Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5

项目摘要 快速放电中间神经元的性别差异促进了AUD相关的PFC功能障碍： 调节mGlu 1和mGlu 5。酒精使用障碍（AUD）影响男性和女性，但女性 不成比例地受到几种疾病后果的伤害。受酒精影响而失调的一个关键大脑区域是 前额叶皮层（PFC），表现出显着的性二态性，是至关重要的管理适当的 喝酒PFC的输出是由锥体细胞介导的，锥体细胞是一种能传递到边缘系统的突触能神经元， 每一个通常投射到单个皮层下结构。锥体细胞的活动是动态调节， 表达小清蛋白的快速尖峰中间神经元（PV-IN）。越来越多的证据表明， PV-IN的传播调节饮酒行为的性别差异，因此药理学 PV-IN的调节为改善AUD相关的神经病学提供了有希望的手段。PFC PV-IN 表达几种可药用受体，特别是包括代谢型谷氨酸（mGlu）受体亚型1 和5.我们的初步数据表明mGlu 1和mGlu 5以性别特异性方式调节PV-IN， 此外，间歇性自愿饮酒诱导性别特异性改变几个mGlu 1-和mGlu 5-相关 PV-IN生理学。我们的中心假设是PFC PV-IN功能的性别差异是AUD的基础， 调节mGlu 1和mGlu 5可以改善适应不良的变化 是由酗酒引起的这一假设将通过两个具体目标进行检验。 目的1（K99）：为了验证mGlu 1和mGlu 5调节可以改善性别特异性酒精依赖的假设， 通过对PFC PV-IN的作用诱导病理生理学。PV-IN突触生理学和可塑性将是 在离体切片制备中询问。此外，将在体内用纤维检查PV-IN功能。 当雌性和雄性小鼠寻找酒精并执行其他PFC依赖行为时， 目的2（R 00）：检验性别特异性酒精诱导的不同PFC输出失调可以 通过mGlu 1和mGlu 5调节抑制性传递来补救。将采用病毒式方法， 在雌性和雄性转基因光遗传学小鼠（PV-1）中基于投射靶标记PFC锥体细胞 ChR2）。我们将评估间歇性饮酒后PV-IN如何控制特定的PFC输出途径 暴露，以及这些现象是如何调节性别和mGlu 1/mGlu 5。 培训：我将获得饮用模型和体内细胞类型特异性Ca 2+成像的丰富经验。 在酒精模型和纤维光度学方面的培训将使我能够将我对mGlu突触的兴趣 可塑性和PFC电路的未回答的问题，如何性别差异表现在 澳元。我还将接受必要的职业发展培训，以促进过渡到一个独立的初级 在酒精研究界的教师职位。

Project Summary Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5. Alcohol use disorder (AUD) affects both men and women, however women are disproportionately harmed by several disease outcomes. A key brain region dysregulated by alcohol is the prefrontal cortex (PFC), which exhibits significant sexual dimorphism and is essential for managing appropriate drinking. PFC output is mediated by pyramidal cells, glutamatergic neurons that course onto the limbic system, each one typically projecting to a single subcortical structure. Pyramidal cell activity is dynamically regulated by fast-spiking parvalbumin-expressing interneurons (PV-INs). Increasing evidence suggests that excitatory transmission onto PV-INs regulates sex differences in drinking behaviors, therefore pharmacological modulation of PV-INs provides a promising means to ameliorate AUD-related symptomology. PFC PV-INs express several druggable receptors, notably including metabotropic glutamate (mGlu) receptor subtypes 1 and 5. Our preliminary data indicate that mGlu1 and mGlu5 modulate PV-INs in a sex-specific manner, and further, that intermittent voluntary drinking induces sex-specific alterations to several mGlu1- and mGlu5-related PV-IN physiology. Our central hypothesis is that sex differences in PFC PV-IN function underlie AUD- related pathophysiology, and that modulating mGlu1 and mGlu5 can ameliorate maladaptive changes induced by binge-like alcohol consumption. This hypothesis will be tested through two specific aims. Aim 1 (K99): To test the hypothesis that mGlu1 and mGlu5 modulation can ameliorate sex-specific alcohol- induced pathophysiology through actions on PFC PV-INs. PV-IN synaptic physiology and plasticity will be interrogated in an ex vivo slice preparation. In addition, PV-IN function will be examined in vivo with fiber photometry while female and male mice seek alcohol and perform other PFC-dependent behaviors. Aim 2 (R00): To test the hypothesis that sex-specific alcohol-induced dysregulation of distinct PFC outputs can be remediated through mGlu1 and mGlu5 modulation of inhibitory transmission. A viral approach will be used to label PFC pyramidal cells based on projection target in female and male transgenic optogenetic mice (PV- ChR2). We will assess how PV-INs control specific PFC output pathways following intermittent alcohol exposure, and how these phenomena are regulated by sex and mGlu1/mGlu5. Training: I will gain extensive experience with drinking models and in vivo cell type-specific Ca2+ imaging. Training in alcohol models and fiber photometry will allow me to apply my interest in mGlu synaptic plasticity and PFC circuitry to unanswered questions about how sex differences are manifested in AUD. I will also receive essential career development training to facilitate a transition to an independent junior faculty position within the alcohol research community.