SHH 通路在丰富环境调节神经病理性痛海马突触可塑性中的作用及机制

神经病理性疼痛(neuropathic pain,NP)可诱发焦虑/抑郁，这可能与海马可塑性受损有关。丰富环境可调节海马可塑性改善疼痛/抑郁共患，但其机制仍不清楚，阐明丰富环境的作用靶点有助开发新的疾病治疗方法。Sonic Hedgehog(SHH)通路参与神经发育、海马突触可塑性和外周痛敏。预实验发现丰富环境可上调海马GLI1和BDNF的表达，细胞实验提示ADAM17可能参与SHH通路对BDNF的调节。因此提出丰富环境可通过SHH通路调节BDNF表达影响海马可塑性的假说。本课题拟在前期基础上，以SHH通路功能研究为突破口，利用病毒转基因和电生理学综合形态学、分子生物学、行为学等技术从分子、细胞和功能水平系统阐明SHH通路参与丰富环境调节NP海马可塑性的分子基础，探索调控的关键信号分子及其与BDNF表达关系，为临床NP治疗提供新的治疗思路和靶点，并为丰富环境干预的临床转化提供理论依据。

Neuropathic pain (NP) could induce anxiety and depression, which may be related to impairment of hippocampal synaptic plasticity. Environmental enrichment intervention can improve hippocampal plasticity and ameliorate pain/depression comorbidity. However, the molecular mechanism is not yet clear. Therefore，it is worthy to illustrate the intrinsic molecules involved in regulating nervous system by environmental enrichment and will help to develop new treatment strategy for neuropsychiatric disorders. The Sonic Hedgehog (SHH) pathway is an important pathway involved in neurodevelopment, hyperalgesia and hippocampal synaptic plasticity. Previous experiments showed that environmental enrichment could up-regulate the expression of GLI1 and BDNF in hippocampus of NP rats. Subsequent cellular experiments suggest that ADAM17 may participate in the modulation of BDNF by SHH pathway. Therefore, it is supposed that environmental enrichment may regulate the expression of BDNF through SHH pathway and modulate hippocampal plasticity in NP rats. So, on the basis of previous work and the SHH pathway as a breakthrough, this project is designed to illustrate the role of SHH pathway involved in environmental enrichment and hippocampal synaptic plasticity in neuropathic pain by using of virus transgenic technology and electrophysiological recording as well as morphology, molecular biology, behavior methods from molecular, cellular and systemic level to find out the key signaling molecules. It may offer new treatment strategy and targets for clinical treatment of neuropathic pain, as well as providing theoretical basis for the application of environmental enrichment in clinic.