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发展风险因素 酒精使用障碍(AUD)；与青少年使用有关的潜在适应不良可塑性 这很可能是成年人患病风险增加的原因。终纹床核(BNST)是 性二态脑区与应激和负性情感相关 AUDS的复发，因此是这种不适应可塑性的主要靶点。使用一个模型 在雄性和雌性小鼠的青少年间歇性酒精暴露(AIE)中，我们发现中断 BNST谷氨酸能传递和可塑性，但其机制因性别而异(GluN2B- 男性由NMDAR介导，女性由mGluR1/5介导)。在测试过程中 成年后，两种形式的BNST可塑性都恢复到控制水平，但暴露在约束压力下 产生了AIE诱导的性别特异性的重新出现。AIE还增加了谷氨酸 在BNST中的释放，这种影响似乎通过调节突触前而减轻 CRFR1。AIE和成人应激也会产生性别特有的负面影响行为表型 (女性新奇诱导的低吞噬试验，男性的脚部电击--导致冰冻)。作为英国国民警卫队 位于皮质输入与杏仁核下游和下丘脑的交叉点 靶点，这种对BNST和随后的BNST间可塑性的增强驱动可能会敏感 应激反应和负性情感行为的表达。使用以下组合 分子、电生理、遗传和行为方法，我们将评估 AIE使BNST适应成人应激的性别特异性方式。我假设AIE和 成年应激通过激活BNST中谷氨酸的释放协同促进BNST中谷氨酸的释放 CRFR1在雄性小鼠中存在，但在雌性小鼠中不存在(目标1)。CRFR1传输的调制将是 检查其阻止压力对谷氨酸释放和可塑性的影响的能力 评估对压力敏感的输入。其次，我提出了BNST可塑性的性别差异 在不同的投影区(CEA、LH或VTA)。最后，BNST特定的删除，BNST GluN2B-NMDARs和mGluR5s的DREADD激活及其药理拮抗作用 (视性别而定)将被用来评估这些受体在发育过程中的作用。 特定性别的负面影响表型。这项工作的目标是找出潜在的 治疗AUDS的药物疗法和我们的工作表明，这些可能需要区别对待 雄性和雌性。