SIRT1 Antagonizes Postpartum Depression By Up-regulating Glucocorticoid Receptor

Object:Exploring the most effective and stable model of postpartum depression.The potential mechanism of postpartum depression induced by estrogen withdrawal is also investigated,further SRIT1 is investigated whether or not could ameliorate the symptoms of postpartuml depression by targeting GR(Glucocorticoid receptor).Methods:(1)Two postpartum depression models were built as followings:(1)Pharmacological stress model of postpartum depression is built by CORT(Corticosterone)injection from day 1 to day 21 after delivery;(2)Estrogen withdrawal was applied to mimic the postpartum depression.The classical behavioral experiments to evaluate depression-like effect,such as forced swimming test(FST)and tail suspension test(TST)were executed to explore the most effective and stable model of postpartum depression.(2)In order to investigated the precise involvement of GR in the reuglation of postpartum depression,we compared the behavioral results and the protein expression of SIRT1 of model mice who suffer with GR inhibitor(RU486)injection and solvent control;(3)SIRT1 and GR plasmids were overexpressed in HEK293 T cell line by transfection with lipofection.The interaction between SIRT1 and GR was checked by Co-IP technique.(4)Further,we assessed the function of SIRT1 on postpartum depression and its potential mechanims related with GR regulation,SIRT1 agonist-SRT2104 was microinjected into the hippocampus of rats.Behavioral and molecular biological experiments were applied to check the vital role of SIRT1 antagonizing postpartum depression by regulating GR.Results:(1)Compared with the control group,there was no significant difference on immobility duration of rats suffered with CORT injection in the FST and TST,thus,CORT injection may be not an effective method to induce the postpartum depression.While the model of postpartum depression which is built by estrogen withdrawal could mimic the depression-like behavior.(2)The rats who experienced with estrogen withdrawal exhibited anxiety-like mood in the open field test(OFT)and the elevated plus maze test(EPM),further the expression of GR instead of SIRT1 in hippocampus decreased significantly.Rats injected with GR inhibitor-RU486 showed anxiety and depression like behaviour by their concomitant reduction of GR expression in hippocampus.(3)Co-IP results showed that there was a direct interaction between GR and SIRT1.Results of RT-qPCR and Western blot confirmed that SIRT1 could regulated the transcription and expression levle of GR,while no similar results was acquired when GR over expression in vitro.That is,SIRT1 targeting regulation GR participated in the regulation of postpartum depression.(4)Rats experienced microinjection with SIRT1 agonist-SRT2104 could remarkbly reduce depression-like behavior instead of anxiety-like behavior in postpartum depression,accompanied by up-regulation of GR and SIRT1 expression in their hippocampus.Conclusions:(1)Model built by Estrogen withdrawal could effectively mimic postpartum depression-like and anxiety-like symptoms in rats.GR is a potential regulatory target of postpartum depression.(2)SIRT1 can effectively alleviate postprtum depression-like instead of anxiety-like behavior by targeting GR.