 和皮质神经元 - 编码任务功能，包括奖励和努力预测性线索。临床 临床前的证据表明，这些皮层结构（伏隔核和岛状皮质） 批判性地参与推动目标指导的行为和监视内部状态的过程 可能支持努力价值的不同方面。为了促进这些实验，我们已经开发了 验证了与成像兼容的工作价值任务 以及享乐（完整的）奖励在低和高及时的条件下寻求行为。使用此任务，我们将 确定慢性社会心理压力的影响，这是抑郁症状的危险因素，对艰苦的奖励 寻求和电路功能（AIM 3）。重要的是，只有一部分经历压力的人会发展 抑郁，而许多人仍然保持“弹性”。揭示神经生物学基础的个体差异 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，我们将通过对皮质纹状体和 应力敏感和抗性动物中的皮质神经元，希望发现新的分子 候选途径以告知治疗目标。电路解剖以及个人和人群的培训 - 级别的神经活动数据分析将由主要导师Liston博士提供，并由Drs完成。 Victor和Rajasethupathy在Weill Cornell Medicine和Rockefeller的实验室中拥有所有可用资源 大学。作为同事Macosko博士（哈佛医学院），将在单细胞RNA-培训候选人 - 在Anrather博士的本地支持下进行测序方法。 Nestler博士（西奈山）将提供其他指导 关于压力的动物模型。候选人的导师和外部咨询委员会将促进她 过渡到独立研究计划，重点是健康的融合行为的电路机制 疾病指出，通过实施结构化和全面的培训计划。