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

项目摘要/摘要 慢性无法控制的压力会导致或加剧许多高度流行和衰弱的疾病 神经精神障碍，如严重的抑郁症和精神分裂症。这类应激相关的障碍通常 分享共同的激励症状，这些症状会导致人们减少对追求一次- 期望的结果。多巴胺在自愿运动、动机和基于奖励的过程中起着关键作用 学习，但它对自我发起的目标导向行为的确切贡献仍然知之甚少。这个 背内侧纹状体(DMS)在支持目标定向行为方面有很好的地位，并收到显著的 黑质致密部(SNC)的多巴胺能传入。黑质纹状体的解剖学输入 多巴胺神经元已经被发现，但对这个回路如何调节黑质纹状体知之甚少。 目标导向行动中的多巴胺动态。此外，啮齿动物模型中的慢性应激操作 揭示了应激对邻近的腹侧中脑边缘多巴胺投射的复杂影响 纹状体，以及皮质纹状体输入到DMS的结构和生理变化。然而， 应激对目标定向行为中黑质纹状体多巴胺及其调控回路的影响尚未见报道 被很好地刻画出来了。 因此，拟议的实验将通过检测黑质纹状体多巴胺来解决这些关键差距。 传递(目标1)和调节这些多巴胺动态的纹状体黑质回路(目标2) 执行目标导向的行为。这些K99指导阶段实验将需要集成 具有候选人使用快扫描循环记录多巴胺的专业知识的现代光遗传学技术 伏安法，他们将提供获得体内高级技术培训的机会 新进博士指导下的电生理学和尖端病毒电路操作技术 (导师)和Ed Callaway博士(共同导师)。对这套系统神经科学工具的培训将允许 随后对慢性应激如何改变功能回路的R00独立时相研究 在目标导向的行动和更复杂的成本效益决策中调节黑质纹状体多巴胺 (目标3)。这些实验将需要在进一步指导下实施不同的应力处理 从林炳国博士(顾问)和一个新的决策任务改编自候选人的博士 研究涉及报酬和努力之间权衡的决策。总的来说，这项研究建议在 这一独立之路奖将对慢性压力如何影响 在目标导向行为和动作选择中调节未被研究的多巴胺通路的回路；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；它将为今后对支持机制的调查揭示重要的其他问题 动机行为与心理健康。

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.