Hypothalamic oxytocin influence on extended amygdala CRF neurons in alcohol dependence

项目摘要/摘要 酒精使用障碍(AUD)是一种慢性复发性障碍，其特征是强迫寻求和 酒精消费，是从娱乐使用到滥用再到澳元的转变的结果。大多数澳门氏症患者 没有接受治疗，而且目前的药物并不适用于所有患者，这突显了新的 治疗学。AUD导致大脑应激系统活动增强，导致消极情绪状态 与戒断有关。神经肽催产素(OT)具有抗应激作用，全身应用催产素 减少AUD患者的戒断症状严重程度和饮酒。中央杏仁核(CEA)和床 终纹核(BNST)是大脑的两个区域，被认为是压力处理的中枢，以及 促应激和抗应激神经肽在这些脑区的作用对AUD的发展至关重要。 CEA和BNST的突触活动对急性酒精敏感，并在行为行为中起关键作用。 乙醇消费的影响。CEA和BNST富含神经肽及其受体，包括 促肾上腺皮质激素释放因子(CRF)和催产素，以及乙醇对这些区域突触信号的影响可能是 受神经肽活动的调节。CRF参与了与AUD相关的高度压力和焦虑 戒断时，阻断CEA和BNST内CRF活性可减少饮酒。因此， 在向AUD的转变过程中，抗应激信号和支持应激信号之间的平衡可能被扰乱，其特征是 过度活跃的慢性肾功能衰竭系统。下丘脑室旁核和视上核内的催产素神经元 下丘脑投射到CEA和BNST，投射到含有CRF神经元的特定亚区。因此，OT 可能直接作用于CEA和BNST的CRF神经元，以减轻戒断和饮酒的严重程度。 对于这份多样性补充材料，Emaya Moss(候选人)将在所有目标范围内为实验做出贡献 家长助学金。最初，Emaya将接受PI关于这项研究所需技术的培训， 包括体外切片全细胞膜片钳电生理学、分子生物学技术、慢性 间歇性乙醇(CIE)蒸气依赖模型、立体定向手术、化学遗传学和饮酒 行为。一旦Emaya学会了一种技术，她将开始进行结合了这一技术的实验 在进行附加技术培训的同时，还应加强技术培训。因此，她将对OT的连接性进行研究 和CRF神经元，这些神经元的固有特性和突触功能，这些电路是如何被破坏的 通过CIE蒸气依赖，这些回路如何促进饮酒，以及这些回路中的任何性别差异 措施。此外，在剩余的家长资助期内，Emaya将完成她的研究生课程， 参加周刊俱乐部和实验室会议，还将与PI进行每周辅导会议 关于出版物、赠款、奖项、会议报告、研讨会等，以确保她准备好接受 迈向学术界独立研究人员职业生涯的下一步。

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive seeking and consumption of alcohol, the result of a transition from recreational use to misuse to AUD. Most AUD sufferers do not receive treatment, and current medications do not work for all patients, highlighting the need for new therapeutics. AUD induces heightened activity of brain stress systems, resulting in the negative affective state associated with withdrawal. The neuropeptide oxytocin (OT) is anti-stress, and systemic administration of OT decreases withdrawal symptom severity and drinking in people with AUD. The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are two brain regions considered to be hubs for stress processing, and the role of pro- and anti-stress neuropeptides in these brain regions are critical for the development of AUD. Synaptic activity in the CeA and BNST is sensitive to acute alcohol, and plays a critical role in the behavioral effects of ethanol consumption. The CeA and BNST are rich in neuropeptides and their receptors, including corticotropin releasing factor (CRF) and OT, and ethanol’s effects on synaptic signaling in these regions may be modulated by neuropeptide activity. CRF is involved in the heightened stress and anxiety associated with AUD during withdrawal, and blocking CRF activity in the CeA and BNST can reduce alcohol drinking. Thus, the balance between anti- and pro-stress signaling is likely perturbed during the transition to AUD, characterized by an overactive CRF system. OT producing neurons in the paraventricular and supraoptic nuclei of the hypothalamus project to both the CeA and BNST, to specific subdivisions that contain CRF neurons. Thus, OT may act directly on CRF neurons of the CeA and BNST to decrease withdrawal severity and alcohol drinking. For this Diversity Supplement, Emaya Moss (candidate), will contribute to experiments within all Aims of the parent grant. Initially, Emaya will receive training from the PI in the techniques necessary for this research, including ex vivo slice whole-cell patch clamp electrophysiology, molecular biology techniques, the chronic intermittent ethanol (CIE) vapor dependence model, stereotaxic surgeries, chemogenetics, and alcohol drinking behavior. Once Emaya has learned a technique, she will begin to work on experiments incorporating that technique while training in additional techniques. As such, she will perform research into the connectivity of OT and CRF neurons, intrinsic properties and synaptic function of these neurons, how these circuits are disrupted by CIE vapor dependence, how these circuits contribute to alcohol drinking, and any sex differences within these measures. In addition, throughout the remaining parent grant period, Emaya will finish her graduate coursework, attend weekly journal clubs and lab meetings, and will also have weekly mentorship meetings with the PI focused on publications, grants, awards, conference presentations, workshops, etc. to ensure she is prepared to take on the next steps toward a career as an independent researcher in academia.