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

项目摘要 从历史上看，男性被诊断患有酒精使用障碍（AUD）的比率高于女性，但更高。 在酗酒的妇女中观察到对健康产生不良后果的风险。近年来，差距 在诊断AUDs方面，男女之间的差距已经缩小。尽管如此， 调查因素介导的复发相关行为的性别差异。男人和女人似乎 对酒精配对线索或压力驱动酒精渴望或复发相关的能力的敏感性差异 行为，例如男性对奖励配对线索特别敏感，而女性则表现出升级的压力- 诱导的渴望酒精寻求复发的动物模型表明， 提示诱导的恢复，而女性显示压力促进恢复的海拔。神经 介导这些性别差异的电路和信号系统才刚刚开始被理解。核 NAc谷氨酸信号传导是恢复乙醇寻求的关键调节剂，并且离散 神经元投射在压力和线索诱导的恢复中起着不同的作用。此外，本发明还 谷氨酸信号传导的药理学调节可以减少对乙醇寻求的恢复。尽管遭到强烈 有证据表明，NAc内的谷氨酸信号传导对于调节男性、性别 谷氨酸能投射到NAc的参与或谷氨酸受体表达的差异， 慢性酒精暴露后的转运蛋白尚未得到广泛研究。R21将 测试总体假设，即性别差异在谷氨酸回路功能的差异， 倾向于压力和线索诱导的恢复。具体来说，我们将评估先天和乙醇 依赖性驱动的神经功能在线索或压力诱导的恢复的性别差异。目标1是 旨在检验慢性酒精暴露促进性别特异性模式恢复的假设。 我们预计，CIE促进线索诱导的恢复男性，但压力诱导的恢复女性。 我们将进一步使用光度法评估边缘下、腹侧海马和海马体中的钙信号， 基底外侧杏仁核神经元投射到NAc，以确定这些回路是否在 提示和压力诱导的恢复性和乙醇依赖驱动的方式。目标2将调查 CIE对NAc中谷氨酸受体和转运蛋白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 提供了相当多的信息，性别差异的神经回路和环境因素调节 恢复乙醇寻求。我们还将获得有关性别差异对影响的重要知识， 慢性酒精暴露对谷氨酸信号传导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 针对男性和女性的治疗策略。

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.