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: 10181728
• 负责人: JENNIFER URBANO BLACKFORD
• 金额: $ 67.49万
• 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/10181728
• 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; 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（AUDS）是常见的残疾条件。对重要的意识越来越 音频的性别差异；例如，妇女因饮酒而经历更严重的健康并发症 还会更快地产生饮酒的负面后果。虽然auds的速率相对 男性稳定，女性的速度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AUDS对男性和女性的不同影响的基础，但迄今为止对 存在这个主题。成瘾的动物模型已经大大了解了我们对 成瘾 - 激烈/中毒，提取/负面影响和关注/预期 - 及其基础 病理生理学。例如，慢性酒精暴露会导致神经适应性大脑的变化 保持体内稳态。在撤回/负面影响阶段，多动压力系统产生 症状包括动画和抑郁症，这被认为会导致通过负面 加强。妇女患焦虑症和与压力有关的疾病的率较高，这可能有助于性 早期禁欲的差异。早期禁欲的动物模型突出了参与 Stria末端（BNST）的床核。 BNST也是最性别二态性大脑区域之一， 表明BNST参与了早期戒酒期间与性别有关的差异。我们以前 公布了人类BNST结构连通性的性别差异的证据。此外，来自 我们的NIAAA资助R21提供了性别差异的初步证据：女性的结构更强， BNST网络内的功能连通性，压力反应的增强以及早期的焦虑较高 节制。当前的研究将侧重于早期戒酒期间BNST网络的性别差异 通过研究三个特定目的酒精：（1）确定BNST是否存在与性别相关的差异 早期禁欲期间的内在功能或结构连通性； （2）确定是否有性别 早期戒酒期间，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，压力响应之间的关系中与性别相关的差异， 和早期戒酒的负面影响。根据动物模型的发现和我们在人类中的试验数据， 我们预测，在早期戒酒期间，BNST将在活动模式和 连通性“应得”，并响应轻度压力的任务。我们预计女性会表现出更强的结构 以及BNST网络内的功能连通性，压力反应的增强以及更高的焦虑 早期禁欲。这项研究的成功完成将填补关键的知识差距，确定是否是否 男性和女人在早期产生负面影响的BNST网络中表现出神经生物学差异 戒酒。结果将提供基本信息，以告知未来研究 退休机制，可以指导特定于性别或个性化治疗的AUD的发展。