星形胶质细胞特异性CB1受体-2型纤维母细胞生长因子参与中枢神经系统次声损伤的机制研究

Long-term exposure to infrasound impairs the function of central nervous system (CNS), possibly through the “cross-talk” between astrocytes and neurons. However, the mechanisms remain unclear. The cooperation between cannabinoid receptor 1 (CB1R) on the membrane of astrocytes and fibroblast growth factor 2 (FGF2) released by astrocytes participate in the modulation of neuronal plasticity and function. In our previous studies, long-term exposure to infrasound impaired the ability of learning and memory by activation of astrocytes, increase of neuronal apoptosis and reduction of CB1R expression in rat hippocampus. Therefore, we proposed the hypothesis that neuronal endogenous cannabinoids modulate the astrocytic synthesis and release of FGF2 through CB1R. Exposure to infrasound interrupts CB1R-FGF2 signaling and results in the impairment of CNS plasticity and function. In this project, the expression levels of CB1R and FGF2 in the hippocampus will be investigated after infrasound exposure by immunohistochemistry and microdialysis. In addition, neural plasticity and cognitive function will be investigated by three-dimensional remodeling cellular morphology and behavioral experiments. The involvement and the molecule mechanisms of astrocyte specific CB1R-FGF2 signaling in infrasound-induced CNS injury will be investigated by using astrocytes-specific CB1R knocking-out animal, neuropharmacological and molecular biological experiments. This work will provide new insights into the protective strategy and therapeutic target against infrasound-induced CNS injury.

次声暴露通过神经元-胶质细胞交互作用损害中枢神经系统（CNS）功能，但其机制不清。星形胶质细胞表面大麻素受体1（CB1R）和星形胶质细胞合成的2型纤维母细胞生长因子（FGF2）协同参与神经元-胶质细胞交互作用，影响神经可塑性及功能。我们的前期研究发现次声激活海马星形胶质细胞，增加神经凋亡并下调CB1R表达，导致学习记忆障碍。综上我们提出：神经元释放的内源性大麻素配体，通过CB1R调节星形胶质细胞合成FGF2，进而调控神经可塑性及功能，而次声通过干扰星型胶质细胞CB1R-FGF2通路损害CNS功能。本课题拟应用免疫组化、微透析、三维重塑形态学、行为学等方法探讨次声对海马CB1R和FGF2表达、神经可塑性及认知功能的影响；应用特异敲除星形胶质细胞CB1R动物、神经药理和分子生物学方法，探讨星形胶质细胞CB1R-FGF2通路参与次声损伤的分子机制。本研究可望为次声损伤CNS的防护提供治疗靶点。

次声频率介于0.0001-20Hz，可引起中枢神经系统损伤。本课题组既往发现，高强度次声暴露引起海马胶质细胞活化、细胞因子水平升高和神经元丢失，提示炎症反应是次声引起学习记忆障碍的重要原因。然而，尚不清楚次声暴露引起海马炎症损伤的具体机制。. 本项目发现：高强度次声暴露后，①海马神经元及星形胶质细胞形态、数量均出现变化，神经元表达大麻素受体1（CB1R）减少，星形胶质细胞表达成纤维细胞生长因子受体1(FGFR1)减少。②海马星形胶质细胞激活，TNF-α、IL-1β、IL-18、IL-6、IFN-γ等炎性因子水平升高。③活化FGF2-FGFR1通路可抑制次声引起的海马炎性反应，减少神经元丢失；抑制FGF2-FGFR1通路，可加重次声引起的海马炎性反应，加重神经元丢失。④活化FGF2-FGFR1通路，可抑制高强度次声暴露后IκBα的磷酸化及p65入核，降低培养液上清中TNF-α、IL-1β、IL-18、IL-6、IFN-γ等炎性因子的水平，减少神经元丢失；抑制FGF2-FGFR1通路加重高强度次声暴露后的炎症损害，增加神经元的丢失。⑤CB1R抑制剂不影响FGF2-FGFR1通路活化对高强度次声暴露后星形胶质细胞炎症反应的保护作用。⑥活化FGF2-FGFR1通路可抑制反应性星形胶质细胞向A1亚型转化，抑制FGF2-FGFR1通路具有相反作用。. 综上，高强度次声暴露可抑制FGF2-FGFR1通路，促进星形胶质细胞IκBα磷酸化、p65核转位和促炎因子的释放，促进星形胶质细胞活化并向反应性星形胶质细胞向A1亚型转化，并加重神经元损伤。活化FGF2-FGFR1通路可减轻高强度次声暴露引起的海马炎性反应，此种保护作用不依赖于CB1R。本研究提示FGF2-FGFR1通路是次声暴露后神经损伤治疗的潜在靶点，FGFR1特异性抑制剂PD173074有希望成为次声暴露后神经损伤的防治药物。

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