Mice Midbrain Estrogen Receptors Function In Modulation Of Locomotion And Emotion And The Underlying Mechanisms

Background and object: In women,estrogen fluctuation has been accompanied with higher risk of mood disorders,such as premenstrual dysphoric disorder(PMDD),perimenopausal depression(PMD),and postpartum depression(PPD).In addition,women has higher prevalence of mood disorders such as major depression disorder(MDD)and generalized anxiety disorder(GAD).Estrogen plays a major role in these processes.Estrogen binds and signals through at least two known receptors,estrogen receptor 1(Esr1 or ERα)and 2(Esr2 or ERβ).Previous studies utilizing mice of systematic knockout of either receptor revealed that deletion of Esr1 mainly resulted a severe defect in reproductive behavior such as mating and maternal while a small number research reported changed emotion.In contrast,majority of research reported that Esr2 deletion had minor effects on reproducetive behavior while modulating emotion such as anxiety or depression in both sexes.So how do estrogen receptors regulate emotion in adult mice? And what is the neuronal substrates within which estrogen receptors function to regulate emotion? Unlike previous study in hypothalamic estrogen receptors in regulating instinctive behavior such as mating and aggression,we focused on the function of midbrain estrogen receptors.Estrogen receptors had enrichment expression in midbrain such as dorsal raphe nucleus(DRN)and periaqueductal gray(PAG).These two brain areas are key brain areas in emotion regulation.Methods: There were three parts in this research.For the first part,to test the function of estrogen in anxiety and depression,we monitored the process of estrogen decrease and increase by ovariectomy and gonadotropin releasing hormone agonist.For the second part,to test different estrogen receptors(ERs)in emotion regulation,we generated a conditional allele of Esr2 and a pre-existed conditional allele of Esr1,which allowed for a site-specific deletion of ERs expression in midbrain through the injection of Cre-expressing viruses.For the last part,to test the function of PAG estrogen receptor positive neurons in female mice locomotion and anxiety regulation,we did chemogenetic activation and inhibition in PAG Esr1+ neurons.Results: For the first part,we found female mice had increased locomotion and depression with estrogen sharp increased while had no significant changes in anxiety or depression with estrogen decreased.For the second part,we found that PAG Esr1 regulated female mice locomotion without affecting female mice anxiety.In contrast,DRN estrogen receptors did not influence locomotion but regulated emotion.Female DRN Esr1 deletion had a mild trend of anxiolytic effect while female DRN Esr2 deletion had a mild anxiogenic and a trend of anti-depression effect.Meanwhile,DRN Esr2 had sex differences in emotion regulation.Male DRN-specific deletion of Esr2 led to reduced anxiety and depression-like behaviors.For the last part,we found PAG Esr1+neurons chemoggenetic activation decreased locomotion but had no impact in anxiety.Conclusion: we have proved the biphasic effects of estrogen receptors in anxiety regulation and we also found the sex differences of estrogen receptors in anxiety and depression,thus providing a theoterical basis for further designing sex-specific therapy to treat mood disorders.