Mechanisms underlying sex differences in stress-induced alcohol seeking

压力引起的寻酒性别差异的潜在机制

• 批准号: 10271239
• 负责人: Mary M Torregrossa
• 金额: $ 37.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271239
• 关键词: Acute; Adult; Alcohol abuse; Alcohol consumption; Alcohol-Related Disorders; Alcohols; Amygdaloid structure; Behavior; Behavioral; Brain; Brain region; Calcium Signaling; Clinical; Cocaine; Cues; Data; Dependence; Development; Electrophysiology (science); Excitatory Amino Acid Antagonists; Exposure to; Extinction (Psychology); Female; Gender; Generations; Genetic; Glutamatergic Agents; Glutamates; Gonadal Hormones; Health; Hormones; Human; Image; Immunohistochemistry; Individual; Intervention; Laboratory Study; Lead; Learning; Life; Measures; Mediating; Memory; Modeling; NMDA receptor antagonist; Neurobiology; Neurons; Outcome; Pattern; Pharmaceutical Preparations; Pharmacology; Population Dynamics; Rattus; Regulation; Relapse; Reporting; Rewards; Risk; Rodent Model; Self Administration; Sensory; Sex Differences; Slice; Stress; Synapses; Testing; Thalamic structure; Training; Woman; Yohimbine; acute stress; alcohol craving; alcohol cue; alcohol exposure; alcohol relapse; alcohol response; alcohol seeking behavior; alcohol use disorder; base; binge drinking; calcium indicator; classical conditioning; cocaine relapse; cohort; craving; epidemiologic data; epidemiology study; glutamatergic signaling; high risk drinking; improved; in vivo; male; men; microendoscope; microscopic imaging; nerve supply; neurobiological mechanism; neuroimaging; neuromechanism; noradrenergic; psychological trauma; recruit; relating to nervous system; response; sex; sexual dimorphism; social; stressor; therapy development; treatment effect

Project Summary/Abstract Historically, alcohol abuse and alcohol use disorders (AUDs) have been more common in men than women. However, recent epidemiological data in younger cohorts of women suggest that this gender gap is closing. Rates of risky/binge drinking in women are going up at a much faster rate than in men, women show a faster transition from social use to dependence, and women suffer greater alcohol-related health problems. Thus, identifying sex-specific neurobiological factors that underlie the development of problem drinking could lead to improved treatment approaches. In particular, women have been shown to have increased craving in response to alcohol-related cues and stressors relative to men, and neuroimaging studies show that this effect is associated with differential activation of brain circuits including the amygdala. We have found that female rats also show a greater relapse-like response to alcohol-associated cues, particularly when combined with an acute stressor, similar to the human studies. Moreover, we also have evidence for increased glutamatergic signaling in the basolateral amygdala (BLA) of female rats, raising the possibility that alcohol-associated memories may be more readily encoded in the BLA of females relative to males, and/or that the neurons encoding alcohol memories are more responsive to acute stress and able to drive activity in circuits controlling craving and relapse. Importantly, we have previously shown that differences in circulating gonadal hormones do not mediate the sex difference in behavior, suggesting that fundamental differences at the synaptic or circuit level underlie differential relapse-like behavior. For example, we have found that glutamatergic synapses from sensory thalamus to the BLA are critical for the encoding and extinction of cocaine-associated memories, and that depotentiating these synapses is sufficient to reduce cocaine relapse-like behavior. However, no one has previously investigated whether alcohol-cue memories are similarly encoded or if there are differences between males and females in the neural mechanisms mediating alcohol memory formation. Thus, in Aim 1 we will compare plasticity related mechanisms in the BLA regulating alcohol memory formation and extinction in males and females. In Aim 2, we will use genetically-encoded calcium indicators and miniature microendoscopes to image neural activity (calcium signals) in males and females when alcohol-cues are presented in the presence or absence of acute stressors. Finally, in Aim 3 we will use comprehensive cFos mapping to determine if males and females engage similar or different circuits during stress+/-alcohol-cue- induced relapse-like behavior. These results will inform if sex differences are due to altered circuit engagement that would point to sex specific neural targets for treatment. All together, these studies will provide a comprehensive analysis of how alcohol-cue memories are formed, modulated by stress, what other circuits are engaged, and if there are sex differences in any of these neurobiological factors that could explain the increasing vulnerability of females to alcohol-related disorders.

项目概要/摘要 从历史上看，酗酒和酒精使用障碍（AUD）在男性中比女性更常见。 然而，最近年轻女性群体的流行病学数据表明，这种性别差距正在缩小。 女性危险饮酒/酗酒率的上升速度比男性快得多，女性的饮酒速度更快 从社会使用到依赖的转变，妇女遭受更严重的与酒精相关的健康问题。因此， 确定导致饮酒问题发生的性别特异性神经生物学因素可能会导致 改进的治疗方法。特别是，女性表现出对这种反应的渴望增加。 与男性相关的酒精相关线索和压力源，神经影像学研究表明，这种影响 与包括杏仁核在内的大脑回路的差异激活有关。我们发现雌性老鼠 对与酒精相关的暗示也表现出更大的类似复发的反应，特别是与酒精相结合时 急性应激源，类似于人类研究。此外，我们还有证据表明谷氨酸能增加 雌性大鼠基底外侧杏仁核（BLA）中的信号传导，增加了与酒精相关的可能性 相对于男性，女性的 BLA 中的记忆可能更容易编码，和/或神经元 编码酒精记忆对急性压力更敏感，并且能够驱动控制电路的活动 渴望和复发。重要的是，我们之前已经证明循环性腺激素的差异 不介导行为中的性别差异，表明突触或回路的根本差异 水平是不同的复发样行为的基础。例如，我们发现谷氨酸能突触来自 感觉丘脑到 BLA 对于可卡因相关记忆的编码和消除至关重要 削弱这些突触的能力足以减少可卡因复发样行为。然而，没有人有 之前研究过酒精提示记忆是否有相似的编码或者是否存在差异 男性和女性之间介导酒精记忆形成的神经机制。因此，在目标 1 中，我们 将比较 BLA 中调节酒精记忆形成和消退的可塑性相关机制 男性和女性。在目标 2 中，我们将使用基因编码的钙指示剂和微型 当酒精提示出现时，显微内窥镜可对男性和女性的神经活动（钙信号）进行成像 在存在或不存在急性应激源的情况下出现。最后，在目标 3 中我们将使用全面的 cFos 映射以确定男性和女性在压力+/-酒精提示-期间是否参与相似或不同的回路 诱发类似复发的行为。这些结果将告知性别差异是否是由于电路参与改变所致 这将指出治疗的性别特异性神经靶点。总之，这些研究将提供 全面分析酒精提示记忆如何形成、受压力调节以及其他回路是什么 参与，并且这些神经生物学因素中是否存在性别差异可以解释 女性越来越容易罹患酒精相关疾病。