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.

项目摘要/摘要 从历史上看，酗酒和饮酒障碍（AUD）在男性中比女性更普遍。 然而，年轻女性队列中最近的流行病学数据表明，这种性别差距正在截断。 女性的危险/暴饮暴食率比男性的速度快得多，女性显示的速度更快 从社会使用到依赖性，妇女遭受与酒精有关的健康问题的更大。因此， 确定性别特异性的神经生物学因素，这些因素是饮酒问题的发展可能导致的 改进的治疗方法。特别是，妇女已被证明对响应有所增加 相对于男性与酒精有关的提示和压力源，神经影像学研究表明，这种影响是 与包括杏仁核在内的脑回路的差异激活有关。我们发现雌鼠 还显示出对酒精相关提示的复发样的反应，尤其是与 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 雌性大鼠的基底外侧杏仁核（BLA）的信号传导，从而提高了与酒精相关的可能性 记忆可能更容易地在女性相对于男性和/或神经元的bla中编码 编码酒精记忆对急性压力的反应更快，并且能够在控制电路中驱动活动 渴望和复发。重要的是，我们先前已经表明循环性腺激素的差异 不要调解行为的性别差异，表明突触或电路处的基本差异 水平是差异复发样行为的基础。例如，我们发现来自 对BLA的感觉丘脑对于可卡因相关的记忆的编码和灭绝至关重要，并且 这些突触的销售足以减少可卡因复发样的行为。但是，没有人 先前调查的酒精信使记忆是否类似地编码或是否存在差异 在介导酒精记忆形成的神经机制中的男性和女性之间。因此，在目标1中我们 将比较调节酒精记忆形成和灭绝的BLA中与可塑性相关的机制 男性和女性。在AIM 2中，我们将使用遗传编码的钙指标和微型 当酒精含量时，微观镜检查以成像男性和女性的神经活动（钙信号） 在存在或不存在急性应激源的情况下提出。最后，在AIM 3中，我们将使用全面的首席财务官 映射以确定男性和女性在压力期间是否参与相似或不同的电路 诱导复发样行为。这些结果将告知性别差异是否是由于电路参与的改变引起的 那将指出性别特定的治疗神经靶标。这些研究一起将提供 全面分析酒精信明的记忆，由压力调节，其他电路是什么 参与，如果这些神经生物学因素中的任何一个都存在性别差异，可以解释 女性对与酒精有关的疾病的脆弱性增加。