丘脑底核调节PD皮层--基底节异常HVSs的神经环路机制研究

Pathological synchronous oscillations in the cortex-basal ganglia (BG) loop are potentially causal to motor deficits in Parkinson's disease (PD). High-voltage spindles (HVSs), which exhibit a characteristic spike-and-wave pattern and an oscillation frequency ranging between 5 and 13 Hz, have been reported to widely and abnormally appear in the cortical-BG networks in 6-OHDA lesioned rats. However,little is known about how the abnormal HVSs may change in PD. Synchronous oscillations in the brain mainly determined by neural circuit and single neuron characteristic. Our previous studies confirmed the key role of subthalamic nucleus (STN) in modulation of abnormal HVSs in PD. In PD, the neuronal excitability and firing pattern of STN are changed while it is still unknown how these changes contribute to the abnormal HVSs in the cortex-BG networks. Based on our previous studies, the present study plan to apply optogenetics combing synchronized electrophysiological recordings in freely moving 6-OHDA lesioned rats, to clarify the causality between the changes of neuronal excitability and firing pattern in the STN and abnormal HVSs in cortical-BG networks of PD. And then, to explore the sownstream of STN and dissect the neural circuit underlying the STN modulation on HVSs. Lastly, to verify the target of STN for HVSs modulation by combing with in vivo pahrmacological intervention. This study aim to elucidate the neural circuit of STN for abnormal HVSs modulation in the cortex-BG networks of PD，which is contribute to understand the mechanism of STN-DBS in PD treatment, and will supply new ideas and theoretical basis for the diagnosis and the treatment of PD.

皮层--基底节(BG)环路的异常同步振荡与帕金森病(PD)密切相关，同步振荡异常程度与PD症状轻重呈正相关。异常HVSs是PD皮层--BG环路的一种异常同步振荡活动，机制不明。我们前期研究证实丘脑底核（STN）在PD异常HVSs的调节中起关键作用，PD状态下STN神经元兴奋性及放电模式发生改变，但这些改变是通过怎样的神经环路调节皮层--BG整个环路异常HVSs的尚不清楚。本项目拟利用光遗传学结合自由活动大鼠在体电生理同步记录技术，在6-OHDA PD模型大鼠，明确STN神经元兴奋性及放电模式改变与PD皮层--BG异常HVSs变化的因果关系；探索STN调节异常HVSs的下游核团，解析STN调节HVSs的神经环路构成；结合在体药理学干预，阐明STN投射纤维在下游靶区释放谷氨酸的作用靶点。本项目旨在阐明STN调节PD皮层--BG异常HVSs的神经环路机制，为临床PD的诊治提供新的思路和理论依据。

帕金森病（Parkinson’s disease，PD）是一种中老年人常见的神经系统退行性疾病，临床表现以运动迟缓、肌强直、静止性震颤和姿势反射障碍等为特征。相当多的证据显示皮层-基底节（basal ganglia，BG）环路的异常同步振荡与PD的发病有着直接关系，同步振荡异常程度与PD症状轻重呈正相关。我们前期研究发现异常HVSs是PD皮层--BG环路的一种异常同步振荡活动，丘脑底核（STN）在PD异常HVSs的调节中起关键作用，但其调控的具体神经环路尚不清楚。为此，我们提出假说：PD状态下，STN神经元特性发生改变以及上游突触传递失衡，STN神经元过度兴奋，放电模式发生改变，从而导致皮层--BG 环路出现异常 HVSs。对此，我们利用光遗传学结合自由活动大鼠在体电生理同步记录技术，在6-OHDA PD模型大鼠，我们发现光遗传学抑制STN神经元活动可缓解PD异常HVSs并改善运动不能的症状，表现为异常HVSs个数减少，持续时间缩短，HVSs期间皮层—BG同步性减弱，而光遗传学兴奋STN神经元可加重异常HVSs，表现为异常HVSs个数增加，持续时间延长，HVSs期间皮层—BG同步性增加。在STN下游靶区方面，我们发现STN主要是通过兴奋SNr介导异常HVSs调控作用，进一步结合药理学干预实验，我们明确STN在SNr投射纤维释放谷氨酸主要作用于NMDA受体。此外，我们还发现6-OHDA PD模型大鼠除了出现运动障碍症状，还出现了非运动症状（抑郁），表现为强迫游泳实验不动时间显著长于对照大鼠，而且与异常HVSs的个数正相关，值得进一步深入研究。本课题基本阐明了STN调控PD皮层—BG异常HVSs的神经环路机制，为临床PD的诊治提供新的思路和理论依据。

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