Mechanism Of Cognitive Dysfunction Associated With Polycystic Ovary Syndrome

BackgroundPolycystic ovarian syndrome(PCOS)is a complex neuroendocrine disorder common in women of childbearing age.The main clinical features include amenorrhea or menstrual disorder,sparse or anovulatory ovulation,hyperandrogenemia,and polycystic changes in the ovaries.Cognitive dysfunction has been reported in PCOS patients,but the specific mechanism is not clear.The hippocampus is a key functional area for the formation and storage of cognitive memory.Neural stem cells and neurogenesis of the dentate gyrus in the hippocampus are important prerequisites for its normal cognitive function.Overactivation of neural stem cells in the dentate gyrus leads to depletion of stem cells,which in turn leads to reduced neurogenesis and,ultimately,cognitive impairment.Some studies have found that the degree of cognitive dysfunction in PCOS patients is closely related to the level of androgen,suggesting that androgen may be the key factor causing cognitive dysfunction,but there are few studies on this aspect.Kisspeptin,an upstream regulator of GnRH neurons,has been found to be elevated in PCOS patients,and Kisspeptin activates hippocampal neurons.So Kisspeptin may also play a role in PCos-related cognitive dysfunction.Therefore,this study intends to use DHT and DHEA to construct PCOS mouse models,respectively explore the effects of androgen and Kisspeptin on hippocampal neural stem cell activation and neurogenesis,and analyze the relationship between androgen and Kisspeptin.To explore whether androgens mediate cognitive dysfunction in polycystic ovary syndrome mice through Kisspeptin.It is expected to make a breakthrough in the study of cognitive dysfunction in PCOS and provide theoretical support for the development of new therapeutic targets based on androgens and Kisspeptin in the future.ObjectiveTo explore whether androgens mediate cognitive dysfunction in polycystic ovary syndrome mice through Kisspeptin.Methods1.Explore the changes in hippocampal region and cognitive function of PCOS model mice:Construct the PCOS mouse model,and verify the successful construction of the model through monitoring the changes of estrous cycle and ovarian pathology.The changes in the hippocampus of PCOS mice were investigated by detecting the indexes of hippocampal neurogenesis,the number of neural stem cells and their activated states,the number of neural progenitor cells and their proportion of activated states,and the continuous division of neural stem cells.The changes of cognitive function were explored through water maze and new object recognition experiments.2.To explore the effect of androgen on the activation and neurogenesis of hippocampal neural stem cells:PCOS mouse model was constructed after the androgen receptor was knocked down in one hippocampal region of mice,and the number of neural stem cells and the changes of neurogenesis in bilateral hippocampal region were detected.3.To explore the effect of Kisspeptin on the activation and neurogenesis of neural stem cells in hippocampal region:Kisspeptin was continuously stimulated for one month after knocking out GPR54 in one hippocampal region of mice,and the number of neural stem cells and the changes in neurogenesis in bilateral hippocampal region were detected.GPR54 in the hippocampus of PCOS mice was knocked out to detect the number of neural stem cells and neurogenesis in the hippocampus.4.Explore the relationship between androgen and Kisspeptin:lateral ventricle catheterized and continuously injected androgen to detect Kisspeptin level changes in hypothalamic arcuate nucleus.After knocking down the androgen receptor of Kisspeptin neurons in PCOS mice,the changes of neural stem cells and neurogenesis in hippocampus were detected.Results1.Overactivation of neural stem cells in the hippocampus of PCOS mice resulted in depletion of neural stem cells,reduced neurogenesis and cognitive dysfunction,suggesting that high levels of androgens may be associated with cognitive impairment in PCOS mice.2.PCOS mice with hippocampal androgen receptor knocked still showed neural stem cell depletion and decreased neurogenesis,suggesting that androgen-induced cognitive impairment in PCOS mice did not directly affect the hippocampus.3.Kisspeptin activates neural stem cells in the hippocampus,leading to increased neurogenesis.After knockdown of GPR54,Kisspeptin can block the activation of neural stem cells in the hippocampus of PCOS mice,and prevent neural stem cell depletion and neurogenesis reduction,suggesting that high Kisspeptin level may mediate the occurrence of related cognitive impairment in PCOS mice.4.Continuous injection of androgens into the lateral ventricle can cause elevated Kisspeptin levels.Knockdown of the androgen receptor in Kisspeptin neurons of PCOS mice resulted in increased neural stem cells and neurogenesis in hippocampus.In addition,the PCOS mice in the knockout group showed no cognitive impairment.These findings suggest that high levels of androgens may mediate cognitive dysfunction in PCOS mice by promoting Kisspeptin secretion.ConclusionsHigh levels of androgens may promote Kisspeptin secretion by binding to the androgen receptor of Kisspeptin neurons in the hypothalamus,while sustained high levels of Kisspeptin binding to GPR54 in the hippocampus leads to overactivation of neural stem cells in the hippocampus leading to depletion and neurogenesis reduction.Finally,the related cognitive dysfunction occurred in PCOS model mice.