Neural Mechanisms of Habit Formation for Behaviors Motivated by Drugs of Abuse and Natural Reward

7.项目摘要/摘要 这项提案的总体目标是阐明从休闲到娱乐的转变背后的神经回路 强制使用药物，并在这样做的过程中，为候选人提供学习先进技术的培训 涉及药物使用和滥用的神经回路。 物质使用障碍的特征是强迫使用药物，尽管有负面后果，这 可能是由于养成了强烈的吸毒“习惯”。这些习惯由僵硬、僵硬的药物组成- 寻求行为，他们的立场与“目标导向”的毒品寻求形成对比，后者更灵活，更受驱使 通过追求期望的结果(例如，欣喜若狂的状态或戒除后的解脱)。习惯可以从行为中产生 受到自然奖励(例如食物)或药物的激励，最初以目标为驱动的行为可以转变为 习惯性控制。研究表明，从目标驱动的行为到习惯的转变伴随着一种转变 从腹侧到背侧纹状体的行为控制，最近的证据表明，这种纹状体内 移位是从杏仁基底外侧核(BLA)向中央杏仁核(CEA)移位的“下游”。然而， 这一理论缺乏直接证据，特别是在信号机制的形式上。而且，虽然 有证据表明，多巴胺能传入BLA和CEA对于维持线索药物是必不可少的。 目前尚不清楚杏仁核中的多巴胺受体如何参与药物摄取的启动或 吸毒习惯的养成。 因此，候选人将进行三组实验，每一组都检查从目标导向的转变 在自然奖赏和可卡因自我给药背景下的习惯性行为：(1)记录神经 同时在BLA和CEA中激活，(2)使用光遗传策略来刺激或抑制多巴胺能 输入到BLA或CEA，以及(3)使用化学发生策略(DREADD)来抑制来自 内侧前额叶皮质(MPFC)至BLA或CEA。通过这种方式，拟议的实验将阐明 信号机制，多巴胺的作用，以及不同的mPFC输入在BLA/CEA控制目标中的作用。 定向行为与习惯性行为。 在获奖期间，候选人将接受技术和理论方面的严格培训。 药物使用和成瘾的自我管理研究。应聘者还将获得培训和经验 神经回路解剖的先进技术，包括光遗传学和化学遗传学。这项工作将 在候选人的专用实验室空间和候选人独特的跨部门实验室进行 顾问委员会，都在匹兹堡大学蓬勃发展的神经科学界。此外, 培训将侧重于出版、资质和求职技能，有效地为应聘者做好准备 在五年内申请更多的助学金和终身教职。

7. Project Summary/Abstract The overall objective of this proposal is to shed light on neural circuits underlying the transition from recreational to compulsive drug use, and, in doing so, to provide the candidate with training in advanced techniques to study the neural circuitry involved in drug use and abuse. Substance use disorders are characterized by compulsive drug use in spite of negative consequences, which might arise from the development of strong drug-taking “habits.” These habits consist of rigid, inflexible drug- seeking behavior, and they stand in contrast to “goal-directed” drug-seeking, which is more flexible and driven by pursuit of a desired outcome (e.g. a euphoric state or relief from withdrawal). Habits can arise from behavior motivated by either natural reward (e.g. food) or drugs, and behavior that is initially goal-driven can transition to habitual control. Studies have shown that the shift from goal-driven behavior to habit is accompanied by a shift in behavioral control from the ventral to the dorsal striatum, and recent evidence suggests that this intra-striatal shift is “downstream” of a shift from the basolateral amygdala (BLA), to the central amygdala (CeA). However, direct evidence for this theory is lacking, especially in the form of a signaling mechanism. Moreover, although there is evidence that dopaminergic input to the BLA and CeA is essential for the maintenance of cued drug- seeking, it is unclear how dopamine receptors in the amygdala are involved in the initiation of drug-taking or the formation of drug-seeking habits. Therefore, the candidate will pursue three sets of experiments, each examining the transition from goal-directed to habitual behavior in the context of both natural reward and cocaine self-administration: (1) recording neural activity simultaneously in the BLA and CeA, (2) using an optogenetic strategy to stimulate or inhibit dopaminergic input to the BLA or CeA, and (3) using a chemogenetic strategy (DREADDs) to inhibit specific projections from the medial prefrontal cortex (mPFC) to the BLA or CeA. In this way, the proposed experiments will elucidate the signaling mechanism, the role of dopamine, and the role of divergent mPFC inputs in BLA/CeA control of goal- directed vs. habitual behavior. During the award period, the candidate will undergo rigorous training in the techniques and theory underlying self-administration studies of substance use and addiction. The candidate will also gain training and experience in advanced techniques for neural circuit dissection, including optogenetics and chemogenetics. This work will take place in both the candidate’s dedicated lab space and the labs of the candidate’s unique cross-departmental advisory committee, all within the flourishing neuroscience community of the University of Pittsburgh. In addition, training will focus on publishing, grantsmanship, and job search skills, effectively preparing the candidate to apply for larger grants and a tenure-track position within five years.