Ion channel mechanisms of striatal dopaminergic motor stimulation

纹状体中多巴胺的损失迅速导致运动不能，并且是帕金森病的关键病理。我-- 多巴，通过多巴胺，强烈刺激帕金森病患者的运动活动，多巴胺- 耗尽的动物然而，多巴胺的离子通道和神经生理机制 深刻的运动功能仍然未知;这种知识差距是改善治疗的障碍。 这种疾病。 使用合适的小鼠模型，用颜色标记的纹状体黑质神经元和纹状体苍白球神经元， 一致的多巴胺去神经支配，并在控制良好的脑切片中结合膜片钳记录 准备和四极峰记录在自由移动的小鼠，这个项目将测试我们的假设， 多巴胺D1受体激活上调阈下激活和持续钠电流， 纹状体黑质神经元，从而增加这些神经元的运动促进尖峰输出， 多巴胺的运动刺激;当D1受体超敏感时，这些作用会增强， 多巴胺去神经支配，如帕金森病。同时，多巴胺D2受体激活 下调纹状体锥体神经元的持续钠电流，因此降低了运动神经元的钠电流。 抑制这些神经元的尖峰输出，进一步促进多巴胺的运动刺激;这些 当D2受体在多巴胺去神经后超敏感时，作用也增强。 初步结果支持我们的假设。 综上所述，本项目将采用综合的方法来定义基本的离子通道， 多巴胺D1受体激活兴奋纹状体黑质神经元的神经生理学机制， 多巴胺D2受体激活抑制纹状体锥体神经元。这项研究的结果将提供关键的 深入了解多巴胺如何刺激运动活动的长期问题，也将奠定一个 改善帕金森病运动症状治疗的科学基础。

Loss of dopamine in the striatum quickly leads to akinesia and is a key pathology of Parkinson's disease. L- dopa, via dopamine, strongly stimulates motor activity in Parkinson's disease patients and dopamine- depleted animals. However, the ion channel and neurophysiological mechanisms underlying dopamine's profound motor function remain unknown; this knowledge gap is an obstacle to improving the treatment of this disease. Using suitable mouse models with color-labeled striatonigral neurons and striatopallidal neurons and consistent dopamine denervation, and combining patch clamp recording in a well controlled brain slice preparation and tetrode spike recording in freely moving mice, this project will test our hypothesis that dopamine D1 receptor activation upregulates the subthreshold-activating and persistent sodium current in striatonigral neurons and thus, increases the motor-promoting spike output from these neurons, contributing to dopamine's motor stimulation; these effects are enhanced when the D1 receptors are supersensitive after dopamine denervation such as in Parkinson's disease. Simultaneously, dopamine D2 receptor activation downregulates the persistent sodium current in striatopallidal neurons and hence decreases the motor- inhibiting spike output from these neurons, further contributing to dopamine's motor stimulation; these effects are also enhanced when the D2 receptors are supersensitive following dopamine denervation. Preliminary results support our hypothesis. In summary, this project will use integrative approaches to define fundamental ion channel and neurophysiological mechanisms by which dopamine D1 receptor activation excites striatonigral neurons and dopamine D2 receptor activation inhibits striatopallidal neurons. Results of this research will provide critical insights into the long-standing question of how dopamine stimulates motor activity and will also lay a scientific foundation for improving the treatment for the motor symptoms of Parkinson's disease.