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

滥用药物和自然奖励引起的行为习惯形成的神经机制

• 批准号: 10041029
• 负责人: Sara Morrison
• 金额: $ 14.28万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10041029
• 关键词: Advisory Committees; Alcohol or Other Drugs use; Amygdaloid structure; Area; Award; Behavior; Behavior Control; Brain; Brain region; Cocaine; Communities; Corpus striatum structure; Cues; Designer Drugs; Development; Dissection; Dopamine; Dopamine Receptor; Dorsal; Drug abuse; Drug usage; Electrophysiology (science); Environment; Environmental Risk Factor; Euphoria; Food; Goals; Grant; Habits; Halorhodopsins; Human; Individual; Light; Maintenance; Medial; Neurons; Neurosciences; Occupations; Outcome; Palate; Pharmaceutical Preparations; Positioning Attribute; Prefrontal Cortex; Process; Publishing; Research; Rewards; Role; Self Administration; Signal Transduction; Substance Addiction; Substance Use Disorder; Techniques; Testing; Time; Training; Universities; Ventral Striatum; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; addiction; craving; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug of abuse; drug reward; drug seeking behavior; experience; experimental study; flexibility; motivated behavior; neural circuit; neuromechanism; neurotransmission; novel; optogenetics; receptor; relating to nervous system; satisfaction; selective expression; skills; tenure track; theories

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.

7.项目总结/摘要 这项建议的总体目标是阐明神经回路的基础过渡，从娱乐 强迫性药物使用，并在这样做的同时，为候选人提供先进技术的培训， 与药物使用和滥用有关的神经回路 物质使用障碍的特点是强迫性吸毒，尽管有负面后果， 这可能是由于强烈的吸毒“习惯”的发展。这些习惯包括严格的，不灵活的药物- 寻求行为，他们站在相反的“目标导向”的药物寻求，这是更灵活和驱动 通过追求期望的结果（例如欣快状态或从戒断中解脱）。习惯可以从行为中产生 受自然奖励（例如食物）或药物的激励，最初由目标驱动的行为可以过渡到 习惯性控制研究表明，从目标驱动的行为转变为习惯， 在行为控制从腹侧到背侧纹状体，最近的证据表明，这种纹状体内 转移是从基底外侧杏仁核（BLA）转移到中央杏仁核（CeA）的“下游”。然而，在这方面， 这一理论缺乏直接证据，特别是缺乏信号机制的证据。而且虽然 有证据表明，向BLA和CeA的多巴胺能输入对于维持线索药物是必不可少的， 尽管如此，目前还不清楚杏仁核中的多巴胺受体是如何参与吸毒的开始或 形成吸毒习惯。 因此，候选人将进行三组实验，每组都检查从目标导向的转变 习惯性行为的背景下，自然奖励和可卡因自我管理：（1）记录神经 同时在BLA和CeA中的活性，（2）使用光遗传学策略刺激或抑制多巴胺能 输入到BLA或CeA，和（3）使用化学发生策略（DREADDs）来抑制来自BLA或CeA的特异性投射， 内侧前额叶皮质（mPFC）到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- 习惯性行为vs.习惯性行为 在获奖期间，候选人将接受严格的技术和理论培训 药物使用和成瘾的自我管理研究。候选人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中进行 咨询委员会，都在蓬勃发展的匹兹堡大学神经科学界。此外，本发明还提供了一种方法， 培训将侧重于出版，营销和求职技能，有效地准备候选人， 在五年内申请更大的赠款和终身职位。