钙结合蛋白阳性中间神经元 mGlu 受体调控前额叶皮层生理性别差异和 binge drinking。

Parvalbumin interneuron mGlu receptors govern sex differences in prefrontal cortex physiology and binge drinking.

机构信息

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Neuropsychopharmacology. 2024 Nov;49(12):1861-1871. doi: 10.1038/s41386-024-01889-0. Epub 2024 May 21.

Abstract

Despite established sex differences in the prevalence and presentation of psychiatric disorders, little is known about the cellular and synaptic mechanisms that guide these differences under basal conditions. The proper function of the prefrontal cortex (PFC) is essential for the top-down regulation of motivated behaviors. The activity of the PFC is tightly controlled by parvalbumin-expressing interneurons (PV-INs), a key subpopulation of fast-spiking GABAergic cells that regulate cortical excitability through direct innervations onto the perisomatic regions of nearby pyramidal cells. Recent rodent studies have identified notable sex differences in PV-IN activity and adaptations to experiences such as binge drinking. Here, we investigated the cellular and molecular mechanisms that underlie sex-specific regulation of PFC PV-IN function. Using whole-cell patch-clamp electrophysiology and selective pharmacology, we report that PV-INs from female mice are more excitable than those from males. Moreover, we find that mGlu and mGlu metabotropic glutamate receptors regulate cell excitability, excitatory drive, and endocannabinoid signaling at PFC PV-INs in a sex-dependent manner. Genetic deletion of mGlu receptors from PV-expressing cells abrogates all sex differences observed in PV-IN membrane and synaptic physiology. Lastly, we report that female, but not male, PV-mGlu mice exhibit decreased voluntary drinking on an intermittent access schedule, which could be related to changes in ethanol's stimulant properties. Importantly, these studies identify mGlu and mGlu receptors as candidate signaling molecules involved in sex differences in PV-IN activity and behaviors relevant to alcohol use.

摘要

尽管在精神疾病的患病率和表现上存在已确立的性别差异,但对于指导这些差异的基础条件下的细胞和突触机制知之甚少。前额叶皮层 (PFC) 的正常功能对于动机行为的自上而下调节至关重要。PFC 的活动受到表达 parvalbumin 的中间神经元 (PV-INs) 的紧密控制,PV-INs 是快速放电 GABA 能细胞的关键亚群,通过直接支配附近锥体细胞的体区来调节皮质兴奋性。最近的啮齿动物研究已经确定了 PV-IN 活性以及对狂欢性饮酒等体验的适应方面存在显著的性别差异。在这里,我们研究了基础上存在性别特异性调节 PFC PV-IN 功能的细胞和分子机制。使用全细胞膜片钳电生理学和选择性药理学,我们报告说,来自雌性小鼠的 PV-IN 比来自雄性小鼠的更具兴奋性。此外,我们发现 mGlu 和 mGlu 代谢型谷氨酸受体以性别依赖的方式调节 PFC PV-IN 中的细胞兴奋性、兴奋性驱动和内源性大麻素信号。从 PV 表达细胞中遗传缺失 mGlu 受体消除了在 PV-IN 膜和突触生理学中观察到的所有性别差异。最后,我们报告说,雌性,但不是雄性,PV-mGlu 小鼠在间歇性访问方案中表现出减少的自愿饮酒,这可能与乙醇的刺激特性的变化有关。重要的是,这些研究确定 mGlu 和 mGlu 受体作为参与 PV-IN 活性和与酒精使用相关行为的性别差异的候选信号分子。

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