Mechanisms underlying sex differences in stress-induced alcohol seeking

项目摘要/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，最近在年轻女性群体中的流行病学数据表明，这种性别差距正在缩小。 女性高风险饮酒率的上升速度比男性快得多，女性表现出更快的 从社交使用过渡到依赖，妇女遭受更多与酒精有关的健康问题。因此， 确定导致问题饮酒的特定性别的神经生物学因素可能会导致 改进治疗方法。特别是，女性被证明对此的渴望有所增加 与男性有关的酒精相关线索和压力源，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不同激活有关。我们发现雌性老鼠 也显示出对酒精相关线索更大的复发反应，特别是当与 急性应激源，类似于人体研究。此外，我们也有证据表明谷氨酸能 雌性大鼠杏仁基底外侧核(BLA)中的信号，增加了酒精相关的可能性 记忆可能更容易编码在女性的BLA中，而不是男性，和/或神经元 编码酒精记忆对急性压力更敏感，并能够驱动控制电路中的活动 渴望和故态复萌。重要的是，我们之前已经证明，循环性腺激素的差异 不要调节行为上的性别差异，这表明突触或回路上的根本差异 水平是差异复发样行为的基础。例如，我们发现谷氨酸能突触来自 BLA的感觉丘脑对可卡因相关记忆的编码和消亡至关重要，并且 使这些突触去增强足以减少可卡因复发的行为。然而，没有人有过 先前研究过酒精线索记忆的编码是否相似或是否存在差异 在调节酒精记忆形成的神经机制中，男性和女性之间的差异。因此，在目标1中，我们 将比较白血球蛋白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，我们将使用遗传编码的钙指示器和微型 当酒精提示时，显微内窥镜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出现的。最后，在目标3中，我们将使用综合CFO 确定男性和女性在应激/-酒精-暗示-过程中参与相似或不同回路的映射 诱发故态型行为。这些结果将告诉我们，性别差异是否由于回路参与的改变所致 这将指向治疗的性别特异性神经靶点。总而言之，这些研究将提供一个 全面分析酒精线索记忆是如何形成的，受压力的调制，还有哪些其他回路 如果这些神经生物学因素中的任何一个存在性别差异，可以解释 女性对酒精相关疾病的易感性增加。

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.