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: 9757511
• 负责人: Joseph Richard Luchsinger
• 金额: $ 2.98万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757511
• 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; Comorbidity; 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; cost; economic cost; endocannabinoid signaling; endogenous cannabinoid system; experience; experimental study; feeding; human imaging; imaging modality; imaging study; in vivo; mortality; negative affect; 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.

项目概要 酒精使用障碍 (AUD) 是影响数百万美国人的主要健康问题，估计每年 成本远远超过2000亿美元。限制澳元影响的一个关键因素是防止复发， 酗酒者共同的苦难。压力极大地增加了恢复期间的可能性 长期禁欲，AUD 患者通常患有焦虑症。调制 内源性大麻素（eCB）系统可以降低对压力源的反应。岛叶和 BNST 已出现 作为涉及澳元退出阶段的地区。有证据表明，岛叶在 禁欲期间经历的负面内感受刺激。 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 脑岛和 BNST 中的焦虑反应性促肾上腺皮质激素释放因子 (CRF) 细胞（BNSTCRF 细胞）。这 控制 BNST 投射岛状 (insulaBNST) 神经元的输入以及这些输入的调制仍然存在 基本的未知数。拟议的研究旨在了解 insulaBNST 电路的调节以及如何调节 它在乙醇退出时发生变化。为此，我们将进一步研究传入信号的分布 insulaBNST 细胞 (subaim 1.1)，在传入区域之间建立单突触连接 (subaim 1.2)，以及 询问这些突触处的乙醇和 eCB 功能（subaim 1.3）。 Subaim 2.1 将确定 酒精戒断对该回路中离体切片生理学的影响，而 subaim 2.2 将建立 通过纤维光度测定使用钙成像对体内酒精戒断的影响。我们希望调查结果 这些实验将有助于更好地理解这些大脑区域之间的相互作用 如何调节这种相互作用。这样做，我们将能够建立正常的生理机能并产生影响 酒精戒断对这个新颖的电路有影响。