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

快速峰值中间神经元的性别差异促进 AUD 相关的 PFC 功能障碍：通过调节 mGlu1 和 mGlu5 进行修复

• 批准号: 10686993
• 负责人: Max E Joffe
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686993
• 关键词: Affect; Alcohol consumption; Alcohols; Area; Behavior; Behavioral; Brain region; Cells; Communities; Data; Development; Disease; Disease Outcome; Electrophysiology (science); Ethanol; Etiology; Exhibits; Faculty; Female; Fiber; Functional disorder; GRM1 gene; GRM5 gene; Glutamates; Image; Interneuron function; Interneurons; Intervention; Label; Lifestyle-related condition; Limbic System; Measures; Mediating; Membrane; Metabotropic Glutamate Receptors; Minor; Modeling; Mus; Neurobiology; Neurons; Output; Parvalbumins; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Photometry; Physiological; Physiology; Population; Positioning Attribute; Predisposition; Prefrontal Cortex; Preparation; Process; Property; Pyramidal Cells; Reporter Genes; Reporting; Schedule; Sex Differences; Shapes; Slice; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Time; Training; Transgenic Mice; Transgenic Organisms; Viral; Woman; alcohol availability; alcohol exposure; alcohol research; alcohol seeking behavior; alcohol use disorder; behavioral pharmacology; career development; cell type; cognitive function; craving; design; drinking; drinking behavior; experience; glutamatergic signaling; in vivo; innovation; interest; maladaptive behavior; male; men; monoamine; motivated behavior; neuroregulation; novel; optogenetics; pharmacologic; receptor; remediation; sex; sexual dimorphism; side effect; translational approach; transmission process

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.

项目摘要 快速加快中间神经元中的性别差异促进与AUD相关的PFC功能障碍：通过 调节MGLU1和MGLU5。饮酒障碍（AUD）会影响男性和女人，但是女人是 几种疾病结果造成了不成比例的伤害。酒精失调的关键大脑区域是 前额叶皮层（PFC）表现出明显的性二态性，对于管理适当 喝。 PFC输出是由锥体细胞，谷氨酸能神经元介导的，这些神经元会导致边缘系统介导 每个通常都投射到单一皮层结构上。锥体细胞活性由 快速刺激的表达白蛋白的中间神经元（PV-INS）。越来越多的证据表明兴奋性 传播到PV-INS可以调节饮酒行为的性别差异，因此药理 PV-INS的调节提供了一种有希望的方法来改善与AUD相关的症状。 PFC PV-INS 表达几种可药物的受体，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MGLU1和MGLU5以性别特定方式调节PV-INS，并且 此外，这种间歇性自愿饮酒会引起对几种MGLU1-和MGLU5相关的性别特异性改变 PV-IN生理学。我们的核心假设是，PFC PV-IN功能的性别差异是AUD- 相关的病理生理学以及调节MGLU1和MGLU5可以改善适应不良的变化 由暴饮暴食诱导的饮酒诱导。该假设将通过两个具体目标进行检验。 AIM 1（K99）：测试MGLU1和MGLU5调制可以改善性别特异性酒精的假设。 通过对PFC PV-INS的作用诱导病理生理。 PV-IN突触生理学和可塑性将是 在离体切片准备中进行了询问。此外，将用纤维在体内检查PV-IN功能 男性和男性小鼠寻求酒精并执行其他PFC依赖性行为。 AIM 2（R00）：检验以下假设：性别特异性酒精引起的不同PFC输出的失调可以 通过MGLU1和MGLU5调制抑制性传播的修复。病毒方法将用于 基于女性和男性转基因光学小鼠的投影靶标（PV-- CHR2）。我们将评估pv-ins如何控制特定的PFC输出途径 暴露，以及这些现象如何受到性和mglu1/mglu5的调节。 培训：我将在饮酒模型和体内细胞类型特异性CA2+成像方面获得丰富的经验。 酒精模型和光纤光度法的培训将使我能够应用我对MGLU突触的兴趣 可塑性和PFC电路，以解决有关性别差异如何表现的未解决问题 奥德我还将获得基本的职业发展培训，以促进过渡到独立的初级 酒精研究界的教师职位。