Regulation Of Mood By Dopamine D1 Receptors On Cerebral Cortical Interneurons

项目摘要/摘要 最近，我们使用Cre/loxP系统选择性地从GABA能神经元中删除了多巴胺D1受体 来自内侧神经节隆起内的Nkx2.1血统。这些细胞在很大程度上产生重要的 内侧额叶皮质内的大脑皮层中间神经元。尽管这些神经元间受体 仅代表一小部分皮质多巴胺D1受体(大多数是兴奋性谷氨酸能投射 这些条件性基因敲除小鼠在一个功能领域--心境--表现出显著的表型。 具体地说，GABA-D1-CKO小鼠在强迫游泳测试中表现出较少的不动，并减少了 在新的有压力的环境中摄入适口的液体；这两种情况都表明有抗抑郁药的作用 效果。这些数据表明了大脑皮层中间神经元参与情绪的新机制。 监管，而且重要的是，这种机制可能是“可以下药的”。目前的提案试图验证这一点 使用额外的行为测量和应激源的模型(目标1)，定义发育计时组件 这种神经适应(目标2)，并开始评估这种反应的细胞和分子基础 (目标3)。当前项目的成功将使我们能够在随后开发独特的治疗策略 通过基因和药物方法选择性地操纵这些受体，这些方法仅限于 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.