卒中后疼痛（CPSP）是脑卒中引起的最常见中枢性疼痛，缺乏有效治疗，严重影响患者卒中后康复与生活质量。CPSP的发病与中枢去抑制、中枢敏化及感觉失衡有关，但具体分子机制不明。我们前期工作表明，死亡相关蛋白激酶1（DAPK1）是介导卒中后神经元死亡的关键分子，敲除DAPK1基因或外源性阻断DAPK1死亡信号，不仅可以减轻脑缺血损伤，也能缓解CPSP。本项目拟在此基础上，运用转基因小鼠局灶性皮层缺血CPSP模型，结合病毒示踪、光遗传学、电生理以及痛行为学检测方法，检测皮层丘脑投射纤维DAPK1与下游底物的相互作用、皮层丘脑投射与丘脑网状结构TRN神经元突触损伤、TRN神经元兴奋性与GABA递质释放、丘脑腹侧基底部VB神经元兴奋性。本研究将揭示缺血性卒中后DAPK1死亡信号通过损伤皮层-丘脑TRN神经元-丘脑VB神经元环路引起CPSP的机制，为临床治疗CPSP提供新策略。

Central post-stroke pain (CPSP) is the most common central pain caused by cerebral stroke and seriously affects the patients’ post-stroke rehabilitation and quality of life. So far, there is no effective treatment for CPSP. It has been suggested that the pathogenesis of CPSP is associated with central disinhibition, central sensitization and sensory imbalance, but the specific molecular signaling pathways and neural circuits are still not fully elucidated. Our previous work demonstrate that Death Associated Protein Kinase 1 (DAPK1) is a key molecular mediates neuronal death in ischemic stroke, and the development of CPSP relied on the damage of cortex-thalamic projecting neurons by cerebral ischemia induced DAPK1-tau death signaling. DAPK1 gene knockout or exogenous blocking DAPK1 death signal can not only relieve cerebral ischemic injury, but also alleviate CPSP. Based on the previous work, the proposed study will use genetically modified mice to perform focal cortical ischemia induced CPSP mice model, combined with applying neural tracing, optogenetics, electrophysiological recording and pain behavior detection methods, we will study the interaction of DAPK1 with downstream substrate in the cortical-thalamus projecting fibers, DAPK1 signaling dependent cortex-thalamic reticular neuronal (TRN) synapse injury, TRN neuronal excitability, the releasing of GABA neurotransmitter, thalamic ventral basal (VB) neuronal excitability. We will recover that cerebral ischemia induced DAPK1 death signaling promotes the injury of cortex-thalamic TRN-thalamic VB neuronal circuit and finally produce CPSP. Our study will further replenish the central disinhibition theory of CPSP, and provide new idea and strategy for the clinical treatment of CPSP.