神经病理性痛状态下前扣带皮层动作电位时间准确性发放改变的突触传递机制研究

Primary injury or dysfunction in the nerve system will cause neuropathic pain, which is not well been treated in our society. Our previous results showed that the temporal precision of action potentials firing in the anterior cingulate cortex was decreased under neuropathic pain condition, the blocking of the activities of GABAA receptors, AMPA receptors and NMDA receptors erased the difference of the temporal precision between the sham and nerve injury group, suggesting that the synaptic transmission is one of the key factor for the temporal precision change under neuropathic pain condition. However, how the different kinds of receptors were involved in was unclear. Our results on the chronic inflammatory pain animal model showed that temporal precision was related to the kinetics of excitatory synaptic transmission, while the AMPA receptors and NMDA receptors showed a quite big difference on the channel kinetics, which shed a light that the AMPA receptors and NMDA receptors may have different effects on the temporal precision of action potentials firing in the ACC. In the current study, we proposed to investigate the contributions of the inhibitory synaptic transmission, mediating by GABAA receptors, the excitatory synaptic transmission, mediating by AMPA receptors and NMDA receptors to the temporal precision change under neuropathic pain condition, we then will further study whether the AMPA receptors and NMDA receptors have different effects on the temporal precision change of action potentials firing, and the dendritic temporal integration change under neuropathic pain condition. The results will help to understand the neuronal mechanism of neuropathic pain. And it will provide the most important supports to understand the electrophysiological function of temporal precision of information coding in the central nerve system.

神经系统原发性损伤或功能障碍会引起神经病理性疼痛。研究结果显示，外周神经损伤引起前扣带皮层动作电位发放的时间准确性降低; 同时阻断GABAA受体、AMPA受体、NMDA受体的活动，动作电位发放的时间准确性改变回复正常状态，提示突触传递是重要影响因素。但是，不同受体的作用是否相同目前还不清楚。已有的数据显示，慢性炎症性痛状态下动作电位发放的时间准确性和兴奋性突触传递及其动力学特征有关。AMPA受体和NMDA受体的动力学特征显著不同，提示它们对动作电位发放的时间准确性影响可能不同。本课题将首先确定神经病理性痛状态下GABAA受体、AMPA受体和NMDA受体对动作电位发放的时间准确性的影响，在此基础上研究AMPA受体、NMDA受体对动作电位发放时间的影响差异及其内在时间性整合规律。实验结果将为理解神经病理性痛的中枢神经生物学机制提供重要理论补充。

本课题结合电生理、光遗传学及药理学技术研究外周神经损伤后前扣带皮层神经元动作电位的时间准确性发放特征的改变，并结合数学模拟及电生理技术，研究神经微环路水平，动作电位发放的时间准确性与多神经元发放同步性的关系。实验结果发现，外周神经损伤后，前扣带皮层兴奋性神经元动作电位的时间准确性发放发生显著改变，表现为时间准确性发放变差，阻断GABAA受体的活动后，不影响时间准确性，阻断AMPA 受体、NMDA 受体介导的突触传递对动作电位时间准确性发放有显著的影响，表现为对照组和实验组之间的差异消失。在丘脑内背核表达AAV2/8-CamkⅡα-ChR2-eGFP后，在前扣带皮层给与蓝光刺激，可以记录到兴奋性突触传递，而且，兴奋性突触传递和动作电位发放之间的时间，可以发现，兴奋性突触传递对动作电位发放的时间准确性有显著影响。用模拟数据研究时间准确性和微环路内神经元动作电位发放同步性的关系，我们发现，用神经元动作电位的时间准确性发放可以预测群体神经元的同步性发放，时间准确性高，则群体神经元的发放动作电位的同步性高。群体神经元发放的同步性进一步影响突触传递的动态特征，从而影响其支配神经元的动作电位发放效率。实验结果为理解神经病理性痛的中枢机制提供了新的思路。为理解神经微环路内时间尺度的信息整合提供了重要信息。本项目支持下，目前已发表SCI文章两篇，和疼痛的专业著作中的一个章节。培养研究生3人。