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.

项目总结/摘要 阿片类药物流行病在美国和世界各地都是一个不断增长的问题。具有深刻 个人，社会和经济后果。阿片类药物的使用在许多情况下会成为阿片类药物使用障碍（OUD）。 个体OUD包括几个阶段，其中之一是高度烦躁的戒断综合征， 阿片类药物戒断综合征（OWS）。戒断症状，包括睡眠失调，以及对那些 症状往往大大有助于复发。我们目前还不了解所有的神经生物学 阿片类药物戒断的潜在机制，也不知道阿片类药物戒断如何改变特定的回路。公 然而，已知两个大脑区域，终纹床核（BNST）和腹侧被盖 （1）在一定的能力范围内。在这一建议的两个目标中，实验将有助于 了解这两个区域之间的通路如何被阿片类药物戒断所改变。我们的初步数据 表明BNST中的GABA能神经元因戒断而改变。BNSTGABA神经元构成了 BNST神经元投射到VTA，在那里它们突触到VTAGABA神经元，并且已经被 与积极强化有关该项目利用病毒操纵，行为研究， 电生理检查，以仔细和具体地确定BNST中戒断的影响。 在该提案的第二部分中，实验集中于VTA中该途径的输出， 以及敲除该通路以阐明该通路在控制行为中的作用。