Sex differences in BNST networks during early abstinence in AUD

AUD 早期戒断期间 BNST 网络的性别差异

• 批准号: 10491267
• 负责人: JENNIFER URBANO BLACKFORD
• 金额: $ 52.96万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491267
• 关键词: Abstinence; Acute; Address; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Animal Model; Animals; Anxiety; Awareness; Behavior; Brain; Brain region; Chronic; Data; Dependence; Development; Diffusion Magnetic Resonance Imaging; Disease; Female; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Funding Agency; Future; Galvanic Skin Response; Health; Homeostasis; Human; Hydrocortisone; Hyperactivity; Influentials; Intervention; Intoxication; Knowledge; Lead; Light; Measures; Mediating; Mental Depression; Methods; National Institute on Alcohol Abuse and Alcoholism; Negative Reinforcements; Neurobiology; Pattern; Physiology; Pilot Projects; Process; Publishing; Recovery; Relapse; Research; Rest; Role; Sex Differences; Sexual Abstinence; Stress; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Testing; Translational Research; Withdrawal; Woman; addiction; alcohol abstinence; alcohol abuse therapy; alcohol consequences; alcohol exposure; alcohol seeking behavior; alcohol use disorder; anxiety symptoms; base; biological adaptation to stress; clinically significant; drinking; effective therapy; experience; in vivo; male; men; negative affect; neural network; novel; personalized medicine; prevent; response; sex; sexual dimorphism; stress related disorder; theories

Alcohol use disorders (AUDs) are common, disabling conditions. There is a growing awareness of important sex differences in AUDs; for example, women experience more serious health complications from alcohol use and also develop negative consequences from alcohol use more quickly. While the rate of AUDs is relatively stable in men, the rate in women is escalating at an alarming rate. Neurobiological differences between sexes are thought to underlie the differential impact of AUDs in men and women, but to date relatively few studies on this topic exist. Animal models of addiction have substantially informed our understanding of the stages of addiction— binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—and their underlying pathophysiology. For example, chronic alcohol exposure causes neuroadaptive brain changes in an attempt to maintain homeostasis. During the withdrawal/negative affect stage, hyperactive stress systems produce symptoms including anxiety and depression which are thought to lead to relapse through negative reinforcement. Women have higher rates of anxiety and stress-related disorders, which may contribute to sex differences in early abstinence. Animal models of early abstinence from alcohol highlight the involvement the bed nucleus of the stria terminalis (BNST). The BNST is also one of the most sexually dimorphic brain regions, suggesting the BNST is involved in sex-related differences seen during early abstinence. We previously published evidence for sex differences in BNST structural connectivity in humans. In addition, pilot data from our NIAAA funded R21 provide initial evidence for sex differences: females had stronger structural and functional connectivity within the BNST network, heightened stress responses, and higher anxiety during early abstinence. The current study will focus on sex differences in the BNST network during early abstinence from alcohol by investigating three specific aims: (1) Determine whether there are sex-related differences in BNST intrinsic functional or structural connectivity during early abstinence; (2) Determine whether there are sex- related differences in stress-related BNST function and BNST network connectivity during early abstinence; (3) Investigate sex-related differences in the relationship between BNST function/connectivity, stress response, and negative affect in early abstinence. Based on findings from animal models and our pilot data in humans, we predict that during early abstinence, the BNST will show sex-specific differences in patterns of activity and connectivity “at-rest” and in response to a mildly stressful task. We expect women will show stronger structural and functional connectivity within the BNST network, heightened stress responses, and higher anxiety during early abstinence. The successful completion of this study will fill a critical knowledge gap, determining whether men and women show neurobiological differences in BNST networks underlying negative affect during early abstinence from alcohol. The results will provide foundational information to inform future studies investigating mechanisms of relapse and can guide the development of sex-specific or personalized treatments for AUD.

酒精使用障碍 (AUD) 是常见的致残性疾病。人们越来越意识到重要的 澳元的性别差异；例如，女性因饮酒而出现更严重的健康并发症 并且还会更快地因饮酒而产生负面后果。虽然澳元的汇率相对 男性的发病率稳定，但女性的发病率正在以惊人的速度上升。性别之间的神经生物学差异 被认为是 AUD 对男性和女性产生不同影响的原因，但迄今为止关于这方面的研究相对较少 这个话题是存在的。成瘾动物模型极大地丰富了我们对成瘾各个阶段的理解 成瘾——暴饮暴食/中毒、戒断/负面影响、全神贯注/期待——及其潜在的原因 病理生理学。例如，长期接触酒精会导致大脑发生神经适应性变化，试图 维持体内平衡。在退缩/负面影响阶段，过度活跃的压力系统会产生 包括焦虑和抑郁在内的症状被认为会通过消极情绪导致复发 加强。女性患焦虑症和压力相关疾病的比例较高，这可能会影响性行为 早期禁欲的差异。早期戒酒的动物模型强调了 终纹床核（BNST）。 BNST 也是性别二态性最强的大脑区域之一， 表明 BNST 与早期禁欲期间出现的性别相关差异有关。我们之前 发表了人类 BNST 结构连接性性别差异的证据。此外，试点数据来自 我们的 NIAAA 资助的 R21 为性别差异提供了初步证据：女性具有更强的结构和能力 BNST 网络内的功能连接、早期压力反应增强和焦虑程度更高 节制。目前的研究将重点关注早期戒断期间 BNST 网络中的性别差异 酒精通过调查三个具体目标：（1）确定 BNST 是否存在性别相关差异 早期戒断期间的内在功能或结构连接； (2) 判断是否存在性别 早期戒断期间与压力相关的 BNST 功能和 BNST 网络连接的相关差异； (3) 研究 BNST 功能/连通性、压力反应、 以及早期禁欲的负面影响。根据动物模型的研究结果和我们在人类身上的试点数据， 我们预测，在早期禁欲期间，BNST 将在活动模式上表现出性别特异性差异 连接“静止”并响应轻度压力任务。我们预计女性将表现出更强的结构性 BNST 网络内的功能连接、应激反应加剧和焦虑感增加 及早禁欲。这项研究的成功完成将填补一个关键的知识空白，确定是否 男性和女性在早期负面影响的 BNST 网络中表现出神经生物学差异 戒酒。结果将为未来的研究提供基础信息 复发机制，并可以指导针对 AUD 的性别特异性或个性化治疗的开发。