Sensitivity and resilience to increased alcohol drinking in males and females following traumatic stress

创伤应激后男性和女性对饮酒增加的敏感性和恢复力

• 批准号: 10394413
• 负责人: DEBORAH A. FINN
• 金额: $ 37.3万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394413
• 关键词: Alcohol consumption; Alcohol-Induced Disorders; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Behavioral; Biological; Brain; Brain region; CRF receptor type 1; Clozapine; Development; Disease; Ethanol; Exposure to; FOS gene; Female; Heart Rate; Heterogeneity; Hippocampus (Brain); Immunohistochemistry; Incidence; Individual; Intake; Intervention; Label; Maps; Medial; Modeling; Molecular; Mus; Neurons; Odors; Oxides; Patients; Pattern; Pharmacology; Pharmacology Study; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Proteins; Recovery; Reporting; Risk Factors; Rodent; Role; Sex Differences; Signal Transduction; Stress; Symptoms; Testing; Trauma; Water; alcohol use disorder; antagonist; anxiety-related behavior; comorbidity; designer receptors exclusively activated by designer drugs; drinking; epidemiology study; male; prevent; resilience; response; stressor; targeted treatment; therapy development; traumatic stress

Project Summary Post-traumatic stress disorder (PTSD) is twice as prevalent in females as in males, with a proportion of individuals also developing an alcohol use disorder (AUD). Using predator odor stress (PS) as an animal model of PTSD, we determined that two PS exposures significantly increased anxiety-related behavior and neuronal activation in the hippocampus (HC) of male and female C57BL/6J (B6) mice. Notably, intermittent PS significantly increased alcohol (ethanol) intake by 60% (males) and 71% (females), with heterogeneity in the response. Further, “sensitivity” to PS-enhanced ethanol intake conferred significantly greater corticotropin releasing factor receptor-1 (CRFR1) protein levels in female versus male HC, consistent with evidence for sex differences in CRFR1 signaling following stress. The proposed studies build on the above evidence by testing the hypothesis that comorbidity of PTSD and AUD is due to increased CRFR1 expression in HC neurons projecting to mPFC and that sex differences in CRFR1 induction by PS contribute to this comorbidity. Aim 1 will determine whether sex differences exist in the association between PS-enhanced ethanol drinking and alteration in anxiety, heart rate (HR), and/or compulsive ethanol drinking in B6 mice. We predict that PS-enhanced drinking in “sensitive” mice will be associated with an increase in anxiety, HR, and compulsive drinking and that there will be sex differences in the pattern of changes. Aim 2 will map changes in CRFR1 expression and neuronal activation by PS and by PS-enhanced drinking in crfr1-gfp mice. We predict that there will be sex differences in brain regional CRFR1-colabelled activity patterns in response to intermittent PS and in the relationship with ethanol intake. Aim 3 will manipulate the activity of CRFR1- expressing neurons using chemogenetic or pharmacologic approaches and determine the impact on PS- enhanced drinking. Two studies will use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in crfr1-cre mice to test the necessity and sufficiency of CRFR1 in ventral CA1, with inhibitory (Gi) and excitatory (Gq) DREADDs, respectively. We predict that preventing PS-induced activation of ventral CA1 (Gi DREADD) will block PS-enhanced drinking only in “sensitive” mice, whereas activating the ventral CA1 (Gq DREADD) will enhance ethanol intake in mice drinking ethanol without intermittent PS. A complementary study will determine whether systemic administration of a CRFR1 antagonist will reduce PS-enhanced drinking intake in B6 mice, with the prediction that the antagonist will be most effective in “sensitive” mice. Aim 4 will determine whether manipulation of the projection from ventral CA1 to mPFC is important for PS-enhanced drinking in B6 mice, by injecting Gi DREADDs into ventral CA1 and clozapine-N-oxide into mPFC. We predict that preventing PS-induced activation of the ventral CA1 to mPFC projection will block PS-enhanced drinking. Collectively, the information will elucidate sex differences in mechanisms underlying sensitivity to PS- enhanced drinking that can be targeted for the treatment of PTSD-induced AUD.

项目摘要 创伤后应激障碍（PTSD）在女性中的普遍性是男性的两倍，而男性的比例为 个人还患有饮酒障碍（AUD）。使用捕食者气味应力（PS）作为动物 PTSD模型，我们确定两个PS暴露显着增加了与动画相关的行为和 男性和雌性C57BL/6J（B6）小鼠的海马（HC）中的神经元激活。值得注意的是，间歇性PS 明显增加酒精（乙醇）的摄入量60％（男性）和71％（女性），异质性在 回复。此外，对PS增强乙醇摄入的“敏感性”明显更大的皮质激素 雌性与雄性HC的释放因子受体1（CRFR1）蛋白水平，与性别的证据一致 应力后CRFR1信号传导的差异。拟议的研究以上述证据为基础 PTSD和AUD的合并症是由于HC中CRFR1的表达增加引起的。 投射到MPFC的神经元以及PS诱导CRFR1的性别差异有助于此 合并症。 AIM 1将确定PS增强之间的关联中是否存在性别差异 B6小鼠中动画，心率（HR）和/或强迫性乙醇饮酒的乙醇饮酒和改变。我们 预测“敏感”小鼠中的PS增强饮酒将与焦虑，人力资源和焦虑症的增加有关 强迫性饮酒，并且变化模式将存在性别差异。 AIM 2将映射更改 CRFR1的表达和PS的神经元激活以及CRFR1-GFP小鼠的PS增强饮用。我们预测 响应于 间歇性PS以及与乙醇摄入的关系。 AIM 3将操纵CRFR1的活性 使用化学发生或药物方法表达神经元，并确定对PS-的影响 增强的饮酒。两项研究将使用设计器药物专门激活的设计器受体 （Dreadds）在CRFR1-CRE小鼠中，以抑制性（GI）测试CRFR1的必要和充分性 和兴奋性（GQ）恐怖分子。我们预测可以防止PS诱导的腹CA1激活 （GI Dreadd）仅在“敏感”小鼠中阻止PS增强饮用，而激活腹CA1（GQ） Dreadd）将增强饮用乙醇的小鼠而无需间歇性PS的乙醇摄入量。一项完整的研究 将确定全身给药CRFR1拮抗剂是否会减少PS增强饮用 B6小鼠的摄入量，预测拮抗剂将在“敏感”小鼠中最有效。目标4意志 确定对通风CA1到MPFC投影的操纵是否对PS增强很重要 在B6小鼠中饮用，将GI Dreadds注入腹侧CA1中，将氯氮平-N-氧化物注入MPFC中。我们预测 阻止PS诱导的腹侧CA1激活MPFC投影将阻止PS增强饮酒。 总的来说，这些信息将阐明对PS-敏感的机制的性别差异 增强的饮酒量可用于治疗PTSD诱导的AUD。