GR-SGK1-Rac1信号通路在慢性痛导致海马突触可塑性再塑中的作用

Chronic pain cannot only result in sensory dysfunction, but can also lead to impairment of cognition and mental diseases. These outcomes induced by chronic pain are associated with the alterations of synaptic plasticity in hippocampus and due to the complexicity of the underlying mechanisms, effective treatment of chronic pain are lack in clinic. As a member of the Rho family of small G protein, Rac 1 has shown to be involved in the regulation of the synaptic plasticity in hippocampus, and the serum and glucocorticoid inducible kinase 1 (SGK1) can interact with Rac 1 and the glucocorticoid receptor (GR), implicating that the Rac1 and the GR signaling pathways may have crosstalk under the mediation of the SGK1. Our preliminary experiments showed that the GR and phosphorylated Rac1were down-regulated in the hippocampus of a neuropathic pain model. Accordingly we hypothesize that chronic pain can cause dysfunction of the HPA axis, thus corticosterone levels in the blood could be increased and lead to the down-regulation of the GR in the hippocampus, which further activated the Rac1 signaling pathway through the SGK1 and resulted in alterations of synaptic plasticity in the hippocampus, and finally lead to alterations of pain-related behaviors, the cognition and the emotion. This proposal plans to use the spinal nerve injury model to test the aforementioned hypothesis with cell and molecular biological, electrophysiological and behavioral assays, and provide experimental evidence for the clarification of the mechanisms underlying chronic pain induced alterations of the synaptic plasticity in the hippocampus and cognitive and emotional disorders.

慢性痛不仅可以造成感觉系统功能障碍，还会导致焦虑、抑郁和认知障碍等精神共病，而突触可塑性再塑的改变是导致慢性痛伴精神共病的主要机制之一。我们前期实验发现，大鼠在神经病理性痛模型建立2周后出现抑郁样表现，皮质酮水平增高，海马区糖皮质激素受体（GR）和Rho家族小G蛋白Rac1蛋白磷酸化水平表达均明显下调；海马突触传递效能减弱，LTP诱出率降低而LTD诱出率增多。据此我们推测慢性痛可引起血中皮质酮水平增高，导致GR表达下调，再通过SGK1介导下调Rac1信号通路，引起海马突触传递效能减弱，最终导致大鼠的痛相关行为、学习认知及精神共病。本项目拟采用大鼠坐骨神经部分结扎的慢性痛模型，探讨GR-SGK1-Rac1信号通路在海马突触可塑性再塑的变化，为慢性痛引起精神共病的发生机制提供新的理论依据，从而为防治该病提供新的靶点。

慢性痛不仅可以造成感觉系统功能障碍，还会导致焦虑、抑郁和认知障碍等精神共病。目前慢性痛临床治疗手段十分有限，突触可塑性再塑的改变是导致慢性痛伴精神共病的主要机制之一。本课题主要采用大鼠坐骨神经部分结扎模型作为慢性痛模型，应用细胞和分子生物学、电生理以及行为学方法研究GR-Rac1信号通路在慢性痛导致海马突触可塑性再塑中的作用。研究发现：1）神经病理性痛大鼠2周、4周出现皮质酮、CRH、ACTH、醛固酮水平增高；2）免疫荧光标记技术检测GR和Rac1在正常大鼠中海马组织中大部分共标，并且都主要分布在胞浆；3）海马区糖皮质激素受体（GR）和Rho家族小G蛋白Rac1蛋白磷酸化水平表达均明显下调；4）免疫共沉淀实验发现GR与Rac1存在相互作用；5）慢性痛大鼠海马突触传递效能减弱，LTP诱出率降低而LTD诱出率增多；6）慢性痛条件下大鼠出现与情绪相关的抑郁样行为表现。本项目通过探讨GR-Rac1信号通路在海马突触可塑性再塑的变化，为慢性痛引起精神共病的发生机制提供新的理论依据，从而为防治该病提供新的靶点。