帕金森病大鼠丘脑底核神经元共振特性的变化及其机制研究

Parkinson's disease(PD), a slowly progressive neurodegenerative disorder characterized by motor dysfunction, has become a major public health issue as the proportion of elder increases in the population. Currently, there is no ideal therapy for PD, and additional effective treatments for this devastating disease are urgently needed. To achieve this goal, it is critical to understand its pathogenesis of neuronal dysfunction. Unfortunately, none of the current theories, including the theory of depletion of dopamine, could explain all of the symptoms in PD. With the emergence of new techniques, studies have shown that temporally and spatially organized activity among distributed neuronal populations often takes the form of synchronous oscillations. These synchronous oscillations may evolve to dynamically control the grouping of neurons into organized assemblies. It is well known that the abnormal synchronous oscillatory activity in cortical and basal ganglia networks has become the major electrophysiological mechanisms underlying the symptoms in PD. Recent research has revealed a close association between electrical oscillations in neural networks and resonance in neurons. Resonance is the ability of neurons to respond selectively to inputs at preferred frequencies, which can serve as a substrate for coordinating network activity around a particular frequency..The results of our studies have shown that there is a θ-frequency resonance mediated by hyperpolarization-activated cation current(Ih) in subthalamic nucleus (STN) neurons, and the resonance mediates a frequency-selective coupling between inputs and firing. So we hypothesis that abnormal synchronous oscillatory activity in basal ganglia networks，which results in symptoms of PD and the change of sensitive frequency of STN nucleus, was induced partly by the variances of resonance property of STN neurons in PD. In order to verify the hypothesis and reveal the mechanism underlying the symptoms of PD , we should investigate the variances of resonance property of STN neurons in the model of PD on rats and brain slices of rats by whole-cell patch-clamp recordings, and try to explore their possible ionic mechanisms. In addition，the relationship between Ih and resonance of STN neurons would be explored after stereotaxic injection into the STN of adeno-associated virus carrying an HCN2 subunit expression construct. This investigation is very urgent，because we would possibily make an important medical breakthrough in the research on pathogenesis of PD.

多巴胺单向调节学说是解释帕金森病(PD)发病机理的经典理论，但该学说无法解释PD的所有症状，文献和我们的研究均表明基底节-皮层环路的异常同步振荡是导致PD症状的电生理基础。单个神经元的共振是实现神经网络同步振荡的基础，我们已证实丘脑底核(STN)单个神经元存在由超极化激活的阳离子流（Ih）介导的共振现象。故提出假设：PD时STN神经元的共振特性可能会改变，导致神经元、核团的敏感频率变化，进而导致基底节-皮层环路异常同步振荡，产生PD症状。本课题拟分别在大鼠动物及脑片水平复制PD模型，利用膜片钳技术研究PD大鼠STN神经元共振特性及Ih的改变，分别明确多巴胺1、2型受体阻断剂对STN神经元共振的影响及其机制，用腺病毒将Ih通道（HCN2）的基因导入神经元，探索Ih和PD大鼠STN神经元共振的关系，以期揭示PD异常振荡的形成机制，有可能在PD的病理机制上有所突破，为PD的治疗提供新靶点。

基底节皮层环路的异常同步振荡是PD的电生理基础，HVSs节律是PD基底节皮层环路异常振荡的主要节律之一，神经元共振是神经网络振荡活动的基础。我课题组前期研究发现HVSs节律与多巴胺D2受体(非D1受体)关系密切，并证实STN神经元存在共振现象。本课题证实了HCN2介导的Ih介导了STN神经元的共振，多巴胺D2受体(非D1受体)阻断剂通过阻断多巴胺对GPCRs的作用，抑制HCN2介导的Ih，进而影响STN神经元共振的。HVSs与STN神经元的共振频率处于同一频段，二者均由HCN2介导的Ih介导，且均受多巴胺D2受体调节。抑制正常大鼠STN局部HCN2通道表达，导致了大鼠HVSs节律过度活动，并引起动物类似PD的行为学改变。增强STN局部HCN通道活性，可显著减轻PD大鼠HVSs节律过度活动，改善基底节皮层环路的异常振荡。上述结果证实了我们先前提出的假说，PD条件下，多巴胺缺失，对D2受体(非D1受体)作用减弱，STN神经元HCN2通道表达下降，Ih电流受到抑制，使STN神经元共振特性改变，影响STN放电的频率选择性，导致皮层、基底节 HVSs节律过度活动，产生基底节皮层环路的异常振荡，进而导致PD症状。揭示了PD病理状态下异常振荡的形成机制，并为PD的治疗提供新靶点。发表SCI论文2篇，其中IF大于5分1篇。