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

目标导向行动过程中压力对黑质纹状体多巴胺调节回路的影响

• 批准号: 10704758
• 负责人: Nick Garber Hollon
• 金额: $ 24.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704758
• 关键词: Affect; Anatomy; Anhedonia; Animal Model; Animals; Award; Behavior; Characteristics; Chronic; Chronic stress; Complex; Corpus striatum structure; Costs and Benefits; Cues; Data; Decision Making; Dopamine; Educational process of instructing; Electrophysiology (science); Foundations; Future; Goals; Impairment; Individual; Investigation; Lead; Learning; Major Depressive Disorder; Mental Depression; Mental Health; Mental disorders; Mentors; Midbrain structure; Modernization; Motivation; Movement; Mus; Neuromodulator; Neurons; Neurosciences; Outcome; Pathway interactions; Performance; Periodicity; Phase; Physiological; Play; Population; Property; Reproducibility; Research; Response to stimulus physiology; Rewards; Rodent Model; Role; Scanning; Schizophrenia; Signal Transduction; Source; Stimulus; Stress; Substantia nigra structure; Symptoms; System; Technical Expertise; Techniques; Testing; Training; Update; Ventral Striatum; Ventral Tegmental Area; Viral; Withdrawal; Work; career development; depression model; dopaminergic neuron; experimental study; extracellular; in vivo; insight; motivated behavior; neuropsychiatric disorder; novel; optogenetics; outcome prediction; pars compacta; programs; stress related disorder; stressor; tool; transmission process

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.

项目摘要 /摘要 慢性不可控制的应力会导致或加剧许多高度流行和使人衰弱的压力 神经精神疾病，例如严重抑郁症和精神分裂症。这种与压力有关的疾病经常 共享常见的动机症状，导致一次追求活动的参与度降低 - 期望的结果。多巴胺在自愿运动，动机和奖励中起关键作用 学习，但它对以自我启发的目标为导向行为的精确贡献仍然很少理解。这 背侧纹状体（DMS）在支持目标指导的行为方面已建立并获得突出的行为 来自底虫的多巴胺能输入Nigra Pars Compacta（SNC）。这些杂纹的解剖学输入 已经鉴定出多巴胺神经元，但对该电路如何调节黑质纹状体知之甚少 目标指导动作过程中的多巴胺动态。此外，啮齿动物模型中的慢性应力操纵 已经揭示了压力对相邻的中唇胶多巴胺对腹侧的复杂作用 纹状体以及DMS皮质纹状体输入的结构和生理变化。但是， 压力对斑纹纹状体多巴胺的影响和在目标指导行为期间调节其电路的影响尚未 表现得很好。 因此，提出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 在小鼠中调节这些多巴胺动力学（AIM 2）的传输（AIM 1）和纹状体电路 执行目标指导行为。这些K99指导的阶段实验将需要集成 现代的光遗传技术具有候选人在使用快速扫描循环录制多巴胺方面的专业知识 伏安法，他们将提供与体内高级技术培训的机会 Xin Jin博士的指导下的电生理学和尖端的病毒电路操作技术 （导师）和埃德·卡拉威（Ed Callaway）博士（同事）。这套系统的培训神经科学工具将允许 随后的R00 R00独立阶段调查慢性应力如何改变功能电路 在目标指导的行动和更复杂的成本效益决策过程中调节黑质多巴胺 （目标3）。这些实验将需要在进一步的指导下实施明显的压力操纵 来自Byungkook Lim博士（顾问）和一项新颖的决策任务 研究涉及奖励与努力之间的决定的决定。总的来说，研究提出了 这项获得独立奖的途径将对慢性压力如何影响慢性压力产生前所未有的见解 在目标指导行为和行动选择中调节未经检查的多巴胺途径的电路；会 提供技术培训和职业发展以启动候选人的独立研究 程序;它将揭示重要的其他问题，以便将来对支持机制的调查 动机行为和心理健康。