Determining if Activity in Specific Lateral Habenula Output Pathways Motivates Avoidance of Synthetic Opioid Withdrawal or Cue Induced Reinstatement

确定特定外侧缰核输出通路的活动是否会促使避免合成阿片类药物戒断或提示诱导的恢复

• 批准号: 10300262
• 负责人: Kevin R. Coffey
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300262
• 关键词: Abstinence; Acute; Animals; Award; Behavior; Behavioral; Behavioral Model; Brain region; CAV2 gene; Calcium; Cell Nucleus; Complex; Coupled; Cues; Disease; Distress; Dose; Drug Delivery Systems; Emotional; Emotions; Environment; Epidemic; Euphoria; Exposure to; Extinction (Psychology); Fentanyl; Fiber; Future; Grant; Habenula; Head; Image; Individual; Injections; Jaw; Lateral; Learning; Light; Malaise; Mentors; Mentorship; Midbrain structure; Modeling; Motivation; Naloxone; Negative Reinforcer; Neural Pathways; Neurobiology; Neurons; Opiate Addiction; Opioid; Opsin; Oral; Output; Pain; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positive Reinforcer; Process; Production; Public Health; Rattus; Relapse; Research; Rewards; Role; Scientist; Self Administration; Stress; Substance abuse problem; Tegmentum Mesencephali; Testing; Time; Training; Ultrasonics; United States; Ventral Tegmental Area; Withdrawal; Writing; addiction; base; behavior test; behavioral response; career; combat; design; dorsal raphe nucleus; dysphoria; experience; experimental group; experimental study; gene therapy; improved; in vivo calcium imaging; model development; negative affect; next generation; novel; novel therapeutics; opioid abuse; opioid mortality; opioid withdrawal; optogenetics; overdose death; programs; response; reward processing; skills; synthetic opioid; tool; vocalization

Project Summary Opioid abuse has reached epidemic proportions in the United States and is responsible for more than 40,000 overdose deaths each year 1. In particular, synthetic opioid addiction has proven to be extremely difficult to combat, in part because it generates powerful opponent processes in the user. Each dose of synthetic opioid produces rapid and potent euphoria that is strongly associated to drug cues, while withdrawal and abstinence from synthetic opioids induce severe distress. Avoidance of withdrawal and subsequent exposure to drug cues are key deterrents to long-term abstinence. The Lateral Habenula (LHb) is an exciting target for studying neuronal facilitation of relapse, as LHb activity is correlated with both stress evasion and the encoding of motivational value 6. LHb activity during acute withdrawal may motivate relapse via stress avoidance mechanisms, while during abstinence cues that are normally paired with drugs go unrewarded, inducing activity in the LHb. This activity may motivate drug seeking via a process akin to reward prediction error. Under the primary mentorship of Drs. John Neumaier, Michael Bruchas, Paul Phillips, and Charles Chavkin, this K99/R00 Pathway to Independence award will allow me to obtain training in cutting edge in-vivo calcium imaging and optogenetics, and oral self-administration model development. This training will allow me to elucidate the roles of the major LHb output pathways in motivating avoidance of fentanyl withdrawal and cued reinstatement. During the mentored phase of this grant I will be trained to use GCaMP6-based in-vivo calcium imaging to record LHb neurons that project specifically to the ventral tegmental area (VTA), the rostromedial tegmentum (RMTg), or the dorsal raphe nucleus (DRN) during naloxone-precipitated withdrawal, conditioned place aversion testing, and fentanyl reinstatement. I will also be trained to combine in-vivo calcium imaging with red-shifted optogenetic inhibition in order to leverage simultaneous circuit imaging and recording, and test causal relationships between neural pathway activity and behavior. Finally, I will be trained in novel oral fentanyl self-administration (SA) model development, which will be invaluable to my independent research career as a behavioral neuroscientist. During the independent phase of the award, I will combine this training with my prior expertise to determine if activity in each LHb pathway is necessary for expression of withdrawal related negative affect, withdrawal induced CPA, or cued reinstatement to fentanyl seeking. I will do so by simultaneously inhibiting LHb projections and recording from each LHb target region (VTA, RMTg, or DRN) to determine the effect of inhibition on behavior and monoaminergic nucleus activity. In summary, the research proposed in this Pathway to Independence Award will elucidate the role of individual LHb pathways in motivating avoidance of withdrawal and cued reinstatement, as well as their role in the expression of negative affect. This award will provide training in new technical tools, grant writing, lab management, mentorship, and other skills necessary to establish an independent research program capable of producing high impact studies and training the next generation of scientists.

项目摘要 阿片类药物滥用已在美国达到流行病，并负责超过40,000 每年过量死亡1。 战斗，部分是因为它在用户中生成强大的对手进程。每剂合成阿片类药物 产生与毒品提示密切相关的快速而有效的欣快，而戒断和戒酒 从合成阿片类药物引起严重困扰。避免退出并随后接触药物提示 是长期禁欲的关键威慑。外侧Habenula（LHB）是研究的令人兴奋的目标 神经元的复发促进，因为LHB活性与应力逃避和编码相关 动机价值6。急性戒断期间的LHB活动可能会通过避免压力来激励复发 机制，而在通常与药物配对的禁欲提示期间，没有回报，诱导活性 在LHB中。该活动可能会通过类似于奖励预测错误的过程来激发吸毒。在 博士的主要指导。 John Neumaier，Michael Bruchas，Paul Phillips和Charles Chavkin，这是K99/R00 获得独立奖的途径将使我能够在尖端钙内钙成像和 光遗传学和口服自我管理模型的开发。这项培训将使我能够阐明角色 主要LHB输出途径激励避免芬太尼退出和提示恢复原状。期间 这笔赠款的指导阶段我将接受使用基于GCAMP6的体内钙成像来记录LHB的培训 专门投射到腹侧对段区域（VTA），the胶膜的神经元或 在纳洛酮进行戒断，条件的位置厌恶测试和 芬太尼恢复原状。我还将接受培训以将体内钙成像与红移光学遗传学相结合的培训 抑制以利用同时的电路成像和记录，并测试因果关系 神经通路活动和行为。最后，我将接受新的口服芬太尼自我管理（SA）模型的培训 发展，这对我作为行为神经科学家的独立研究生涯将是无价的。期间 该奖项的独立阶段，我将将这项培训与以前的专业知识相结合，以确定活动是否在 每个LHB途径对于表达戒断相关的负面影响，戒断诱导的CPA，必要 或提示恢复到芬太尼寻求。我将同时抑制LHB预测和记录来做到这一点 从每个LHB目标区域（VTA，RMTG或DRN）确定抑制对行为和 单胺能核活性。总而言之，这项在本独立奖项奖中提出的研究 将阐明单个LHB途径在激励避免戒断和提示恢复原处的作用， 以及它们在负面影响表达中的作用。该奖项将提供新技术工具的培训， 赠款写作，实验室管理，指导以及建立独立研究所需的其他技能 能够产生高影响研究并培训下一代科学家的计划。