前扣带回皮层后段深层（Cg2）谷氨酸能神经元在痛觉调制中的作用及环路机制研究

目前临床对疼痛，特别是对神经病理性疼痛的管理还存在很多挑战。充分认识痛觉调制系统的结构与功能有助于发现新的镇痛靶点。前扣带回皮层（ACC）在疼痛时被激活，但在痛觉调制中的作用尚未明确。课题组预实验发现，用光遗传学方法选择性激活ACC后段深层（Cg2）的谷氨酸能神经元能提高动物对机械刺激的痛觉感受阈值，减轻福尔马林引起的疼痛反应，对神经病理性疼痛的感觉成分也有抑制作用。病毒顺行追踪发现这些神经元投射到未定带（ZI）和中脑导水管中央灰质（PAG）的特定区域。本研究拟充分利用光遗传学技术，结合电生理学、药理学、组织化学、行为学等方法，研究和阐明选择性激活或抑制ACC后段Cg2谷氨酸能神经元对急性疼痛和神经病理性疼痛的感觉和情绪成分的调制作用，以及至ZI和PAG 的神经环路在其中的作用机制。本研究将为深入理解不同疼痛状态下ACC在痛觉调制中的作用和环路基础并发现新的药物镇痛靶点提供可靠的实验证据。

There are many challenges in the clinical management of pain, especially of neuropathic pain. More complete understanding of the structure and function of pain modulation system is of significance to the development of new analgesic targets and strategy. Anterior cingulate cortex (ACC) is activated at the presence of pain, but it’s roles in pain modulation are under debate, largely due to the heterogeneity of previous studies. Our pilot study revealed that selective activation of glutamatergic neurons in deeper layer (Cg2) of the caudal part of ACC (cACC) by optostimulation increased the nociceptive threshold to mechanical stimulation and inhibited the pain responses in the formalin test in mice. Of interest, this treatment seemed to attenuate sensory component of neuropathic pain following partial sciatic nerve ligation injury. Antegrade tracing by adeno-associated virus found that these neurons emit projections to certain subregions of zona incerta (ZI) and periaqueductal gray matters (PAG). In order to elucidate the roles of these neurons in pain modulation and the related neural circuitry, the present study plans to investigate the influence of selective manipulation of the activity of glutamatergic neurons in Cg2 of cACC on nociceptive pain and sensory and aversive components of neuropathic pain, by using optogenetics combining methods such as behavioral tests, electrophysiology, pharmacology and so on. Moreover, the functional relationship between the glutamatergic projections of these neurons and neurons in the ZI and PAG will be studied with multidisciplinary methodology, and the roles of these projections in pain modulation, including of nociceptive pain and neuropathic pain, will be examined systemically. This study will provide more knowledge about the pain modulation system under different painful conditions and will be helpful for the findings of new analgesic targets.