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

项目摘要 有效权衡行动选择的成本和收益的能力是生存不可或缺的。许多环境问题 而内部因素会影响在面临能源支出等成本时追求回报的决定。这 决策类型，称为“努力评估”，允许个人在以下情况下驾驭 努力和回报的偶然性改变，使行动的效用最大化。努力价值评估经常受到损害。 在患有包括抑郁症和精神分裂症在内的动机障碍的个人中，他们可能 认为预期的努力成本超过预期回报的价值。前部信号中断 众所周知，扣带回皮质(ACC)会损害努力评估，并使个体偏向次优行为 然而，反应中，离散的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。我们将在体内整合双光子钙成像 (目标1)和光遗传学(目标2)，以描述两种投射定义的ACC亚型-皮质纹状体的作用 以及皮质岛叶神经元--对任务特征进行编码，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，这些流程 可能会支持不同方面的努力估值。为了促进这些实验，我们开发了和 已验证与图像兼容的工作评估任务，该任务可以测量动机(预期性) 以及在低努力和高努力条件下的享乐(消耗性)奖励寻求行为。使用这项任务，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 寻找和电路功能(目标3)。重要的是，只有一部分经历过压力的人才会发展。 在抑郁的同时，许多人仍保持着“弹性”。揭示人类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。在独立的 阶段，我们将通过单细胞转录转录询问皮质纹状体和 应激敏感和抵抗动物的皮质岛叶神经元，希望发现新的分子 用于通知治疗靶点的候选路径。在电路解剖和个人和人群方面的培训- 一级神经活动数据分析将由主要导师利斯顿博士提供，并由利斯顿博士补充。 维克托和拉贾塞图帕西及其在威尔·康奈尔医学和洛克菲勒的实验室中的所有可用资源 大学。作为共同导师，Macosko博士(哈佛医学院)将对候选人进行单细胞RNA方面的培训。 在阿纳拉特博士的支持下，测序方法。内斯特勒博士(Mt.西奈半岛)将提供额外的指导 关于压力的动物模型。候选人的导师和外部咨询委员会将帮助她 向关注健康人群动机行为回路机制的独立研究项目过渡 通过实施一项系统和全面的培训计划，提高对疾病状况的认识。

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.