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：
10475254
负责人：
Sara Morrison
金额：
$ 14.18万
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/10475254
关键词：
Advisory Committees Amygdaloid structure Area Award Behavior Behavior Control Brain Brain region 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 cocaine self-administration 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 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. 项目总结/摘要该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迫性药物使用，并在此过程中为候选人提供先进技术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不顾负面后果仍强迫性使用药物，这可能是由于养成了强烈的吸毒“习惯”。这些习惯包括僵化的、不灵活的吸毒习惯。寻求行为，与“目标导向”的药物寻求形成鲜明对比，后者更加灵活和有驱动力通过追求期望的结果（例如欣快的状态或从退缩中得到缓解）。习惯可以由行为产生。受到自然奖励（例如食物）或药物的激励，最初目标驱动的行为可以转变为研究表明，从目标驱动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这种转变是从基底外侧杏仁核 (BLA) 到中央杏仁核 (CeA) 转变的“下游”。该理论缺乏直接证据，尤其是信号机制的形式。有证据表明 BLA 和 CeA 的多巴胺能输入对于维持提示药物至关重要目前尚不清楚杏仁核中的多巴胺受体如何参与吸毒的启动或养成寻药习惯。因此，候选人将进行三组实验，每组实验都检查从目标导向的转变在自然奖励和可卡因自我给药背景下的习惯行为：（1）记录神经 BLA 和 CeA 中同时存在活性，(2) 使用光遗传学策略刺激或抑制多巴胺能输入到 BLA 或 CeA，以及（3）使用化学遗传学策略（DREADD）来抑制来自通过这种方式，所提出的实验将阐明内侧前额皮质（mPFC）到 BLA 或 CeA 的作用。信号传导机制、多巴胺的作用以及不同 mPFC 输入在 BLA/CeA 控制目标中的作用定向行为与习惯行为。获奖期间，候选人将接受严格的技术和理论培训候选人还将获得有关药物使用和成瘾的自我管理研究的培训和经验。这项工作将研究神经回路解剖的先进技术，包括光遗传学和化学遗传学。既在候选人的专用实验室空间中又在候选人独特的跨部门实验室中进行顾问委员会，均来自匹兹堡大学蓬勃发展的神经科学界。培训将侧重于出版、资助和求职技能，有效地帮助候选人做好准备五年内申请更大的拨款和终身职位。