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

项目总结 新冠肺炎疫情对心理健康和适应不良的应对策略产生了明显影响，如 由于过度饮酒，近年来出现了明显的增长。酗酒是最多的 过度饮酒行为的常见模式，并与患上糖尿病的风险增加有关 酒精使用障碍(AUD)。目前，治疗AUD的药物疗法有限，创造了一种 迫切需要新的治疗干预措施。对神经生物学有更透彻的了解 为了实现这一目标，管理过度、不受控制的饮酒的程序是必要的。在酒馆里畅饮 Dark(DID)模型可作为分子和电路级询问的强大且可重现的平台 促进狂欢饮酒的系统。内源性阿片肽 伤害素/孤儿蛋白FQ(N/OFQ)和伤害素受体(NOP)是一个重要的分子靶点。 选择性的NOP拮抗剂在减轻过度饮酒行为方面显示出巨大的希望。例如, 一种NOP拮抗剂被发现可以减少酗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，因为NOP 拮抗剂可减少DID模型的酒精摄入量，这与文献报道一致。加在一起，这些 研究结果表明，NOP是AUD药物疗法的明确候选者，但到目前为止还没有研究探索 参与饮酒行为的内源性N/OFQ群体，只有一个人探索了 NOP行动的地点。为此，我的初步研究发现，外侧隔(LS)富含N/OFQ (LSN/OFQ)，这种离散的人群在类似酗酒的消费中起到了因果作用。更确切地说， LSN/OFQ的细胞特异性化学激活增加酒精摄入量，而沉默LSN/OFQ减少 喝酒。此外，我发现这种影响仅限于酒精，因为LSN/OFQ操作不会影响 无论是蔗糖摄取还是运动。选择性LSN/OFQ双向调控狂饮行为的研究 是非常令人兴奋的，并为这项提议铺平了道路。在这里，我打算采取多方面的方法来审问 酗酒史对LSN/OFQ电生理图谱的功能影响 用纤维分光光度法测定饮酒行为中这些神经元在体内的活动模式。 最后，我将确定LSN/OFQ的分子图谱，绘制下游投射位点图，并确定 NOP基因缺失对饮酒的影响。因此，这项提议旨在彻底审问 在新的LSN/OFQ种群中的活动，并试图识别该系统通过其 通过NOP受体促进过量饮酒。总而言之，这项赠款提案针对的是一名未被研究的 群体和神经肽系统以细胞类型特定和信号依赖的方式显示出很好的 有望成为治疗AUD的神经解剖学靶点。

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.