脑深部电刺激调控帕金森病异动症的皮层-纹状体中型多棘神经元突触可塑性机制

Levodopa induced dyskinesia（LID）is a common disabled drug complication in the patients with advanced Parkinson disease (PD). Deep brain stimulation of the internal globus pallidus(GPi-DBS) has already been established as the most effective surgical therapy for LID in refractory PD.However,the mechanism of GPi-DBS still not fully clarified. Recent studies have showed that maladaptive corticostriatal synaptic plasticity may play an important role in the pathophysiological mechanism of LID. Our previous study has found that abnormal theta band(5-8 Hz) oscillations existed in cortico-basal circuitry associated with LID in PD rat model. Hence, whether GPi-DBS can adjust synaptic plasticity of cortico-basal ganglionic loop for the treatment of LID? There is still lack of relevant studies. Fluorescence imaging, virus tracking, nerve tracing, multi-channel chronic neuronal recording, patch clamp and immunohistochemistry methods will used in this study to survey underlying synaptic plasticity mechanism for corticostriatal medium spiny neurons (MSNs) by GPi-DBS on the rat model of LID, including maladaptive synaptic plasticity of neuronal structure and conduction in different subtypes MSNs. This study will further produce evidences involved with maladaptive synaptic plasticity in neuronal structure and conduction to explain the effects of GPi-DBS on LID, in order to optimize the therapeutic target, parameter setting of DBS and drug development in moderating maladaptive synaptic plasticity.

左旋多巴诱导异动症（LID）是晚期帕金森病（PD）患者致残性服药并发症，苍白球内侧部脑深部电刺激（GPi-DBS）是目前临床上治疗合并LID的难治性PD最直接、有效的外科术式，但其作用机制尚未明确。有研究提示皮层纹状体突触结构、功能可塑性异常在LID发病中起重要作用，我们前期研究发现LID大鼠皮层-纹状体-黑质网状部环路存在异常θ带（5-8Hz）振荡电活动，GPi-DBS是否通过调节皮层纹状体突触可塑性来治疗LID，目前尚无相关研究。本研究拟在LID大鼠模型基础上,利用神经示踪，荧光成像，慢性多通道神经元记录，膜片钳及免疫组化方法，观察GPi-DBS治疗后皮层纹状体不同亚型中型多棘神经元突触结构以及功能传递的可塑性变化，寻找GPi-DBS治疗LID在皮层纹状体突触结构、功能传递变化规律，以此探讨GPi-DBS治疗LID的作用机制，为优化DBS治疗靶点、参数设置，以及药物开发提供研究依据。

项目背景：左旋多巴诱导异动症（LID）是晚期帕金森病（PD）患者致残性服药并发症，苍白球内侧部脑深部电刺激（GPi-DBS）是目前临床上治疗合并LID的难治性PD最直接、有效的外科术式，但其作用机制尚未明确。GPi-DBS是否通过调节皮层纹状体突触可塑性来治疗LID，目前尚无相关研究。.主要研究内容: 本研究在稳定的LID-PD大/小鼠模型基础上，通过catwalk步态分析、在体多通道系统、膜片钳技术及免疫组化技术探究在依托拉嗪以及GPi-DBS干预下LID-PD模型皮层-基底节环路以及背外侧纹状体中型多棘神经元（MSN）突触可塑性变化。.重要结果: 1）慢性依托拉嗪应用可降低LID-PD大鼠静止期SNr-M1的θ震荡活动,同时降低 LID-PD大鼠对多巴胺能激动剂的反应时间以及改善其异动症行为；2）慢性依托拉嗪应用可降低LID小鼠AIMs评分，且引起背外侧纹状体MSN突触可塑性改变及细胞外因子信号变化；3）慢性GPi-DBS干预LID大/小鼠可改善其异常步态，且背外侧纹状体MSN神经元发生可塑性改变，改善异动症的发生发展。.科学意义: 本研究通过探索慢性药物和GPi-DBS治疗后LID模型的皮层纹状体不同亚型MSN突触结构以及功能传递的可塑性变化，寻找GPi-DBS治疗LID在皮层纹状体突触结构、功能传递变化规律，以此探讨GPi-DBS治疗LID的作用机制，为优化DBS治疗靶点、参数设置，以及药物开发提供研究依据。