左旋多巴诱导的异动症大鼠纹状体促甲状腺激素释放激素调节基底节运动环路脑网络连接的研究

Levodopa induced dyskinesias (LID) is a common motor complication of advanced parkinson's disease (PD), and represent one of the major problems in the dopaminergic administration with Parkinson's disease, seriously disabling the treatment effect and the quality of life, but the pathogenesis remain unknown. Dopamine denervation and dopamine replacement therapy is attributed a key role in the development of LID, although the relative contribution of different potential mechanisms has not been established. It has been known that LID is related with abnormal basal ganglia motor circuit activity caused by striatal direct-pathway medium spinal neurons (dMSNs) adaptive molecular changes and sustained over-activation. Our study indicated that the positive feedback loop might be formed among TRH, ERK1/2 and ΔFosB in dMSNs, and led to the sustained activation of the direct pathway, and inhibiting TRH might inhibit the abnormal electrical activity of striatum and motor cortex in LID rats. Therefore, we hypothesize that the positive feedback loop formed among TRH, ERK1/2 and ΔFosB lead to persistent activation of the striatal dMSNs and change the activation of the basal ganglia motor circuit (brain network connectivity) leading to the development of LID. In this project, It will be explored the dynamic evolution of basal ganglia circuit brain network (structural network and functional network) during LID development and its mechanisms by using the 6-OHDA damaged LID rat model in combination with the functional MRI and electrophysiology techniques and the dynamic changes of intracellular TRH-ERK1/2-ΔFosB, which will clear molecular mechanisms of basal ganglia network evaluation of LID rats. The project will be ultimately helpful to early diagnosis and treatment of LID.

左旋多巴诱导的异动症(LID)是进展期帕金森病（PD）的常见运动并发症。研究表明直接通路纹状体GABA能中型棘状投射神经元（dMSNs）持续过度活化，使基底节皮质运动环路活动异常导致LID发生。我们的研究发现促甲状腺激素释放激素（TRH）可能通过与ERK1/2和ΔFosB形成正反馈环路维持dMSNs持续过度活化；且抑制TRH可以抑制纹状体和运动皮质的电活动改变。因此我们推测TRH通过与ERK1/2和ΔFosB形成正反馈环路使dMSNs持续活化改变了基底节皮质运动环路活动（脑网络连接）导致LID发生发展。本项目拟用6-OHDA损毁PD大鼠模型，结合功能磁共振和电生理技术，动态研究TRH与ERK1/2和ΔFosB形成的正反馈环路对LID基底节皮质运动环路脑网络连接的影响及其分子机制，为LID的早期诊治提供理论依据。

研究背景：左旋多巴诱导的异动症(LID)是长期左旋多巴治疗后进展期帕金森病（PD）的常见运动并发症，其治疗棘手，严重影响进展期帕金森病患者的治疗效果和生活质量。研究表明直接通路纹状体GABA能中型棘状投射神经元（dMSNs）持续过度活化，使基底节皮质运动环路活动异常导致LID发生。但是dMSNs持续过度活化的机制不明。.研究内容：我们使用6-羟基多巴胺PD大鼠模型和反复左旋多巴治疗后LID大鼠模型研究LID发生、发展过程中TRH、p-ERK1/2、FosB-ΔFosB等相关信号分子表达以及三者之间的相互影响，阐述TRH 是否通过与 ERK1/2 和 ΔFosB 形成正反馈环路使 dMSNs 持续活化；另外观察PD大鼠和LID大鼠皮质纹状体电活动，研究TRH对PD和LID大鼠皮质纹状体神经元放电的影响；进一步通过大鼠磁共振技术结合分子生物学方法研究LID发生、发展过程中皮质基底节环路活动改变的结构基础及其机制：最后我们初步探索了早期未用药帕金森病患者临床特征和脑网络连接的改变，研究未用药的早期帕金森病患者静息态功能磁共振的变化及其与临床特征的关联性。.研究结果：过表达FosB可以显著增加TRH的表达，p-ERK1/2可以正向调控ΔFosB与TRH，TRH通过正向调控ERK1/2磷酸化与ΔFosB的表达而参与LID的发生与发展，验证了我们的假说：TRH 通过与 ERK1/2 和 ΔFosB 形成正反馈环路使 dMSNs 持续活化，导致皮质-纹状体电活动异常和LID的发生。左旋多巴治疗可以导致LID大鼠脑结构的动态改变-病变侧纹状体体积进行性增加，其结构和电生理的变化与星形胶质细胞增生、炎症反应、突触超微结构和突触相关蛋白的富集有关。未用药的早期PD患者脑连接存在明显改变，主要累及躯体运动网络、深部灰质网络、边缘网络和视觉网络。上述异常脑连接可能与早期PD的运动症状和非运动症状有关。.科学意义：我们的研究阐明了TRH 通过与 ERK1/2 和 ΔFosB 形成正反馈环路使 dMSNs 持续活化和皮质纹状体电活动异常，揭示了LID发生、发展的结构基础及其机制，打断该正反馈环路可能阻止LID的发生发展，为开辟新的LID的治疗途径提供理论依据。