小胶质细胞CX3CR1信号通路在热习服改善海马神经发生减轻电磁辐射诱导的抑郁样神经行为中的作用及机制研究

Electromagnetic fields (EMF) exposure could initiate the central neverous system (CNS) injury. But the mechanism is not so clear and it is hard to prevent. Our recently studies found that heat acclimation (HA) attenuates depressive behavior, this protective linked to potential effects on hippocampal neurogenesis. Considering the expression of M2 active marker CX3CR1 and the linkage of neurogenesis in M2 activation of microglia induced by HA, we hypothesis that CX3CR1 is robustly induced in HA-activated M2 microglia, leading to hippocampal neurogenesis, and thus ameliorate depressive behavior following EMF exposure. To validate this assumption, we plan to study: (1) The relationship between the enhancement of hippocampal neurogenesis and the amelioration of depressive behavior in HA-activated M2 microglia following EMF exposure. (2) CX3CR1, as a pivotal microglial M2 marker, have a potential protective role in the regulation of HA on EMF-impared hippocampal neurogenesis. (3) The mechanism of CX3CR1 pathway regulate the secretion IGF-1 and BDNF in the attenuation of depressive behavior. This study could explore the mechanism of neuroprotection of HA against EMF-induced nerve injury, and provide a effective and feasible method to protect occupational population against EMF injury.

电磁辐射（EMF）具有神经行为损伤效应，但机理不明，且难于防护。课题组前期研究发现：热习服可减轻EMF诱导的抑郁样行为，并可能与其调节海马神经发生有关。由于热习服可诱导小胶质细胞M2型活化，而CX3CR1又是小胶质细胞M2型活化分子标志物，与神经发生密切相关。据此我们推测：热习服可能通过调节小胶质细胞M2型活化高表达CX3CR1，促进海马神经发生，从而改善EMF导致的抑郁样行为。为进一步验证假设并探讨机理，本项目主要研究①热习服调节小胶质细胞M2型活化、促进海马神经发生与EMF诱导抑郁样行为的相关性；②CX3CR1作为小胶质细胞M2型活化关键分子在热习服调节EMF损伤海马神经发生中的关键作用；③CX3CR1及CREB相关信号通路调节小胶质细胞分泌IGF-1、BDNF改善海马神经发生的机理。本项目不仅可揭示热习服保护EMF损伤神经行为的作用机制，而且有望为EMF暴露职业人群提供有效防护措施。

电磁辐射环境污染对职业暴露人群中枢神经系统的危害正逐步被学者所认知。近年来研究表明，长期电磁辐射暴露可引起抑郁样神经精神症状。前期发现，通过热习服对热耐受能力的提高，可明显减轻电磁辐射导致的抑郁样行为，并可能与其调节海马神经发生有关，但内在作用机理尚不明了。本项目主要观察到长期电磁辐照能导致小鼠成体神经发生障碍及抑郁样行为改变，并发现热习服可减轻电磁辐射致抑郁样行为、海马神经发生损伤及小胶质细胞极性活化的变化，探讨了CX3CR1 及其效应分子在热习服改善海马神经发生减轻EMF 诱导的抑郁样行为中的作用和地位，并证实了通过抑制剂、基因敲除鼠干预CX3CR1的表达，可以阻断热习服小胶质细胞 M2 型活化，部分消除了热习服对电磁辐射致抑郁样行为、海马神经发生损伤及小胶质细胞极性活化的保护作用。应用CX3CR1基因敲除小鼠，发现热习服不仅不能改善电磁辐射诱导的CX3CR1-/-小鼠神经抑郁样行为，且对海马神经发生和小胶质细胞活化的改善不明显。应用CX3CR1抑制剂JMS-17-2等证实了小胶质细胞CX3CR1及其下游PI3K/Akt信号通路参与热习服介导的受损海马神经发生的改善。本项目研究结果丰富了热习服调节小胶质细胞活化改善海马神经发生机理的理论认知，为采用CX3CR1调控小胶质细胞活化表型来防护电磁辐射致神经行为损伤提供了明确线索。