Ion channel mechanisms of striatal dopaminergic motor stimulation

纹状体中多巴胺的丧失会迅速导致动作迟钝，这是帕金森氏症的关键病理。L- 多巴胺通过多巴胺强烈刺激帕金森氏病患者的运动活动，而多巴胺- 耗尽的动物。然而，多巴胺的离子通道和神经生理机制 深刻的运动功能尚不清楚；这种知识差距是改进治疗的障碍。 这种病。 使用带有彩色标记的纹状体黑质神经元和纹状体苍白质神经元的合适的小鼠模型 在控制良好的脑片中持续的多巴胺去神经和结合膜片钳记录 准备和自由活动小鼠的四极体峰电位记录，这个项目将检验我们的假设 多巴胺D_1受体激活上调大鼠的阈下激活和持续性钠电流 纹状体黑质神经元，因此，增加这些神经元的运动促进峰输出，贡献 对多巴胺的运动刺激；当D1受体超敏感时，这些效应在 多巴胺失神经，如帕金森氏症。同时，多巴胺D2受体的激活 下调纹状体双侧丘脑神经元持续钠电流，从而降低运动- 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，这种作用也会增强。 初步结果支持我们的假设。 总而言之，该项目将使用综合方法来定义基本离子通道和 多巴胺D_1受体激活兴奋纹状体黑质神经元的神经生理机制 多巴胺D2受体的激活抑制了纹状体苍白球神经元。这项研究的结果将提供关键的 对多巴胺如何刺激运动活动这一长期存在的问题的见解，也将为 为改善帕金森病运动症状的治疗提供科学依据。

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.