The Role Of Mitochondria On Prenatal Glucocorticoid Exposure-induced Depression-like Behaviors

After the introduction of the theory of fetal origin of adult disease,more and more evidences show that intrauterine adverse environment during fetal time,such as glucocorticoid exposure,can increase the risk of depression and other neuropsychiatric disorders in adulthood.But the mechanism has not yet been clarified.Recent studies have shown that mitochondrial dysfunction may be involved in the development of depression.Therefore,in this paper,we explored the mechanism of mitochondria and other related factors that may influence the development of depression in pregnant women,who wereexposed to excessiveglucocorticoids,and the effects of exercise.In the first part,we focus on the effects of prenatal exposure toexcessive glucocorticoids on offspring’s depression like behaviors;we explored the internal mechanism of prenatal glucocorticoids induced depression like behaviors from the aspects of mitochondrial function and brain glial cell structural changes.In the second part,we carried out a 4 weeks’ medium intensity treadmill exercise on 4 week old rats who were prenatal exposed to excessive glucocorticoid,and found that the depressive behaviors of the adult rats were reduced,the weight of the hippocampus increased and the mitochondrial function improved after exercise.During our laboratory’s previous work,it was found that maternal glucocorticoids exposure during pregnancy can lead to increased serum corticosterone level and depression like behavior in offspring,and this depressive behavior can be transmitted to the second generation through maternal way.Therefore,in the third part of this paper,we studied the effect of higher corticosterone in maternal circulation on offspring’s depression like behaviors and its possible mechanisms related to placenta.Results: A、 The role of mitochondria on prenatal glucocorticoid exposure induced depression-like behaviors a)The offspring of those rats who were exposure to excessive glucocorticoid during pregnancy showed more depression like behaviors than control rats.i.The rats in dex group showed prolonged immobile time in the forced swimming test compared with rats in control group.ii.The rats in dex group showed less preference than the rats in control group in sucrose preference test.B、 The number of living neurons in the hippocampus of rats in dex group was significantly reduced compared with rats in control group.C、 The expression of multiple mitochondrial related genes in the hippocampus of those rats whose mother was exposure to excessive glucocorticoid during pregnancy was changed.Genome-wide expression profiling was used to detect the expression of m RNA,and we found that multiple mitochondrial related genes,including UCP3,slc25a21 and idh2,in the hippocampus of rats in dex group were changed.D、 The function and morphology of mitochondria in the hippocampus ofthose rats whose mother was exposure to excessive glucocorticoid during pregnancy was changed.a)The amount of ATP production in the hippocampus of rats in dex group was significantly reduced compared with rats in control group.At the same time,the ROS production increased significantly,and the membrane potential decreased significantly,suggesting that the mitochondrial function of rats in dex group was abnormal.b)Under the electron microscope,the midrib of mitochondria in the hippocampus ofrats in dex group was swollen and some of the membranes were disintegrated.E、 We found that the morphology of the myelin sheath in the hippocampus of those rats whose mother was exposure to excessive glucocorticoid during pregnancy was changed under electron microscopy.F、 through lateral ventricle injection,mitochondrial specific ROS scavenger mito TEMPO can significantly improve the prenatal glucocorticoid induced depression like behaviors,but there was no such effects when mito TEMPO was injected through intraperitoneal injection.a)After the injection of mito TEMPO in the lateral ventricle,the immobile time of the rats in dex group was significantly reduced in the forced swimming test.b)After the injection of mito TEMPO in the lateral ventricle,the sugar water consumption of the rats in dex group was significantly increased in the sugar water preference test.G、 The effect of exercise on depression like behaviors induced by prenatal glucocorticoid exposure.a)Treadmill exercise can significantly improve the prenatal glucocorticoid exposure induced depression like behaviors.b)The immobile time in forced swimming test was significantly reduced of rats in dex group after 4 weeks’ treadmill exercise.c)The consumption of sugar water in the sucrose preference test was significantly improved of rats in dex group after 4 weeks’ treadmill exercise.d)Treadmill exercise can increase the number of living neurons in the hippocampus ofthose rats whose mother was exposure to excessive glucocorticoid during pregnancy.e)The treadmill exercise can partly reverse the changes of mitochondrial function and morphogenesis caused by prenatal glucocorticoid exposure.f)The treadmill exercise can partly reverse the morphological changes of the myelin sheath in the hippocampus ofthose rats whose mother was exposure to excessive glucocorticoid during pregnancy.H、 the role of higher glucocorticoid level in maternal circulation in the intergenerational transmission of prenatal glucocorticoid-induced depression-like behaviors.a)Subcutaneous embedding of corticosterone release agent in female rats can cause increased depression like behaviors in their offspring.b)Subcutaneous embedding of corticosterone release agent in female rats can damage the mitochondrial function in the hippocampus of their offspring.c)The expression of 11 beta-HSD2 enzyme in placenta of those rats who were subcutaneous embedded with corticosterone release agent was significantly decreased and the expression of 11 beta-HSD1 enzyme had no significant change.