Sex differences in BNST networks during early abstinence in AUD

酒精使用障碍(AUD)是一种常见的致残疾病。越来越多的人意识到 AUD的性别差异；例如，女性因饮酒而经历更严重的健康并发症 而且，饮酒也会更快地产生负面后果。而AUDS的发生率相对较低 在男性中，这一比例稳定，在女性中，这一比例正在以惊人的速度上升。神经生物学性别差异 被认为是AUDS对男性和女性不同影响的基础，但到目前为止，关于AUD的研究相对较少 这个话题是存在的。成瘾的动物模型极大地促进了我们对成瘾的各个阶段的理解 成瘾--狂欢/沉醉、戒断/消极情绪和全神贯注/期待--及其根本原因 病理生理学。例如，长期接触酒精会导致神经适应性大脑改变，试图 保持动态平衡。在退缩/负性情绪阶段，过度活跃的压力系统产生 包括焦虑和抑郁在内的被认为通过阴性而导致复发的症状 增援。女性有更高的焦虑症和压力相关的障碍，这可能与性行为有关 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也是性别差异最大的大脑区域之一， 这表明BNST与早期禁欲期间出现的性别差异有关。我们之前 已发表的证据表明，人类BNST结构连接性存在性别差异。此外，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性和 BNST网络内的功能连接、更高的应激反应和早期更高的焦虑 禁欲。目前的研究将集中在BNST网络中的性别差异，从 通过调查酒精的三个具体目的：(1)确定BNST是否存在性别差异 在早期禁欲期间的内在功能或结构连接；(2)决定是否有性行为- 戒断早期应激相关BNST功能和BNST网络连通性的相关差异； 探讨BNST功能/连通性、应激反应、 以及早期禁欲的负面影响。根据动物模型的发现和我们在人体上的试验数据， 我们预测，在早期禁欲期间，BNST将显示出不同性别的活动模式和 静态连接，以及对压力较小的任务的响应。我们预计女性将表现出更强的结构性 和BNST网络内的功能连接，压力反应增强，以及在 早期禁欲。这项研究的成功完成将填补一个关键的知识缺口，决定 在负性情绪的早期，男性和女性在BNST网络中表现出神经生物学差异 戒酒戒酒。研究结果将为今后的研究提供基础信息。 这一机制可指导针对不同性别的AUD或个人化治疗的发展。

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.