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: 10909436
• 负责人: Dean Kirson
• 金额: $ 6.47万
• 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/10909436
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavioral; Brain; Brain region; Cells; Characteristics; Chronic; Complement; Corticotropin-Releasing Hormone; Dependence; Development; Disease; Electrophysiology (science); Ensure; Equilibrium; Ethanol; Female; Fiber; Goals; Human; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Institution; Laboratories; Maternal Behavior; Mediating; Mentorship; Methodology; Molecular; Mus; Neurons; Neuropeptides; Output; Oxytocin; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Principal Investigator; Public Health; RNA; Rattus; Recreation; Regulation; Relapse; Reproducibility; Research; Role; Severities; Sex Behavior; Signal Transduction; 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 prevention; alcohol use disorder; behavior test; behavioral pharmacology; career; designer receptors exclusively activated by designer drugs; drinking; experience; experimental study; expression vector; insight; male; multimodality; negative affect; neuroadaptation; novel therapeutics; paraventricular nucleus; prevent; problem drinker; protein expression; receptor; sex; sexual dimorphism; supraoptic nucleus; vapor

PROJECT SUMMARY/ABSTRACT Alcoholism is a chronic relapsing disorder characterized by compulsive seeking and consumption of alcohol, the result of a transition from recreational use to abuse and dependence. Most alcoholics do not receive treatment, and current medications do not work for all sufferers, highlighting the need for new therapeutics. Alcohol dependence 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 alcoholics. 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 alcohol dependence. 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 alcohol dependence and 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 alcohol dependence, 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. This project will characterize hypothalamic OT neuronal input to CRF neurons of the CeA and BNST, whether these circuits are disrupted by alcohol dependence, and involvement of these circuits in alcohol dependence induced drinking. Viral vector mediated expression of fluorescent markers and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) will allow for electrophysiological and molecular characterization of OT circuits in the CeA and BNST, and behavioral testing of OT circuit involvement in alcohol dependence induced alcohol drinking. Experimental studies will begin during the K99 phase, and will be completed during the R00 phase at a new institution in the principal investigator’s (PI) independent laboratory. Towards this career goal, during the K99 phase, the PI will train under the mentorship team in new techniques including the use of viral vector based protein expression and synaptic tracing, immunohistochemistry, in situ hybridization, and behavioral pharmacology to complement the PI’s experience with electrophysiology. During the R00 phase, the mentorship team will help establish these techniques in the PI’s independent laboratory to ensure continuity and reproducibility of the research plan. Collectively, this work will provide insight into the role of OT as a potential therapeutic in treating alcohol and stress/anxiety disorders.

项目概要/摘要 酗酒是一种慢性复发性疾病，其特征是强迫性地寻求和消费酒精， 从娱乐用途过渡到滥用和依赖的结果。大多数酗酒者没有接受治疗， 目前的药物并不适用于所有患者，这凸显了对新疗法的需求。酒精 依赖会导致大脑应激系统的活动增强，从而导致消极的情感状态 与戒断有关。神经肽催产素 (OT) 具有抗应激作用，OT 的全身给药 降低戒断症状的严重程度和酗酒者的饮酒量。中央杏仁核 (CeA) 和床核 终纹 (BNST) 是两个被认为是压力处理中心的大脑区域，并且 这些大脑区域中的促应激和抗应激神经肽对于酒精依赖的发展至关重要。 CeA 和 BNST 中的突触活动对急性酒精敏感，并且在行为中起着关键作用 乙醇消耗的影响。 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 受神经肽活性调节。 CRF 与酒精相关的压力和焦虑加剧有关 依赖和戒断，以及阻断 CeA 和 BNST 中的 CRF 活性可以减少饮酒。因此， 在向酒精依赖过渡的过程中，抗应激信号和促应激信号之间的平衡可能会受到干扰， 其特征是 CRF 系统过度活跃。室旁核和视上核中产生 OT 的神经元 下丘脑的神经元投射到 CeA 和 BNST，以及包含 CRF 神经元的特定分区。因此， OT 可能直接作用于 CeA 和 BNST 的 CRF 神经元，以降低戒断严重程度和饮酒。 该项目将表征下丘脑 OT 神经元对 CeA 和 BNST 的 CRF 神经元的输入，无论是 这些回路因酒精依赖而受到干扰，并且这些回路参与酒精依赖 诱导饮酒。病毒载体介导荧光标记和设计受体的表达 由设计药物（DREADD）激活将允许进行电生理学和分子表征 CeA 和 BNST 中的 OT 回路，以及酒精依赖中 OT 回路参与的行为测试 诱发饮酒。实验研究将在 K99 阶段开始，并将在 R00 阶段在首席研究员 (PI) 独立实验室的新机构进行。迈向这个职业 目标，在 K99 阶段，PI 将在导师团队的指导下进行新技术培训，包括使用 基于病毒载体的蛋白质表达和突触追踪、免疫组织化学、原位杂交，以及 行为药理学，以补充 PI 在电生理学方面的经验。在 R00 阶段， 导师团队将帮助 PI 的独立实验室建立这些技术，以确保连续性和 研究计划的可重复性。总的来说，这项工作将深入了解 OT 作为潜在的角色 治疗酒精和压力/焦虑症。