Sex Specific Effects of Adolescent Alcohol Exposure on BNST Plasticity

青少年酒精暴露对 BNST 可塑性的性别特异性影响

• 批准号: 10404918
• 负责人: Tiffany A Wills
• 金额: $ 32.06万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404918
• 关键词: Acute; Adolescence; Adolescent; Adult; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Data; Development; Electrophysiology (science); Exposure to; Female; Freezing; Future; Genetic; Glutamates; Goals; Hippocampus (Brain); Hypothalamic structure; LoxP-flanked allele; Male Adolescents; Mediating; Mental Depression; Modeling; Molecular; Mus; Neurons; Neurotransmitters; Output; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Recording of previous events; Relapse; Risk; Risk Factors; Role; Sex Differences; Shock; Signal Transduction; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Synaptic Transmission; System; Testing; Withdrawal; Work; adolescent alcohol effect; adolescent alcohol exposure; alcohol abstinence; alcohol exposure; alcohol relapse; alcohol testing; alcohol use disorder; alcoholism therapy; antagonist; behavioral phenotyping; behavioral response; biological adaptation to stress; designer receptors exclusively activated by designer drugs; disorder later incidence prevention; experience; foot; innovation; male; mouse model; negative affect; paraventricular nucleus; presynaptic; prevent; receptor; restraint stress; sex; sexual dimorphism; stressor; transmission process; underage drinking

Project Summary/Abstract: Adolescent alcohol use is a known risk factor for the development of alcohol use disorders (AUDs); latent maladaptive plasticity associated with adolescent use likely underlies this increased risk in adults. The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic brain region and critically involved in stress and negative affect-associated relapse in AUDs, and therefore is a prime target for this maladaptive plasticity. Using a model of adolescent intermittent ethanol exposure (AIE) in male and female mice, we find disrupted BNST glutamatergic transmission and plasticity, but the mechanisms differ across sex (GluN2B- NMDAR-mediated in males and mGluR1/5-mediated in females). When tested during adulthood, both forms of BNST plasticity return to control levels but exposure to restraint stress produced a re-emergence of AIE-induced that were sex-specific. AIE also increased glutamate release in the BNST and this effect appears be mitigated through modulation of presynaptic CRFR1. AIE and adult stress also produce sex-specific negative affect behavioral phenotypes (novelty-induced hypophagia test in females, foot shock-induce freezing in males). As the BNST sits at the intersection between cortical inputs and downstream amygdalar and hypothalamic targets, this enhanced drive to the BNST and subsequent inter BNST plasticity likely sensitize the stress response and the expression of negative affect behaviors. Using a combination of molecular, electrophysiological, genetic, and behavioral approaches, we will evaluate the ability of AIE to prime the BNST to adult stress sex-specific manner. I hypothesize that that AIE and adult stress act to synergistically enhance glutamate release in the BNST via activation of CRFR1 in male mice but not female mice (Aim 1). Modulation of CRFR1 transmission will be examined for its ability to block the effects of stress on glutamate release and plasticity and evaluate stress sensitive inputs. Next, I propose that the sex difference in BNST plasticity occur in distinct projection regions (CeA, LH, or VTA). Finally, BNST-specific deletion, BNST DREADD activation, and pharmacological antagonism of GluN2B-NMDARs and mGluR5s (depending on the sex) will be used to assess the role of these receptors in the development of sex-specific negative affect phenotypes. The goal of this work is to identify potential pharmacotherapies to treat AUDs and our work suggest that these likely need to be distinct for males and females.

项目摘要/摘要：青少年饮酒是一个已知的风险因素， 酒精使用障碍（AUDs）;与青少年使用相关的潜在适应不良可塑性 可能是成年人风险增加的原因。终纹床核（BNST）是一个位于大脑中的核团， 性二态脑区和严重参与压力和负面影响相关 在AUD中复发，因此是这种适应不良可塑性的主要目标。使用一个模型， 在雄性和雌性小鼠的青春期间歇性乙醇暴露（AIE）中，我们发现 BNST介导的物质传递和可塑性，但机制在性别上不同（GluN 2B- 雄性中NMDAR介导，雌性中mGluR 1/5介导）。当测试期间 成年后，这两种形式的BNST可塑性恢复到控制水平，但暴露于约束压力 产生了AIE诱导的性别特异性的重新出现。AIE还增加谷氨酸 BNST的释放，这种影响似乎可以通过调节突触前 CRFR1. AIE和成人应激也产生性别特异性的负性情感行为表型 （雌性动物的新奇感诱导食欲减退试验，雄性动物的足部电击诱导冻结）。作为BNST 位于皮质输入和下游杏仁核和下丘脑之间的交叉点 目标，这种增强的驱动力BNST和随后的BNST间的可塑性可能敏感 应激反应和负性情感行为的表达。结合使用 分子，电生理，遗传和行为方法，我们将评估能力 的AIE启动BNST成人应激性别特异性的方式。我假设， 成年应激通过激活BNST中的谷氨酸盐， 雄性小鼠中的CRFR 1，但雌性小鼠中无（目的1）。CRFR 1传输的调制将 检查其阻断应激对谷氨酸释放和可塑性的影响的能力， 评估压力敏感输入。其次，我认为BNST可塑性存在性别差异， 在不同的投影区域（CeA，LH或VTA）。最后，BNST特异性缺失， DREADD激活和GluN 2B-NMDAR和mGluR 5的药理学拮抗作用 （取决于性别）将被用来评估这些受体在发展中的作用， 性别特异性负面情感表型。这项工作的目标是确定潜在的 药物治疗AUDs和我们的工作表明，这些可能需要不同的 男性和女性。