Identification and modulation of insula to BNST circuit specific afferents in ethanol abstinence

乙醇戒断中岛叶到 BNST 回路特异性传入的识别和调节

• 批准号: 10196888
• 负责人: Joseph Richard Luchsinger
• 金额: $ 4.83万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196888
• 关键词: 2-arachidonylglycerol; Abstinence; Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; American; Amphetamine Addiction; Amygdaloid structure; Animals; Anterior; Anxiety; Anxiety Disorders; Attention; Biological; Brain region; CNR1 gene; Calcium; Calcium Signaling; Cells; Chronic; Corticotropin-Releasing Hormone; Data; Economics; Electrophysiology (science); Endocannabinoids; Ethanol; Event; Exercise; Fiber; Goals; Grant; Health; Hour; Image; Insula of Reil; Investigation; Label; Lipids; Methods; Morbidity - disease rate; Motor; Motor Cortex; Mus; Neurons; Nicotine Dependence; Output; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Photometry; Physicians; Physiology; Play; Population; Process; Property; Recurrent disease; Regulation; Relapse; Reporting; Research; Resources; Rest; Rewards; Role; Running; Scientist; Signal Transduction; Slice; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; Techniques; Testing; Tracer; Viral; Withdrawal; addiction; alcohol abstinence; alcohol effect; alcohol exposure; alcohol use disorder; anandamide; biological adaptation to stress; comorbidity; cost; economic cost; endocannabinoid signaling; endogenous cannabinoid system; experience; experimental study; feeding; human imaging; imaging modality; imaging study; in vivo; mortality; negative affect; neural circuit; neuromechanism; novel; physical symptom; postsynaptic; prevent; problem drinker; response; skills; social; stressor; transmission process

PROJECT SUMMARY Alcohol use disorder (AUD) is a major health concern affecting millions of Americans with an estimated annual cost of well over $200 Billion. A critical component in limiting the impact of AUD is preventing relapse, a common tribulation for alcoholics. Stress dramatically increases the likelihood of reinstatement during protracted abstinence, and patients with AUD often have comorbid anxiety disorders. Modulation of the endocannabinoid (eCB) system can decrease the response to stressors. The insula and BNST have emerged as regions implicated in the withdrawal phase of AUD. Evidence suggests that the insula plays a vital role in the negative interoceptive stimuli experienced during abstinence. The BNST, part of the extended amygdala, integrates reward and stress in addiction. Our lab has found functional monosynaptic connections between the insula and anxiety-responsive corticotrophin-releasing factor (CRF) cells in the BNST (BNSTCRF cells). The inputs that control the BNST projecting insular (insulaBNST) neurons and the modulation of those inputs remain essential unknowns. The proposed research aims to understand the regulation of the insulaBNST circuit and how it is changed in ethanol withdrawal. To do so, we will further investigate the distribution of afferents to insulaBNST cells (subaim 1.1), establish monosynaptic connectivity between afferent regions (subaim 1.2), and interrogate ethanol and eCB functionality at these synapses (subaim 1.3). Subaim 2.1 will ascertain the effects of alcohol withdrawal on ex vivo slice physiology in this circuit while subaim 2.2 will establish the implications of alcohol withdrawal in vivo using calcium imaging via fiber photometry. We hope the findings from these experiments will provide a better understanding of the interplay between these brain regions and how this interaction is regulated. In so doing, we will be able to establish the normal physiology and impact that alcohol withdrawal has on this novel circuit.

项目摘要 酒精使用障碍（AUD）是影响数百万美国人的主要健康问题 成本超过2000亿美元。限制AUD影响的关键组成部分是防止复发，一个 酗酒的常见灾难。压力大大增加了恢复原状的可能性 节制持久，AUD患者通常患有焦虑症。调制 内源性大麻素（欧洲央行）系统可以降低对应激源的反应。岛屿和BNST出现了 正如区域与AUD的撤回阶段有关。证据表明，岛屿在 戒酒期间经历的负面互感刺激。 BNST，扩展杏仁核的一部分， 将奖励和压力整合到成瘾中。我们的实验室发现了功能性单突触连接 BNST（BNSTCRF细胞）中的绝缘和焦虑响应性皮质营养因子（CRF）细胞。这 控制BNST投射岛的（胰岛素）神经元的输入和这些输入的调节 基本未知数。拟议的研究旨在了解胰岛电路的调节以及如何 它在乙醇提取中发生了变化。为此，我们将进一步调查传入的分布 胰岛细胞（Subaim 1.1），在传入区域（Subaim 1.2）和 在这些突触中询问乙醇和欧洲央行功能（Subaim 1.3）。 Subaim 2.1将确定 戒酒对本电路中体内切片生理的影响，而Subaim 2.2将确定 使用钙成像通过纤维光度法在体内戒断酒精的含义。我们希望发现 从这些实验中将更好地理解这些大脑区域之间的相互作用和 这种相互作用如何调节。这样，我们将能够建立正常的生理和影响 戒酒在这个新颖的电路上具有。