Hypothalamic oxytocin influence on extended amygdala CRF neurons in alcohol dependence

下丘脑催产素对酒精依赖中扩展杏仁核 CRF 神经元的影响

• 批准号: 10829769
• 负责人: Dean Kirson
• 金额: $ 3.06万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10829769
• 关键词: Academia; Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anxiety; Award; Behavioral; Brain; Brain region; Cells; Chronic; Corticotropin-Releasing Hormone; Dependence; Development; Disease; Educational workshop; Electrophysiology (science); Ensure; Equilibrium; Ethanol; Female; Fiber; Genetic; Goals; Grant; Human; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Journals; Learning; Maternal Behavior; Measures; Mentorship; Methodology; Modeling; Molecular Biology Techniques; Mosses; Mus; Neurons; Neuropeptides; Operative Surgical Procedures; Output; Oxytocin; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Play; Principal Investigator; Property; Public Health; Publications; RNA; Rattus; Recreation; Regulation; Relapse; Research; Research Personnel; Role; Severities; Sex Behavior; Sex Differences; Signal Transduction; Slice; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Training; United States; Viral Vector; Withdrawal; Withdrawal Symptom; Work; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol use disorder; behavioral pharmacology; career; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; experimental study; expression vector; male; meetings; multimodality; negative affect; neural circuit; neuroadaptation; neuromechanism; novel therapeutics; paraventricular nucleus; parent grant; patch clamp; prevent; programs; protein expression; receptor; sex; sexual dimorphism; supraoptic nucleus; symposium; synaptic function; vapor

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.

项目总结/摘要 酒精使用障碍（AUD）是一种慢性复发性障碍，其特征是强迫性寻求和 酒精消费，从娱乐用途过渡到滥用澳元的结果。大多数AUD患者 没有接受治疗，目前的药物并不适用于所有患者，突出了新的需要， 治疗学AUD诱导大脑应激系统的活动增加，导致负面情感状态 与撤退有关。神经肽催产素（OT）具有抗应激作用，全身给予OT 降低AUD患者的戒断症状严重程度和饮酒量。中央杏仁核（CeA）和床 终纹核（BNST）是两个被认为是应激处理中枢的大脑区域， 在这些脑区域中的促应激和抗应激神经肽的作用对于AUD的发展至关重要。 CeA和BNST的突触活动对急性酒精敏感，并在行为学中起着关键作用。 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OT，以及乙醇对这些区域突触信号传导的影响可能是 由神经肽活性调节。CRF与AUD相关的压力和焦虑增加有关 在戒断过程中，阻断CeA和BNST中的CRF活性可以减少饮酒。因此 抗压力信号和促压力信号之间的平衡可能在向AUD过渡期间受到干扰，其特征在于： 过于活跃的CRF系统丘脑室旁核和视上核的催产素能神经元 下丘脑投射到CeA和BNST，投射到包含CRF神经元的特定亚部。因此，OT 可能直接作用于CeA和BNST的CRF神经元，以减少戒断严重程度和饮酒。 对于这个多样性补充，Emaya Moss（候选人），将有助于在所有目标的实验， 家长补助最初，Emaya将接受PI关于本研究所需技术的培训， 包括离体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）蒸汽依赖模型、立体定位手术、化学遗传学和饮酒 行为一旦Emaya学会了一种技术，她将开始进行实验， 技术，同时培训其他技术。因此，她将研究OT的连通性 和CRF神经元，这些神经元的内在特性和突触功能，这些回路是如何被破坏的 通过CIE蒸汽依赖性，这些电路如何有助于饮酒，以及这些电路中的任何性别差异， 措施此外，在剩余的家长补助金期间，Emaya将完成她的研究生课程， 参加每周的期刊俱乐部和实验室会议，并与PI一起参加每周的导师会议， 关于出版物，赠款，奖项，会议演讲，研讨会等，以确保她准备承担 作为学术界独立研究员的下一步。