Regulation Of Mood By Dopamine D1 Receptors On Cerebral Cortical Interneurons

项目总结/摘要 我们最近使用Cre/loxP系统选择性地删除GABA能神经元中的多巴胺D1受体 来自内侧神经节隆起内的Nkx2.1谱系。这些细胞在很大程度上产生了一个关键的 内侧额叶皮质内的大脑皮质中间神经元。虽然这些神经元间的受体 仅代表皮质多巴胺D1受体的一小部分（大多数在兴奋性多巴胺能投射上 神经元），这些条件性基因敲除小鼠在一个功能域-情绪中表现出显著的表型。 具体而言，GABA-D1-cKO小鼠在强迫游泳试验中表现出减少的不动性，并且在强迫游泳试验中表现出减少的潜伏期。 在一个新的压力环境中消耗可口的液体;这些都是抗抑郁药样的指标 效果这些数据表明大脑皮层中间神经元可能有助于情绪的新机制 监管，重要的是，这种机制可能是“药物”。目前的建议旨在确认这一点 模型使用额外的行为措施和压力源（目标1），定义发展时间组件 目的2），并开始评估这种反应的细胞和分子基础 (Aim 3）。当前项目的成功将使我们能够随后开发独特的治疗策略， 通过遗传和药理学方法选择性地操纵这些受体， 特定的神经元亚群。

PROJECT SUMMARY/ABSTRACT We recently used the Cre/loxP system to selectively delete dopamine D1 receptors from GABAergic neurons from the Nkx2.1 lineage within the medial ganglionic eminence. These cells largely produce a subset of crucial cerebral cortical interneurons within the medial frontal cortex. Although these interneuron-localized receptors represent just a small fraction of cortical dopamine D1 receptors (most are on excitatory glutamatergic projection neurons), these conditional knockout mice exhibit a remarkable phenotype in one functional domain – mood. Specifically, GABA-D1-cKO mice exhibit decreased immobility in the forced swim test, and decreased latency to consume a palatable liquid in a novel stressful environment; these are both indicative of an antidepressant-like effect. These data suggest a new mechanism by which cerebral cortical interneurons may contribute to mood regulation, and importantly, this mechanism may be “druggable”. The current proposal seeks to validate this model using additional behavioral measures and stressors (Aim 1), define the developmental timing components of this neuroadaptation (Aim 2), and begin to assess the cellular and molecular underpinnings of this response (Aim 3). Success of this current project will position us to subsequently develop unique therapeutic strategies to selectively manipulate these receptors through genetic and pharmacological approaches that are limited to specific neuronal subpopulations.