The Mechanism Of PPAR? Ameliorates Cognitive Function In Offspring With Maternal Sleep Deprivation During Pregnancy

Maternal sleep loss during gestation is a common social phenomenon,the decrease of sleep duration and quality of mother has caused several harmful consequences to their children,and can damage the mother-infant relationship.Growing clinical evidences have shown that this harm may lead to premature birth,malformation,increased probability of caesarean section and the risk of postpartum depression in pregnant women.However,there is still a lack of research on the children's mental abnormalities caused by maternal sleep loss.Our previous research has shown that maternal sleep deprivation during pregnancy can lead to several cognitive and affective disorders in offspring,in which the neuroinflammation may play a pivotal role.Thus,there is an urgent need to find a direct and effective therapeutic target to intervene in this situation,and explore the pathological mechanisms.Numerous studies indicate that the PPAR? pathway can regulate the inflammatory response.In this study,we aimed to investigate whether PPAR? intervention can regulate the MSD-induced neuroinflammation and cognitive dysfunction in offspring.We used an established maternal sleep deprivation(MSD)model of pregnancy SD rats,which received 72 h sleep deprivation in the last trimester of gestation.Then we detected the spatial learning and memory of the offspring with the Morris Water Maze,quantified the expression of PPAR? and cytokines with qRT-PCR and Western blot,as well as identified the phenotype of microglia and neurogenesis with immunofluorescence staining.The results showed that the cognitive damage of MSD offspring was accompanied by the decrease of PPAR?.Microglia is the resident immune cell of the central nervous system and play an important role in regulating of neuroinflammation.Immunofluorescence staining showed that the microglia in MSD offspring presented significant activation type,which specifically manifest as pro-inflammatory polarization(M1 phenotype).Activation of PPAR? pathway by PPAR? agonist pioglitazone switched M1 to an anti-inflammatory polarization(M2 phenotype).Furthermore,we found a significant reduction of neurogenesis in MSD offspring,and pioglitazone treatment significantly enhanced the neurogenesis.And the experiments in vitro prove that pioglitazone treatment increased M2 microglia and inhibited the neuroinflammation and promoted the neurogenesis.To further demonstrate the role of neurogenesis on the cognitive function in the MSD,we used Temozolomide(TMZ)to inhibit neurogenesis.The results showed that the improvement of cognitive with PPAR? agonist pioglitazone in MSD offspring was reversed when neurogenesis was inhibited.In summary,the PPAR? pathway implicate in mediating neurogenesis via regulating microglia M1/M2 phenotype,and involve in improving cognitive impairment in MSD offspring.These results indicate that regulation PPAR? can ameliorate MSD-induced deficiency of spatial learning and memory,which provides scientific guidance for the improvement of cognitive defect in offspring with maternal sleep deprivation as well as the prevention and treatment of related psychiatric disorders.