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: 10650750
• 负责人: Mary M Torregrossa
• 金额: $ 37.73万
• 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/10650750
• 关键词: Acute; Adult; Alcohol abuse; Alcohol consumption; Alcohol-Related Disorders; Alcohols; Amygdaloid structure; Behavior; Behavioral; Brain; Brain region; Calcium Signaling; Clinical; Cocaine; Cue-induced relapse; Cues; Data; Dependence; Development; Electrophysiology (science); Excitatory Amino Acid Antagonists; Exposure to; Extinction; Female; Gender; Generations; Genetic; Glutamatergic Agents; Glutamates; Gonadal Hormones; Health; Homosynaptic Depression; Hormones; Human; Immunohistochemistry; Individual; Intervention; Laboratory Study; Learning; Life; Maps; Measures; Mediating; Memory; Modeling; NMDA receptor antagonist; Neurobiology; Neurons; Outcome; Pattern; Pharmaceutical Preparations; Population Dynamics; Predisposition; Rattus; Regulation; Relapse; Reporting; Rewards; Risk; Rodent Model; Self Administration; Sensory; Sex Differences; Shock; Slice; Stress; Synapses; Testing; Thalamic structure; Training; Woman; Yohimbine; acute stress; alcohol craving; alcohol cue; alcohol exposure; alcohol memory; alcohol relapse; alcohol response; alcohol seeking behavior; alcohol use disorder; binge drinking; calcium indicator; cocaine relapse; cohort; craving; epidemiologic data; epidemiology study; glutamatergic signaling; high risk drinking; improved; in vivo; male; men; microendoscope; microscopic imaging; nerve supply; neural; neurobiological mechanism; neuroimaging; neuromechanism; noradrenergic; pharmacologic; psychologic; recruit; 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.

项目总结/摘要 从历史上看，酒精滥用和酒精使用障碍（AUD）在男性中比女性更常见。 然而，最近年轻妇女群体的流行病学数据表明，这一性别差距正在缩小。 女性风险/酗酒率的上升速度比男性快得多，女性表现出更快的 从社会使用到依赖的过渡，妇女遭受更多与酒精有关的健康问题。因此，在本发明中， 确定性别特异性神经生物学因素，这些因素是问题饮酒发展的基础， 改善治疗方法。特别是，女性已经被证明有更多的渴望， 与男性相比，酒精相关的线索和压力源，神经成像研究表明，这种影响是 与包括杏仁核在内的大脑回路的差异激活有关。我们发现雌鼠 也显示出对酒精相关线索的更大的复发样反应，特别是当与 急性应激源，类似于人类研究。此外，我们也有证据表明， 雌性大鼠基底外侧杏仁核（BLA）中的信号传导，提高了酒精相关的可能性。 记忆可能更容易编码在BLA的女性相对于男性，和/或神经元 编码酒精记忆对急性压力的反应更敏感，能够驱动控制神经元的回路活动。 渴望和复发。重要的是，我们以前已经表明，在循环性腺激素的差异， 并不介导行为上的性别差异，这表明突触或回路上的根本差异 水平是不同复发样行为的基础。例如，我们已经发现， BLA的感觉丘脑对可卡因相关记忆的编码和消退至关重要， 去增强这些突触足以减少可卡因复发样行为。然而，没有人 先前研究酒精提示记忆是否类似编码或是否存在差异 男性和女性在调节酒精记忆形成的神经机制中的差异。因此，在目标1中， 将比较BLA调节酒精记忆形成和消退的可塑性相关机制， 雄性和雌性。在目标2中，我们将使用基因编码的钙指标和微型 显微内窥镜成像神经活动（钙信号）在男性和女性时，酒精线索是 在存在或不存在急性应激源的情况下呈现。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-线索- 诱发复发性行为这些结果将告知，如果性别差异是由于改变电路接合 这将指向治疗的性别特异性神经靶点。总之，这些研究将提供一个 全面分析了酒精提示记忆是如何形成的，如何受到压力的调节，还有哪些回路 参与，如果这些神经生物学因素中有任何性别差异可以解释 女性越来越容易患上与酒精有关的疾病。