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: 10686106
• 负责人: JENNIFER URBANO BLACKFORD
• 金额: $ 59.48万
• 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/10686106
• 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; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Funding Agency; Future; Galvanic Skin Response; Health; Homeostasis; Human; Hydrocortisone; Hyperactivity; Influentials; Intervention; Intoxication; Knowledge; Light; Measures; Mediating; Mental Depression; Methods; National Institute on Alcohol Abuse and Alcoholism; Negative Reinforcements; Neurobiology; Occupations; Pattern; Physiology; Pilot Projects; Process; Publishing; Relapse; Research; Rest; Role; Sex Differences; 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; biological adaptation to stress; clinically significant; depressive symptoms; drinking; effective therapy; experience; in vivo; long term recovery; male; men; negative affect; neural network; novel; personalized medicine; relapse prevention; 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。越来越多的人意识到， AUDs的性别差异;例如，女性因饮酒而经历更严重的健康并发症 也会更快地产生酒精使用的负面影响。虽然澳元的汇率相对 在男性中保持稳定，但在女性中的比率正在以惊人的速度上升。两性之间的神经生物学差异 被认为是AUDs对男性和女性的不同影响的基础，但迄今为止， 这个话题存在。成瘾动物模型为我们了解成瘾的各个阶段提供了大量信息 成瘾-狂欢/中毒、戒断/负面影响和专注/预期-及其潜在的 病理生理学例如，长期酒精暴露会导致大脑神经适应性变化， 保持体内平衡在退缩/负面影响阶段，过度活跃的压力系统产生 症状包括焦虑和抑郁，这些症状被认为是通过阴性反应导致复发的。 加固.女性有更高的焦虑和压力相关的疾病，这可能有助于性 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也是最具性别二态性的大脑区域之一， 这表明BNST参与了早期禁欲期间观察到的性别相关差异。我们之前 已发表的证据表明，人类BNST结构连接存在性别差异。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：女性有更强的结构和 BNST网络内的功能连接，应激反应增强，早期焦虑增加。 禁欲目前的研究将集中在BNST网络中的性别差异， 酒精通过调查三个具体目标：（1）确定是否有性别相关的差异BNST 在早期禁欲过程中内在的功能或结构连接;（2）确定是否存在性- 在早期戒断过程中与压力相关的BNST功能和BNST网络连接的相关差异;（3） 研究BNST功能/连接、应激反应、 和负面影响。基于动物模型的发现和我们在人类身上的试验数据， 我们预测，在早期禁欲期间，BNST将显示出活动模式的性别特异性差异， 连接“休息”和响应轻度压力的任务。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，应激反应增强， 早期禁欲本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BNST网络中表现出神经生物学差异，这些网络是早期负面情绪的基础。 戒酒这些结果将为未来的研究提供基础信息， 复发的机制，并可以指导开发针对AUD的性别特异性或个性化治疗。