Sex differences in regulation of reinstatement of ethanol seeking by nucleus accumbens glutamate signaling

项目总结 从历史上看，男性被诊断为酒精使用障碍(AUD)的比例高于女性，但更高 在酗酒的女性中观察到了有害健康后果的风险。近年来，这一差距 在AUDS的诊断中，女性和男性之间的差距一直很小。尽管如此，最少的研究已经 调查复吸相关行为性别差异的中介因素。男人和女人似乎都是 对酒精配对线索或压力驱使酒精渴求或与复发相关的能力的不同敏感 行为，比如男性对奖励配对的暗示特别敏感，而女性则表现出不断升级的压力-- 诱导性的渴望。反复饮酒的动物模型表明，雄性啮齿动物也同样容易受到影响 提示诱导复归，而雌性在应激促进复归中表现出升高。神经学 调节这些性别差异的电路和信号系统才刚刚开始被理解。核 伏隔(NAC)谷氨酸信号是乙醇恢复的关键调节因子，而且是离散的 谷氨酸能投射在应激和线索诱导的恢复中起着不同的作用。此外， 对谷氨酸信号的药理学调节可以减少对乙醇寻求的恢复。尽管坚挺 证据表明，NAC内的谷氨酸信号对于调节雄性、性别的恢复至关重要 谷氨酸能投射与NAc的接触或谷氨酸受体和 慢性酒精暴露后的转运蛋白尚未得到广泛调查。此R21提案将 测试伏隔谷氨酸回路功能性别差异导致差异的压倒一切的假设 压力和暗示诱导的恢复的倾向。具体地说，我们将评估先天和乙醇 在线索或压力诱导的恢复过程中，依赖驱动的神经功能的性别差异。目标1是 旨在通过特定性别的模式来测试长期酒精暴露促进恢复的假设。 我们预计，CIE促进了线索诱导的雄性恢复，但促进了雌性的压力诱导恢复。 我们将进一步使用光度法评估下缘、腹侧海马区和 基底外侧杏仁核谷氨酸能投射至NAC，以确定这些回路是否在 线索和压力诱导的恢复以性和酒精依赖驱动的方式。AIM 2将调查 CIE对NAC谷氨酸受体和转运体表达的性别特异性影响 免疫荧光和RNAScope原位杂交。这些实验的结果预计将 提供关于神经回路和环境因素调节的性别差异的大量信息 恢复对乙醇的寻求。我们还将获得有关性别差异对 慢性酒精暴露对谷氨酸信号和复发相关行为的影响。这些发现预计将 能够开发新的药物靶点，以减少复发行为，并建立 针对男性和女性的针对性治疗战略。

PROJECT SUMMARY Historically men have been diagnosed with alcohol use disorders (AUDs) at higher rates than women, but greater risk for adverse health consequences is observed in women who are problem drinkers. In recent years, the gap in diagnosis of AUDs between women and men has been closing. Despite this, minimal research has investigated factors mediating sex differences in relapse-related behavior. Men and women appear to be differentially sensitive to the ability of alcohol-paired cues or stress to drive alcohol craving or relapse-related behaviors, such that men are particularly sensitive to reward-paired cues, while women show escalated stress- induced craving. Animal models of relapse to alcohol seeking indicate that male rodents are similarly susceptible to cue-induced reinstatement, while females show elevations in stress-facilitation of reinstatement. The neural circuits and signaling systems that mediate these sex differences are only beginning to be understood. Nucleus accumbens (NAc) glutamate signaling is a critical regulator of reinstatement to ethanol seeking, and discrete glutamatergic projections play separable roles in stress- and cue-induced reinstatement. Further, pharmacological regulation of glutamate signaling can reduce reinstatement to ethanol seeking. Despite strong evidence that glutamate signaling within the NAc is critical for the regulation of reinstatement in males, sex differences in engagement of glutamatergic projections to the NAc or in expression of glutamate receptors and transporters following chronic alcohol exposure has not been extensively investigated. This R21 proposal will test the overarching hypothesis that sex differences in accumbens glutamate circuit function result in differential propensity toward stress- and cue-induced reinstatement. Specifically, we will assess innate and ethanol dependence-driven sex differences in neural function during cue- or stress-induced reinstatement. Aim 1 is designed to test the hypothesis that chronic alcohol exposure promotes reinstatement with sex-specific patterns. We expect that CIE facilitates cue-induced reinstatement in males, but stress-induced reinstatement in females. We will further use photometric assessment of calcium signaling in infralimbic, ventral hippocampus, and basolateral amygdalar glutamatergic projections to the NAc to determine if these circuits are engaged during cue- and stress-induced reinstatement in a sex- and ethanol dependence-driven manner. Aim 2 will investigate sex-specific effects of CIE on the expression of glutamate receptors and transporters in the NAc through the use of immunofluorescence and RNAscope in situ hybridization. The results of these experiments are expected to provide considerable information on the sex differences in neural circuits and environmental factors regulating reinstatement of ethanol seeking. We will also gain significant knowledge of sex differences in the impact of chronic alcohol exposure on glutamate signaling and relapse-related behavior. These findings are expected to enable development of novel drug targets for the reduction of relapse behavior as well as the establishment of targeted treatments strategies for men and women.