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

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。

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.