电刺激丘脑底核缓解帕金森氏病疼痛的神经环路研究

Pain is the most prominent non-motor symptom observed in patients with Parkinson’s disease (PD). Patients with PD experience various types of pain. Deep brain stimulation (DBS) targeted to the subthalamic nucleus (STN), a surgical procedure widely used for treating motor disorders in PD, effectively relieves various types of PD related pain. However, the precise mechanisms underlying pain relief in PD by STN-DBS remain uncertain. Preclinical and clinical studies suggest that modulation of neuronal excitability in basal ganglia by STN-DBS is associated with pain relief in PD, but the neural circuit pathways remain mysterious. We hypothesize that selective activation of different STN outputs to Internal segment of Globus pallidus (GPi), Substantia nigra reticular (SNr), and ventral Pallidus (VP) by DBS may lead to effective treatment of pain in PD. We will apply following strategies to test our hypothesis. We will use retrograde tracing to selectively label mouse STN neurons projecting to the GPi, the SNr, and the VP, and use brain clearing technique (passive CLARITY) to characterize distribution pattern of STN glutamatergic outputs to GPi, SNr, and VP in 3D. We will use an optogenetic approach to either globally stimulate STN neurons or selectively stimulate STN glutamatergic terminals in the GPi, SNr and VP in PD mice, and determine therapeutical effects on pain symptoms in PD. Overall, the goal of this study is to demonstrate that distinct circuits emanating from STN modulated by STN-DBS contribute pain treatment in PD. Such a study has importance that extends beyond clinical therapeutics.

疼痛是帕金森氏病（PD）最常见的非运动障碍症状之一。临床研究显示丘脑底核深部脑刺激（STN-DBS）不仅能缓解PD运动障碍，还对PD患者的疼痛有一定疗效，但其疗效差异很大，且作用机制不清楚。以往研究认为STN-DBS纠正基底神经节神经元的异常放电，与其缓解PD疼痛有关，但对于STN各输出通路在DBS中的作用尚待探讨。本研究假设STN-DBS选择性调控STN的下游特定投射脑区，该神经通路可能参与STN-DBS缓解PD疼痛的治疗作用。为证明这一假说，本研究将利用逆向示踪和透明脑技术揭示投射至内侧苍白球（GPi）、黑质网状区（SNr）和腹侧苍白球（VP）的STN谷氨酸能神经元的空间分布，并采用光遗传学技术选择性地调节这些神经元对下游脑区的投射纤维，观察PD小鼠疼痛的改善，阐明各STN神经通路对PD疼痛的影响，为提高STN-DBS缓解PD疼痛的疗效提供理论依据。

疼痛是帕金森氏病患者除运动障碍以外的最常见的症状之一，临床研究显示丘脑底核深部脑刺激（STN-DBS）不仅能缓解PD运动障碍，还对PD患者的疼痛有一定疗效，其缓解PD疼痛可能与STN-DBS纠正基底神经节神经元的异常放电有关。因此，本研究提出STN过度兴奋是帕金森病中枢性痛觉过敏产生的重要机制之一的假说。本研究首先建立了单侧6-OHDA损伤黑质多巴胺神经元的帕金森小鼠模型，并验证了帕金森小鼠同时存在痛觉阈值下降、疼痛传导通路过度兴奋和STN神经元放电频率升高的现象。然后，用光遗传学手段抑制STN神经元可显著降低疼痛传导通路的兴奋程度，提高模型小鼠的疼痛阈值。在正常小鼠中，兴奋STN神经元可显著降低疼痛阈值，且通过向SNr和GPi-VP的投射分别调控热痛和机械痛。而在PD小鼠中，通过抑制STN-SNr和STN-GPi/STN-VP投射可分别提高PD小鼠的热痛和机械痛阈值。本研究结果揭示抑制STN神经元或者其下游的特定神经投射可以缓解PD疼痛的不同表型，为提高STN-DBS缓解PD疼痛提供理论依据。