GABAergic alterations in the BNST to VTA circuit following morphine withdrawal

吗啡戒断后 BNST 至 VTA 回路的 GABA 能变化

• 批准号: 10607287
• 负责人: Madigan Bedard
• 金额: $ 3.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607287
• 关键词: Acute; Affect; Affective Symptoms; Animals; Anxiety; Behavior; Behavior Control; Behavioral; Brain region; Cells; Clinical; Coupled; Data; Dependovirus; Diarrhea; Economic Burden; Economics; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epidemic; Experimental Designs; Exposure to; Female; Fright; Future; Glutamates; Hour; Incentives; Individual; Interneurons; Label; Literature; Measurable; Measures; Mediating; Mental Depression; Modification; Morphine; Mus; Negative Reinforcements; Neurobiology; Neurons; Neurosciences; Opioid; Output; Pathway interactions; Persons; Pharmaceutical Preparations; Physiologic pulse; Population; Positive Reinforcements; Publishing; Relapse; Reporter; Research; Rewards; Role; Signal Transduction; Sleep disturbances; Sleeplessness; Structure of terminal stria nuclei of preoptic region; Substance Withdrawal Syndrome; Sweating; Symptoms; Synapses; Synaptic Transmission; Technology; Testing; Therapeutic; Tooth structure; Training; Tremor; United States; Ventral Tegmental Area; Viral; Vomiting; Weight; Whole-Cell Recordings; Withdrawal; Withdrawal Symptom; behavioral study; comparison control; designer receptors exclusively activated by designer drugs; experimental study; gamma-Aminobutyric Acid; improved; in vivo; interest; knock-down; male; negative affect; neural circuit; neurobiological mechanism; opioid epidemic; opioid exposure; opioid misuse; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; optogenetics; physical symptom; prevent; relapse prevention; skills; sleep behavior; sleep pattern; sleep regulation; small hairpin RNA; social; transmission process; voltage clamp

Project Summary/Abstract The opioid epidemic is a continuously growing problem in the United States and across the world. It has profound personal, social, and economic consequences. Opioid use can become Opioid Use Disorder (OUD) in many individuals. OUD consists of several stages, one of which is a highly dysphoric withdrawal syndrome known as Opioid Withdrawal Syndrome (OWS). The withdrawal symptoms, including sleep dysregulation, and fear of those symptoms often contributes drastically to relapse. We do not currently understand all of the neurobiological mechanisms underlying opioid withdrawal, nor how particular circuits are modified by opioid withdrawal. It is well known, however, that two brain regions, the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA), are involved in some capacity. In the two aims of this proposal, the experiments will help to understand how the pathway between these two regions is modified by opioid withdrawal. Our preliminary data shows that the GABAergic neurons in the BNST are altered by withdrawal. BNSTGABA neurons make up the bulk of the BNST neurons projecting to the VTA, where they synapse onto VTAGABA neurons, and have been implicated in positive reinforcement. This project utilizes viral-manipulations, behavioral studies, and electrophysiological examinations to carefully and specifically determine the effects of withdrawal in the BNST. In the second portion of this proposal, the experiments are focused on the output of this pathway in the VTA as well as a knockdown of this pathway to elucidate the role of this pathway in controlling behavior.

项目摘要/摘要 阿片类药物的流行在美国和全世界都是一个不断增长的问题。它有着深厚的内涵 个人、社会和经济后果。阿片类药物使用可在许多情况下成为阿片类药物使用障碍(OUD) 个人。OUD由几个阶段组成，其中一个阶段是高度焦虑性戒断综合症，称为 阿片戒断综合征(OWS)。戒断症状，包括睡眠失调，以及对那些 症状往往极大地导致复发。我们目前并不了解所有的神经生物学 阿片类药物戒断的潜在机制，以及阿片类药物戒断如何改变特定回路。这很好 然而，已知的两个大脑区域，终纹床核(BNST)和腹侧被盖 地区(VTA)，都在一定程度上参与其中。在这项提议的两个目标中，实验将有助于 了解阿片类药物戒断如何改变这两个区域之间的通路。我们的初步数据 结果表明，戒断后BNST内的GABA能神经元发生改变。BNSTGABA神经元构成了大部分 投射到VTA的BNST神经元，在那里它们与VTAGABA神经元突触，并且 与阳性强化有关。这个项目利用了病毒操纵、行为研究和 电生理检查，以仔细和具体地确定戒断对BNST的影响。 在本提案的第二部分中，实验集中在VTA AS中的这一通路的输出 以及敲除这一途径，以阐明这一途径在控制行为中的作用。