Neuropeptide-dependent parabrachial control of the BNST during alcohol abstinence-induced negative affect

戒酒引起的负面情绪期间 BNST 的神经肽依赖性臂旁控制

• 批准号: 10283084
• 负责人: Anel Ariana Jaramillo
• 金额: $ 15.04万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283084
• 关键词: Abstinence; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Animal Model; Anti-Anxiety Agents; Anxiety; Award; Behavior; Behavioral; Bioavailable; Brain Stem; Calcitonin Gene-Related Peptide; Cells; Chronic; Clinical Trials; Communication; Complex; Corticotropin-Releasing Hormone; Data; Development; Diagnostic; Electrophysiology (science); Ethanol; Female; Fiber; Foundations; Fright; Goals; Individual; Lead; Learning; Maintenance; Measures; Mental Depression; Mentors; Mus; Neural Pathways; Neurons; Neuropeptides; Pain; Pathway interactions; Peptides; Peripheral; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase; Photometry; Population; Pre-Clinical Model; Regulation; Relapse; Reporter; Research; Resolution; Role; Sex Differences; Signal Transduction; Site; Specificity; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Training; Transgenic Animals; Transgenic Organisms; addiction; affective disturbance; alcohol abstinence; alcohol behavior; alcohol exposure; alcohol use disorder; anxiety-like behavior; career; career development; cell type; chronic alcohol ingestion; comorbidity; experience; hypothalamic-pituitary-adrenal axis; in vivo; insight; interest; negative affect; neural circuit; neurophysiology; neuroregulation; novel; parabrachial nucleus; peptide hormone; pituitary adenylate cyclase activating polypeptide; preclinical study; response; sex; sexual dimorphism; sobriety; therapeutic target; tool; vapor

PROJECT SUMMARY/ABSTRACT Abstinence from alcohol use induces a negative affective state that can lead to maladaptive responses to stress and relapse. Preclinical studies have begun to identify neurocircuits and peptide targets that regulate negative affect during abstinence. As the field has begun to develop a deeper understanding of the circuitries participating in addiction and negative affect, the next step is to understand how communication within these circuits is modulated particularly at the neuropeptide and microcircuit level. The bed nucleus of the stria terminalis (BNST) is a fundamental component of abstinence-relevant neurocircuitry as it modulates stress and alcohol-related behavior in a neuropeptide-dependent manner. To investigate peptide-specific BNST circuitry modulating negative-affect during abstinence, we will focus on afferents from the parabrachial nucleus (PBN), a brainstem region that functions as a danger signal. PBN projections to the BNST release calcitonin gene- related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP), peptides that modulate pain and fear circuits, respectively. Our studies implicate heterogenous and sexually dimorphic control within the PBNàBNST circuit as PBN projections induce heterogeneous ex vivo activity in BNST cells and female-specific anxiety-like behavior with BNSTPBN activation. Furthermore, our preliminary studies suggest a role for the PBN in alcohol-withdrawal, as inactivation is anxiolytic following alcohol exposure. This proposal will significantly build on this foundational evidence by investigating how CGRP and PACAP contribute to PBNàBNST circuit induced abstinence-induced behavior, in vivo and ex vivo activity. Accordingly, the mentored K99 phase will build on my in vivo fiber photometry recordings and provide training in ex vivo recordings to determine the role of CGRP on BNSTàPBN activity, abstinence-induced behavior (AIM1), and the contribution of PACAP on the CGRP-neuromodulation (AIM2). The independent R00 phase will investigate the role of PACAP on BNSTàPBN at the microcircuit level and alcohol-related states, with the goal to further delineate the intricacies of peptide crosstalk (AIM3). The proposed studies and related career development training plan in this MOSAIC Pathway to Independence Award collectively provide the ideal mechanism to transition the applicant to a career as an independent addiction neuroscientist. The results will significantly advance our understanding of neurocircuit mechanisms at the peptide and microcircuit level in protracted abstinence while informing the use of peptidergic pharmacotherapies in alcohol use disorders.

项目摘要/摘要 戒酒的戒酒会导致负面情感状态，这可能导致适应不良的反应 压力和缓解。临床前研究已开始鉴定调节的神经循环和胡椒靶 戒酒期间的负面影响。随着该领域的开始，对电路有了更深入的了解 参与成瘾和负面影响，下一步是了解其中的沟通方式 电路特别在神经肽和微电路水平上进行调节。床的床核 末端（BNST）是与戒酒相关的神经循环的基本组成部分，因为它调节了压力和 以神经肽依赖性方式与酒精相关的行为。研究肽特异性的BNST电路 在禁欲期间调节负面影响，我们将专注于副核（PBN）的传入， 充当危险信号的脑干区域。 PBN投影到BNST释放降钙素基因 - 相关肽（CGRP）和居腺酸腺酸环化酶激活多肽（PACAP），胡椒粉 分别调节疼痛和恐惧电路。我们的研究暗示异源和性二态 PBN投影在pbnàbnst电路内诱导BNST细胞中诱导异质的外活性 和BNSTPBN激活的女性特异性动画行为。此外，我们的初步研究 提出了PBN在酒精抽水中的作用，因为在酒精暴露后失活是抗焦虑。这 提案将通过调查CGRP和PACAP如何基于这一基本证据。 有助于Pbnàbnst电路引起的节制诱导的行为，体内和离体活动。 彼此之间，修补的K99阶段将建立在我的体内光纤光度法上并提供训练 在离体记录中确定CGRP在Bnstàpbn活动中的作用，戒酒诱导的行为 （AIM1），以及PACAP对CGRP神经调节的贡献（AIM2）。独立R00阶段 将研究PACAP在微电路水平上对Bnstàpbn的作用，并与酒精相关的状态 目标是进一步描述胡椒串扰的复杂性（AIM3）。拟议的研究和相关职业 在这项马赛克独立奖中的发展培训计划共同提供了理想 将申请人转变为独立成瘾神经科学家职业的机制。结果将 显着提高我们对胡椒和微电路水平的神经回路机制的理解 在告知使用辣椒药物疗法中，持久节制在酒精使用障碍中。