下丘脑后核-腹侧被盖区谷氨酸能神经环路调控神经病理性疼痛的细胞及分子机制研究

慢性疼痛已成为严重危害人类健康的常见临床病症之一，但其发生机制尚不清楚。我们前期研究发现，中脑腹侧被盖区多巴胺能神经元活性的异常适应性变化在介导慢性疼痛中发挥重要作用。文献显示，下丘脑后核发出大量谷氨酸能纤维支配腹侧被盖区，因此我们提出：下丘脑后核及其下游投射脑区腹侧被盖区构成的谷氨酸能神经环路可能参与介导了慢性疼痛的发生和维持。本项目将综合利用光遗传学、化学遗传学、投射选择性电生理记录以及逆向-翻译核糖体亲和纯化等先进的神经科学技术结合病毒学工具和转基因动物，在慢性坐骨神经结扎诱发的神经病理性疼痛模型上，系统研究该环路在慢性疼痛调控中的作用，及其相关细胞和分子机制，以为临床治疗学的突破（如深部脑刺激技术）和新型药物研发提供神经生物学依据。

Chronic pain has become one of the most common clinical conditions that seriously threaten human health. However, the mechanism of chronic pain is not clear yet. Our previous studies have demonstrated that the maladaptation of ventral tegmental area (VTA) dopaminergic neurons play important role in chronic pain modulation. In addition, it is reported that posterior hypothalamic nucleus (PH) sends a substantial glutamatergic projection to the VTA. Based on these pieces of evidence, we hypothesize that the glutamatergic neural circuit between PH and its projection targets VTA is involved in the induction and maintenance of chronic pain. Here, utilizing advanced neuroscience technologies, such as optogenetics, chemogenetics, projection selective electrophysiological recording and retro-translating ribosome affinity purification, combined with viral tools and transgenic animals, we will investigate the role of PH-VTA glutamatergic circuit in chronic pain regulation and related cellular and molecular mechanisms in a chronic constriction injury (CCI) induced neuropathic pain model. We expect our research will provide neurobiological evidence for the breakthrough in clinical therapies (such as deep brain stimulation), and provide new targets for the development of ideal analgesics.