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

基本信息

批准号：
10684146
负责人：
Sara Morrison
金额：
$ 14.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10684146
关键词：
Acceleration Advisory Committees Amygdaloid structure Area Award Behavior Behavior Control Brain Brain region Communities Corpus striatum structure Cues Dedications Designer Drugs Development Dissection Dopamine Dopamine Receptor Dorsal Drug Exposure Drug abuse Drug usage Electrophysiology (science)Environment Environmental Risk Factor Euphoria Food Genetic Goals Grant Habits Halorhodopsins Human Individual Maintenance Medial Neurons Neurosciences Occupations Outcome Pharmaceutical Preparations Positioning Attribute Prefrontal Cortex Process Publishing Rattus Recreation Research Rewards Role Self Administration Signal Transduction Stress Substance Addiction Substance Use Disorder Techniques Testing Time Training Universities Ventral Striatum Ventral Tegmental Area Withdrawal Withdrawal Symptom Work addiction cocaine self-administration craving dopaminergic neuron drug of abuse drug reward drug seeking behavior experience experimental study flexibility genetic approach motivated behavior neural neural circuit neuromechanism neurotransmission novel optogenetics receptor satisfaction selective expression skills substance use tenure track theories

项目摘要

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。项目摘要/摘要该提案的总体目的是阐明从娱乐活动过渡的基础神经回路强迫毒品使用，并为此为候选人提供先进技术的培训涉及吸毒和滥用的神经元电路。药物使用障碍的特征是强迫药物使用，尽管有负面后果，也许是由于强大的毒品“习惯”的发展而产生的。这些习惯由刚性，不灵活的药物组成寻求行为，它们与“目标指导”寻求毒品形成鲜明对比，这是更灵活和驱动的通过追求预期的结果（例如，欣快的状态或免除退出）。习惯可能是由行为引起的由自然奖励（例如食物）或药物的动机，以及最初是目标驱动的行为可以过渡到习惯控制。研究表明，从目标驱动的行为到习惯的转变是通过转移来实现的在从腹侧到背纹状体的行为控制中，最近的证据表明这种纹状体转移是从基底外侧杏仁核（BLA）到中央杏仁核（CEA）的“下游”。然而，缺乏有关该理论的直接证据，尤其是在信号机制的形式中。而且，不过有证据表明，对BLA和CEA的多巴胺能输入对于维持提示的药物至关重要寻求，目前尚不清楚杏仁核中的多巴胺受体如何参与吸毒或寻求毒品习惯的形成。因此，候选人将进行三组实验，每个实验检查从目标定向的过渡在自然奖励和可卡因自我管理的背景下进行习惯行为：（1）记录中立仅在BLA和CEA中的活动，（2）使用光遗传策略刺激或抑制多巴胺能输入BLA或CEA，（3）使用化学遗传策略（Dreadds）抑制特定项目 BLA或CEA的中位前额叶皮层（MPFC）。这样，提出的实验将阐明信号传导机制，多巴胺的作用以及MPFC输入在BLA/CEA控制目标中的作用 - 指导与习惯行为。在奖励期间，候选人将接受严格的技术和理论培训对物质使用和成瘾的自我管理研究。候选人还将获得培训和经验在神经回路的晚期技术中，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的实验室中进行咨询委员会都在匹兹堡大学荧光神经科学社区内。此外，培训将着重于出版，授予技巧和求职技能，有效地为候选人做准备在五年内申请较大的赠款和终身制职位。