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

基本信息

批准号：
10608086
负责人：
Andrey E Ryabinin
金额：
$ 37.32万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10608086
关键词：
Alcohol consumption Alcohols Amygdaloid structure Animal Model Anxiety Behavioral Biological Brain region CRF receptor type 1 Classification Clozapine Development Disease Ethanol Euthanasia Exposure to FOS gene Female Genetic Heart Rate Heterogeneity Hippocampus Immunohistochemistry Incidence Individual Intake Intervention Label Maps Medial Modeling Molecular Mus Neurons Odors Oxides Patients Pattern Pharmacology Study Post-Traumatic Stress Disorders Predisposition Prefrontal Cortex Prevalence Proteins Recovery Recreation 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 pharmacologic prevent resilience response stressor targeted treatment therapy development traumatic stress

项目摘要

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.

项目概要创伤后应激障碍 (PTSD) 在女性中的患病率是男性的两倍，其中个体也患有酒精使用障碍（AUD），将捕食者气味应激（PS）视为动物。 PTSD 模型中，我们确定两次 PS 暴露显着增加了焦虑相关行为，并且雄性和雌性 C57BL/6J (B6) 小鼠海马 (HC) 中的神经元激活值得注意的是间歇性 PS。酒精（乙醇）摄入量显着增加 60%（男性）和 71%（女性），且存在异质性此外，对 PS 增强的乙醇摄入的“敏感性”会导致促肾上腺皮质激素显着增加。女性与男性 HC 中释放因子受体 1 (CRFR1) 蛋白水平，与性别证据一致压力后 CRFR1 信号传导的差异拟议的研究通过测试建立在上述证据的基础上。假设 PTSD 和 AUD 的共病是由于 HC 中 CRFR1 表达增加所致投射到 mPFC 的神经元以及 PS 诱导 CRFR1 的性别差异导致了这一点目标 1 将确定 PS 增强之间的关联是否存在性别差异。 B6 小鼠的乙醇饮用和焦虑、心率 (HR) 和/或强迫性乙醇饮用的改变。预测“敏感”小鼠的 PS 增强饮酒将与焦虑、心率和心率的增加有关。强迫性饮酒的模式会存在性别差异的变化，目标2也会发生变化。我们预测 crfr1-gfp 小鼠中 PS 和 PS 增强饮酒的 CRFR1 表达和神经激活。大脑区域 CRFR1 联合标记的活动模式会存在性别差异，以响应间歇性 PS 以及与乙醇摄入量的关系将控制 CRFR1- 的活性。使用化学遗传学或药理学方法表达神经元并确定对 PS-的影响两项研究将使用由设计药物专门激活的设计受体。 (DREADDs) 在 crfr1-cre 小鼠中测试腹侧 CA1 中 CRFR1 的必要性和充分性，具有抑制性 (Gi) 我们预测分别会阻止 PS 诱导的腹侧 CA1 激活。 (Gi DREADD) 只会在“敏感”小鼠中阻止 PS 增强的饮酒，而激活腹侧 CA1 (Gq DREADD）将增加没有间歇性 PS 的小鼠的乙醇摄入量。将确定 CRFR1 拮抗剂的全身给药是否会减少 PS 增强的饮酒 B6 小鼠的摄入量，预测拮抗剂对“敏感”小鼠 Aim 4 最为有效。确定从腹侧 CA1 到 mPFC 的投影操作对于 PS 增强是否重要我们预测，通过将 Gi DREADD 注射到腹侧 CA1 并将氯氮平-N-氧化物注射到 mPFC 中，B6 小鼠饮酒。阻止 PS 诱导的腹侧 CA1 到 mPFC 投射的激活将阻止 PS 增强的饮酒。总的来说，这些信息将阐明 PS-敏感性机制中的性别差异。增强饮酒可用于治疗 PTSD 引起的 AUD。