神经病理性疼痛引起视觉皮层神经可塑性改变及其机理的研究

Blind individuals usually have sharper tactile and hearing ability than non-blind people. Therefore, loss of a sensory modality leads to widespread changes in synaptic function across sensory cortices, which are thought to be the basis for cross-modal adaptation. Nearly 70% of chronic pain patients suffer from deficits in working memory and damage in attention, which is important for working memory formation. Whether the long-term chronic pain can induce cross-modal plasticity in visual and auditory cortices are still unknown. Our current data showed that in the mice which were undertaken neuropathic pain induced by SNI and CCI, the mEPSC and mIPSC recorded in cells from layer 2/3 changed not only in the pain-related sensory cortices but also in visual and auditory cortices. Moreover, the vision in awake animals suffered from neuropathic pain was impaired. Therefore we hypothesize that cross-modal modification of cortical neural networks in the auditory, visual cortex and somatosensory cortices occurs after chronic neuropathic pain. Dual whole-cell recording will be used to probe the synaptic efficacy with regard to glutamatergic and GABAergic transmission in different sensory cortices. Findings will be reinforced by Western blot analysis for changes in the specific receptor subunits in postsynaptic density fractions. The LTP/ LTD will be studied in different pathways among these sensory cortices to find out through which inputs the chronic pain generated in somatosensory cortex affects the plasticity in visual cortex. Moreover, the molecular mechanism underlying this cross-modal plasticity will be also investigated. Finally, we will examine whether the cross-modal modification of neural activities in visual cortex could be prevented by up-regulation of intracortical inhibition, induced by the injection of diazepam. Taken together, these will provide insight on how cortical neural substrates are selectively modified after chronic neuropathic pain. Our data may further understanding on cross-modal modification among cortices and provide insight on how to selectively maintain visual function in patients suffered from neuropathic pain.

盲人具有较强的触觉和听觉功能，单个感觉皮层通常和其它感觉皮层相互作用，呈现皮层跨模态可塑性。慢性疼痛患者常伴有注意力下降，工作记忆受损。为了研究慢性疼痛是否引起不同感觉皮层间的跨模态可塑性，近期研究发现：SNI和CCI的神经病理性疼痛模型小鼠，不仅体感皮层S1区和前扣带回（ACC）第2/3层细胞的mEPSC振幅和频率都较对照动物上调，视皮层和听皮层上mEPSC也出现振幅的上调，但mIPSC 振幅却下调，清醒状态下动物的视觉功能改变，提示神经病理性疼痛导致视、听皮层内部神经突触可塑性的改变，但其生理机制不明。本课题将进一步用分子生物学、电生理学和双光子Ca2+成像的方法研究由神经病理性疼痛导致的视皮层可塑性改变的生理机制，并探讨干预由慢性疼痛引起的视皮层功能改变的可能措施。该研究为临床上神经病理性疼痛的病人提供通过选择性的保护视皮层内部神经环路来调整皮层功能的实验依据。

长期的神经病理性疼痛可导致神经系统的结构和功能异常，但目前其对视觉皮层功能的影响却鲜有报道。我们之前的研究发现SNI模型小鼠视觉皮层2/3层锥体神经元mEPSC振幅升高而mIPSC振幅不变，但具体机制未明。本课题进一步采用电生理、双光子钙成像、在体单细胞记录等方法，研究神经病理性疼痛对小鼠视皮层可塑性以及视觉功能的影响，并探讨了其中的内在机理，得到以下结论：.1.SNI模型小鼠视皮层2/3层锥体神经元兴奋性突触传递增强。通过电生理研究发现，SNI模型小鼠视皮层2/3层锥体神经元mEPSC振幅增大，AMPA电流增大而GABA电流不变，导致兴奋/抑制（E/I）平衡倾向于兴奋转变，神经元兴奋性增强。以上说明SNI导致小鼠视皮层可塑性改变；.2. SNI模型小鼠视皮层2/3层锥体神经元方向、方位选择性受损。通过在体双光子钙成像以及在体单细胞记录研究发现，首先SNI模型小鼠视皮层2/3层锥体神经元自放放电频率升高，与电生理得出兴奋性增强结果一致，其次SNI导致小鼠OSI、DSI减小，降低其对水平、垂直方位的选择性。以上说明SNI可能导致小鼠视觉功能改变；.3.中缝核的五羟色胺（DRN 5-HT）神经元参与SNI模型小鼠视皮层可塑性及其功能改变。通过电生理研究发现，DRN 5-HT能神经元投射到视皮层2/3层锥体神经元，5-HT通过锥体细胞上的5-HT1A受体引起超极化的抑制作用。由于SNI模型小鼠DRN 5-HT能投射系统受损，对视皮层2/3层锥体神经元抑制性减弱，导致其兴奋性增高。化学遗传兴奋SNI模型小鼠DRN 5-HT能投射系统，恢复其视皮层2/3层锥体神经元兴奋性，以及方向、方位选择性。这些结果说明DRN 5-HT能神经元通过5HT-1A受体参与SNI模型小鼠视皮层可塑性以及视觉功能改变。