Role of nociceptin-containing neurons of the lateral septum in binge-like alcohol consumption

侧隔膜含有伤害感受肽的神经元在暴饮暴食中的作用

• 批准号: 10537830
• 负责人: Harold L Haun
• 金额: $ 6.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2024-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537830
• 关键词: Address; Alcohol consumption; Alcohols; Applications Grants; Attenuated; Behavior; Brain; COVID-19 pandemic; Calcium; Cells; Chronic; Consumption; Coping Skills; Dangerousness; Data; Development; Diagnosis; Drug Targeting; Electrophysiology (science); Fellowship; Female; Fiber; Genetic; Goals; Heavy Drinking; Hypothalamic structure; Individual; Intake; Knock-out; Lateral; Literature; Locomotion; Maps; Measures; Mediating; Mental Health; Mental disorders; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; National Research Service Awards; Neurobiology; Neurons; Neuropeptides; ORL1 receptor; Palpable; Patients; Pattern; Peptides; Pharmacotherapy; Photometry; Play; Population; Process; Recording of previous events; Reproducibility; Research; Research Personnel; Research Project Grants; Rewards; Risk; Role; Signal Transduction; Site; Slice; Structure; Sucrose; Synaptic Transmission; System; Time; Training; Viral; alcohol abuse therapy; alcohol measurement; alcohol research; alcohol use disorder; antagonist; binge drinking; career; cell type; drinking; drinking behavior; endogenous opioids; experience; experimental study; in vivo; interest; knock-down; male; neuroadaptation; nociceptin; novel; novel therapeutic intervention; patch clamp; receptor; receptor expression; skills; therapeutic development; therapeutic target; training opportunity

PROJECT SUMMARY The COVID-19 pandemic has had a palpable impact on mental health, and maladaptive coping strategies, such as excessive alcohol consumption, have seen a marked increase in recent years. Binge drinking is the most common pattern of excessive drinking behavior and is associated with an increased risk for the development of an alcohol use disorder (AUD). Presently, pharmacotherapies for the treatment of AUD are limited, creating a pressing need for novel therapeutic interventions. A more thorough understanding of the neurobiological processes that govern excessive, uncontrolled alcohol drinking is necessary to meet this goal. The Drinking in the Dark (DID) model serves as a robust and reproducible platform for molecular and circuit level interrogation of systems that promote binge-like alcohol consumption. The endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and the nociceptin receptor (NOP) is one molecular target of interest and selective NOP antagonists have shown great promise in attenuating excessive drinking behavior. For example, a NOP antagonist was found to decrease number of heavy drinking days and amount consumed per week in treatment-seeking patients with an AUD. My preliminary results support this therapeutic target in that a NOP antagonist decreased alcohol intake in the DID model, which is consistent with the literature. Together, these findings point to NOP as a clear candidate for AUD pharmacotherapies, and yet no studies to date have explored the endogenous N/OFQ populations that are involved in alcohol drinking behavior and only one has probed the site of NOP action. To this end, my preliminary studies have identified the lateral septum (LS) as rich in N/OFQ (LSN/OFQ) and that this discrete population plays a causal role in binge-like alcohol consumption. More specifically, cell-type specific chemogenetic activation of LSN/OFQ increased alcohol intake while silencing LSN/OFQ decreased drinking. In addition, I have found this effect to be specific to alcohol, since LSN/OFQ manipulation did not affect sucrose intake nor locomotion. The finding of selective LSN/OFQ bidirectional control over binge drinking behavior is highly exciting and paves the way for this proposal. Here, I aim to take a multifaceted approach to interrogate the functional consequence of a history of binge drinking on the electrophysiological profile of LSN/OFQ and determine the activity patterns of these neurons in vivo during alcohol drinking behavior with fiber photometry. Lastly, I will determine the molecular profile of LSN/OFQ and map the downstream projection sites, and determine the effect of genetic NOP deletion therein on alcohol intake. Thus, this proposal aims to thoroughly interrogate activity in the novel LSN/OFQ population and seeks to identify mechanistic processes by which this system promotes excessive drinking through the NOP receptor. In summary, this grant proposal targets an understudied population and neuropeptide system in a cell-type specific and signaling-dependent fashion that shows great promise as a neuroanatomic target for the treatment of AUD.

项目概要 COVID-19 大流行对心理健康和适应不良的应对策略产生了明显的影响，例如 近年来，由于过度饮酒，饮酒量明显增加。酗酒是最 过度饮酒行为的常见模式，并与罹患以下疾病的风险增加相关： 酒精使用障碍（AUD）。目前，治疗 AUD 的药物疗法有限，因此 迫切需要新的治疗干预措施。对神经生物学有更深入的了解 为了实现这一目标，有必要制定控制过度、不受控制饮酒的流程。饮酒于 暗 (DID) 模型可作为分子和电路级询问的稳健且可重复的平台 促进酗酒的系统。内源性阿片样肽 伤害感受肽/孤啡肽 FQ (N/OFQ) 和伤害感受肽受体 (NOP) 是一种令人感兴趣的分子靶标， 选择性 NOP 拮抗剂在减少过度饮酒行为方面显示出巨大的前景。例如， 研究发现，NOP 拮抗剂可减少酗酒天数和每周饮酒量 寻求治疗并持有 AUD 的患者。我的初步结果支持这一治疗目标，因为 NOP 拮抗剂减少了DID模型中的酒精摄入量，这与文献一致。在一起，这些 研究结果表明 NOP 是 AUD 药物疗法的明确候选者，但迄今为止还没有研究探索过 涉及饮酒行为的内源性 N/OFQ 人群，并且只有一个人探究了 NOP 作用位点。为此，我的初步研究发现侧隔膜 (LS) 富含 N/OFQ (LSN/OFQ) 并且这个离散群体在酗酒中起着因果作用。更具体地说， LSN/OFQ 的细胞类型特异性化学遗传学激活增加了酒精摄入量，而沉默 LSN/​​OFQ 则减少了酒精摄入量 喝。此外，我发现这种效应是酒精特有的，因为 LSN/​​OFQ 操作不会影响 蔗糖摄入或运动。选择性LSN/OFQ双向控制酗酒行为的发现 非常令人兴奋，并为该提案铺平了道路。在这里，我的目标是采取多方面的方法来质疑 酗酒史对 LSN/​​OFQ 电生理特征的功能影响 使用光纤光度测定法确定饮酒行为期间这些神经元的体内活动模式。 最后，我将确定 LSN/​​OFQ 的分子概况并绘制下游投影位点，并确定 其中基因NOP缺失对酒精摄入量的影响。因此，本提案旨在彻底质问 新型 LSN/​​OFQ 群体中的活动，并试图识别该系统的机械过程 通过 NOP 受体促进过度饮酒。总之，这项拨款提案针对的是尚未充分研究的 群体和神经肽系统以细胞类型特异性和信号依赖的方式显示出巨大的 有望成为治疗 AUD 的神经解剖学靶标。