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: 10730264
• 负责人: Anel Ariana Jaramillo
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730264
• 关键词: Abstinence; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Animal Model; Anti-Anxiety Agents; Anxiety; Award; Behavior; Behavioral; Biological Availability; Brain Stem; Calcitonin Gene-Related Peptide; Cell Nucleus; Cells; Chronic; Clinical Trials; Communication; Complex; Corticotropin-Releasing Hormone; Data; Development; Electrophysiology (science); Ethanol; Female; Fiber; Fright; Goals; Individual; Learning; Maintenance; Measures; Mental Depression; Mentors; Mus; Neural Pathways; Neurons; Neuropeptides; Pain; Pathway interactions; Peptides; Peripheral Nervous System; 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; diagnostic tool; 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; polypeptide; preclinical study; response; sex; sexual dimorphism; skills; sobriety; therapeutic target; 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.

项目概要/摘要 戒酒会导致负面情绪状态，从而导致适应不良反应 压力和复发。临床前研究已开始确定调节神经回路和肽靶标 禁欲期间的负面影响。随着该领域开始对电路有更深入的了解 参与成瘾和负面影响，下一步是了解这些内部的沟通方式 特别是在神经肽和微电路水平上对电路进行调节。纹状体的床核 终末肌（BNST）是与禁欲相关的神经回路的基本组成部分，因为它可以调节压力和 以神经肽依赖性方式与酒精相关的行为。研究肽特异性 BNST 电路 调节禁欲期间的负面影响，我们将重点关注来自臂旁核（PBN）的传入， 充当危险信号的脑干区域。 PBN 对 BNST 释放降钙素基因的预测 相关肽（CGRP）和垂体腺苷酸环化酶激活多肽（PACAP），这些肽 分别调节疼痛和恐惧回路。我们的研究表明异质性和性别二态性 PBNàBNST 回路内的控制，因为 PBN 投射会诱导 BNST 细胞的异质离体活性 以及 BNSTPBN 激活时女性特有的焦虑样行为。此外，我们的初步研究 表明 PBN 在酒精戒断中发挥作用，因为酒精暴露后失活具有抗焦虑作用。这 该提案将通过调查 CGRP 和 PACAP 如何在这一基础证据的基础上建立重要的基础 有助于 PBNàBNST 回路诱导的禁欲诱导行为、体内和离体活动。 因此，受指导的 K99 阶段将建立在我的体内光纤光度测量记录的基础上并提供培训 离体记录以确定 CGRP 对 BNSTàPBN 活性、戒断诱导行为的作用 (AIM1)，以及 PACAP 对 CGRP 神经调节的贡献 (AIM2)。独立R00相 将研究 PACAP 对 BNSTàPBN 在微电路层面和酒精相关状态的作用， 目标是进一步描述肽串扰（AIM3）的复杂性。拟议的研究和相关职业 MOSAIC 独立之路奖中的发展培训计划共同提供了理想的 将申请人转变为独立成瘾神经科学家的职业的机制。结果将 显着促进我们对肽和微电路水平的神经回路机制的理解 长期戒酒，同时告知在酒精使用障碍中使用肽能药物疗法。