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: 10700009
• 负责人: Harold L Haun
• 金额: $ 7.18万
• 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/10700009
• 关键词: Address; Alcohol consumption; Alcohols; Applications Grants; Attenuated; Behavior; Brain; COVID-19 pandemic; Calcium; Cells; Chronic; Consumption; Coping Skills; Dangerousness; Darkness; 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; Neuroanatomy; 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; neuronal patterning; nociceptin; novel; novel therapeutic intervention; patch clamp; receptor; receptor expression; skill acquisition; 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.

项目摘要 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， 近年来，由于过度饮酒，已经出现了显着增长。酗酒是最 过度饮酒行为的常见模式，并与发展的风险增加有关 酒精使用障碍（AUD）目前，用于治疗AUD的药物疗法是有限的， 迫切需要新的治疗干预。更深入地了解神经生物学 控制过度、不受控制的饮酒的过程是实现这一目标所必需的。饮酒在 Dark（DID）模型是一个可靠的、可重复的平台，用于分子和电路级的询问 促进酗酒的系统。内源性阿片样肽 伤害感受素/孤啡肽（N/OFQ）和伤害感受素受体（NOP）是一种感兴趣的分子靶标， 选择性NOP拮抗剂在减轻过度饮酒行为方面显示出巨大的前景。比如说， 一种NOP拮抗剂被发现可以减少重度饮酒天数和每周饮酒量， 寻求治疗的AUD患者。我的初步结果支持这个治疗目标， 拮抗剂减少了DID模型中的酒精摄入，这与文献一致。所有这些 研究结果指出NOP是AUD药物治疗的明确候选者，但迄今为止还没有研究探索 内源性N/OFQ群体参与饮酒行为，只有一个人探讨了 NOP作用部位。为此，我的初步研究已经确定了外侧隔（LS）富含N/OFQ (LSN/OFQ），这一离散人群在酗酒中起着因果作用。更具体地说， 细胞类型特异性化学发生激活的LSN/OFQ增加了酒精摄入量，而沉默的LSN/OFQ降低了酒精摄入量。 喝酒此外，我发现这种效应是特定于酒精的，因为LSN/OFQ操纵并不影响 蔗糖摄入量和运动量。选择性LSN/OFQ双向控制酗酒行为的研究 非常令人兴奋，并为这一提议铺平了道路。在这里，我的目标是采取多方面的方法来审问 酗酒史对LSN/OFQ电生理特征的功能影响， 用纤维光度法测定饮酒行为过程中这些神经元的活动模式。 最后，我将确定LSN/OFQ的分子概况，并绘制下游投射位点， 其中遗传NOP缺失对酒精摄入的影响。因此，这项建议旨在彻底审问 活动在新的LSN/OFQ人口，并寻求确定机制的过程，该系统 通过NOP受体促进过量饮酒。总而言之，这项拨款提案的目标是一个未被研究的 在细胞类型特异性和信号依赖性的方式，显示出巨大的群体和神经肽系统， 有望成为治疗AUD的神经解剖学靶点。

项目成果

Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice.

解开终纹腹侧床核释放促肾上腺皮质激素释放因子和 GABA 对小鼠自我给药乙醇的影响。

• DOI: 10.1101/2023.03.02.530838
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: CA,Gianessi;GB,Gereau;HL,Haun;D,Pati;T,Sides;SL,D'Ambrosio;K,Boyt;WP,Kelson;CW,Hodge;TL,Kash
• 通讯作者: TL,Kash