Stress effects on circuitry regulating nigrostriatal dopamine during goal-directed action

项目总结/摘要 慢性不可控制的压力可以沉淀或加剧许多高度流行和衰弱 神经精神障碍，如重度抑郁症和精神分裂症。这种与压力有关的疾病通常 分享共同的动机症状，导致减少参与活动，以追求一次- 期望的结果。多巴胺在自主运动、动机和奖励中起着关键作用。 学习，但其确切的贡献自我发起的目标导向行为仍然知之甚少。的 背内侧纹状体（DMS）在支持目标导向行为方面建立良好， 多巴胺能输入从黑质pars延髓（SNc）。这些黑质纹状体的解剖输入 多巴胺神经元已经被鉴定出来，但关于这种回路如何调节黑质纹状体的神经元却知之甚少。 目标导向行动中的多巴胺动力学此外，在啮齿动物模型中的慢性应激操作 揭示了压力对邻近中脑边缘多巴胺向腹侧投射的复杂影响， 纹状体，以及结构和生理变化的皮质纹状体输入的DMS。但 压力对黑质纹状体多巴胺的影响以及在目标导向行为中调节多巴胺的回路， 被很好地描述了。 因此，拟议的实验将通过检查黑质纹状体多巴胺来解决这些关键差距 传递（目的1）和纹状体黑质回路调节这些多巴胺动力学（目的2） 表现出目标导向的行为这些K99指导阶段实验将需要整合 现代光遗传学技术与候选人的专业知识，记录多巴胺使用快速扫描循环 伏安法，他们将提供机会，获得先进的技术培训，在体内 在金鑫博士的指导下， （导师）和艾德卡拉威博士（共同导师）。这套系统神经科学工具的培训将允许 随后的R 00独立阶段研究慢性应激如何改变功能电路 在目标导向的行动和更复杂的成本效益决策过程中调节黑质纹状体多巴胺 (Aim 3）。这些实验将需要在进一步指导下实施不同的压力操作 Byungkook Lim博士（顾问）的一项新的决策任务， 研究涉及回报和努力之间权衡的决策。总的来说， 这个独立之路奖将产生前所未有的洞察力如何慢性压力影响， 在目标导向行为和行动选择中调节未被研究的多巴胺通路的电路;它将 提供技术培训和职业发展，以启动候选人的独立研究 计划;它将揭示重要的其他问题，为今后的调查机制，支持 动机行为和心理健康。

Project Summary / Abstract Chronic uncontrollable stress can precipitate or exacerbate many highly prevalent and debilitating neuropsychiatric disorders such as major depression and schizophrenia. Such stress-related disorders often share common motivational symptoms that result in reduced engagement in activities in pursuit of once- desired outcomes. Dopamine plays critical roles in voluntary movement, motivation, and reward-based learning, but its precise contribution to self-initiated goal-directed behavior remains poorly understood. The dorsomedial striatum (DMS) is well established in supporting goal-directed behavior and receives prominent dopaminergic input from the substantia nigra pars compacta (SNc). Anatomical inputs to these nigrostriatal dopamine neurons have been identified, but little is known about how this circuitry regulates nigrostriatal dopamine dynamics during goal-directed action. Furthermore, chronic stress manipulations in rodent models have revealed complex effects of stress on the adjacent mesolimbic dopamine projections to the ventral striatum, as well as structural and physiological alterations of corticostriatal inputs to the DMS. However, the effects of stress on nigrostriatal dopamine and the circuitry regulating it during goal-directed behavior has not been well characterized. The proposed experiments therefore will address these critical gaps by examining nigrostriatal dopamine transmission (Aim 1) and the striatonigral circuitry regulating these dopamine dynamics (Aim 2) in mice performing goal-directed behavior. These K99 mentored phase experiments will entail the integration of modern optogenetic techniques with the candidate's expertise in recording dopamine using fast-scan cyclic voltammetry, and they will provide opportunities for acquiring advanced technical training with in vivo electrophysiology and cutting-edge viral circuit-manipulation techniques under the guidance of Dr. Xin Jin (mentor) and Dr. Ed Callaway (co-mentor). Training in this suite of systems neuroscience tools will permit subsequent R00 independent phase investigations of how chronic stress alters the functional circuitry regulating nigrostriatal dopamine during goal-directed actions and more complex cost-benefit decision making (Aim 3). These experiments will entail distinct stress manipulations implemented following further guidance from Dr. Byungkook Lim (consultant) and a novel decision-making task adapted from the candidate's doctoral work examining decisions involving tradeoffs between reward and effort. Collectively, the research proposed in this Pathway to Independence award will yield unprecedented insight into how chronic stress affects the circuitry regulating an under-examined dopamine pathway in goal-directed behavior and action selection; it will provide the technical training and career development to launch the candidate's independent research program; and it will reveal important additional questions for future investigations of mechanisms supporting motivated behavior and mental health.