母亲妊娠期间睡眠剥夺损伤子代认知功能的神经免疫机制研究

Sleep complaints are very common among pregnant women, not only affect the health of mothers and fetuses, but also lead to abnormal behavior of offspring after birth. Growing evidences suggest that the pathogenesis for the cognitive function impairment in offspring of prenatal stress is mainly on neuroinflammatory response and the resulting reduction in neurogenesis. Microglia regulate the balance of pro- and anti-inflammatory cytokines in the brain. The purpose of this study is to investigate the effect of microglial activated phenotypes on maternal sleep deprivation (MSD)-induced long-term cognitive and behavioral consequences in offspring. Sleep deprivation is performed by modified small-platform method and their prepuberty male offspring are used to evaluate the cognitive function. PPARγ agonist pioglitazone, antagonist GW9662, AAV-PPARγ and PPARγ-siRNA are selected to discuss the role of PPARγ on the switch of microglial activated phenotypes. In vivo and in vitro experiments, combined with neurogenesis inhibition are chose to estimate the protective pathway of cognitive function in MSD offspring. This project reveals the neuroprotective role of PPARγ-mediated microglial activated phenotypes for the purpose of exploring early intervention target and therapeutic strategy in offspring of prenatal stress-induced behavioral impairment.

女性妊娠期间睡眠不足是非常普遍的现象，不仅影响母亲和胎儿的健康，还会导致子代出生后的行为异常，近年研究表明中枢炎症及由此引起的神经发生减少是产前应激影响认知行为的重要病理基础。小胶质细胞是中枢炎症因子失平衡的细胞基础，本课题以小胶质细胞为切入点，探索妊娠期间睡眠不足影响子代认知功能的神经免疫机制。以水平台的方式建立大鼠妊娠期睡眠剥夺模型，观察对其子代认知行为的影响；采用PPARγ激动剂Pioglitazone、抑制剂GW9662、AAV-PPARγ和PPARγ-siRNA，探讨PPARγ途径切换小胶质细胞表型的调节机制；采用干预神经发生和体内外实验相结合，探寻神经发生是否为小胶质细胞表型改善睡眠剥夺子代认知行为的实现途径。本项目旨在揭示小胶质细胞依赖于PPARγ途径在妊娠期间睡眠剥夺子代认知行为中的神经保护作用，以期寻找改善产前应激所致子代行为损伤的早期干预靶点和治疗策略。

采用大鼠妊娠期间睡眠剥夺探讨产前应激与子代情感障碍的作用途径和机制，发现母亲睡眠剥夺的子代青春期认知与行为异常，它与小胶质细胞的稳态相关。应激诱导的小胶质细胞抑制神经发生并与情感障碍相关联。PPARγ信号通路是切换小胶质细胞表型的重要枢纽，在决定疾病的转归中发挥重要作用，调控小胶质细胞表型在应激相关的神经精神疾病的治疗中具有重要意义。