| Background & ObjectivePostpartum depression(PPD)is a serious mental disorder caused by multiple factors,which has a great negative impact on social and public health safety.PPD is the most common complication in the perinatal period,and suicide due to PPD accounts for about20% of postpartum deaths.In addition,the mother’s depression also has an adverse effect on the baby’s behavior,mood,and cognitive development.Some patients even have infanticide,which causes great harm to the baby’s life and health.The occurrence and development of PPD are mainly related to acute and chronic stress,pain,inflammation,hormonal disorders,and environmental risk factors.It is worth noting that,compared with depression caused by chronic stress,ovarian hormone disorder is the most important pathophysiological mechanism in its occurrence and development.Therefore,the postpartum depression model based on reproductive hormone disorder needs to be further developed and explained the pathophysiological mechanism of PPD.The rapid antidepressant effect of ketamine has been repeatedly confirmed in patients with depression and in animal models of chronic unpredictable mild stress(CUMS).However,in the past,preclinical studies on depression were mainly focused on male animal models,while the postpartum depression models specific to female animals have received little attention.However,in fact,the internal pathophysiological and neurobiological mechanisms of depression have significant gender differences.Therefore,the conclusions drawn from the traditional CUSM model cannot be extended to the PPD model.It is necessary to establish a unique animal model for PPD research.As the S-enantiomer of racemic ketamine,S-ketamine has been shown to have a stronger and lasting NMDA receptor antagonism.In recent years,it has been approved by the U.S.Food and Drug Administration(FDA)for refractory depression that does not respond to other antidepressants.It shows that it has great application prospects in the treatment of depression.However,there is no preclinical study on the benefit of S-ketamine for postpartum depression.As a new type of antidepressant,expanding its indications for postpartum depression is also a current hot research issue.Therefore,this study explored the pathophysiological mechanism of postpartum depression caused by ovarian hormone disorders by establishing a hormone-simulating model of post-pregnancy hormone withdrawal depression.And explore the antidepressant effect of low-dose S-ketamine which is more suitable for "postpartum" compared with high-dose S-ketamine.Finally,it provides a theoretical basis for S-ketamine to prevent and treat postpartum depression.Method1.Construction and Grouping of PPD Rats ModelTwo-month-old SPF female SD rats were randomly divided into control group(Sham group),model group(PPD group),low-dose(2.5mg/kg)S-ketamine group(L group),and high-dose(10mg/kg)S-ketamine group(group H).After the rats were acclimatized to the environment for a week,bilateral oophorectomy was performed,and after a week of recovery,the hormone simulated pseudopregnancy(HSP)program was performed for 23 consecutive days.After hormone withdrawal,the effect of the hormone withdrawal depression model was judged through the sugar water preference test(SPT)and the open field test(OFT).The successfully modeled rats were used in the follow-up experiments,and the abnormal index rats were excluded(rats with indicators outside the range of the mean ± 3 * standard deviation are considered abnormal).In the control group,only the adipose tissue around the ovary was removed.2.Assessment of depression-like behaviors by behavioral experimentsThe experimental animals performed behavioral experiments after being treated with normal saline or S-ketamine injection.The sugar water preference test(SPT)is used to assess anhedonia in rats;the open field test(OFT)is used to indicate the level of spontaneous activity in rats;the elevated plus maze test(EMT)is used to evaluate anxiety;the forced swimming test(FST)is used to assess the degree of despair.3.The study of HSP and S-ketamine on synaptic plasticity of rat hippocampusThe effects of the PPD model and S-ketamine treatment on hippocampal synaptic plasticity were detected from the level of synaptic molecules,synaptic morphology,and electrophysiology.Specifically,the levels of synapse-related proteins(BDNF,PSD-95,and Syn-1 in rat hippocampus)were detected by Western blot;dendritic spine density in the hippocampal CA1 area of rats was detected by Golgi-Cox staining;ultrastructure and synaptic parameters in hippocampal CA1 area were observed and analyzed by transmission electron microscope(TEM);electrophysiological experiments to detect the level of longterm potentiation(LTP)in the Schaffer-CA1 area of the hippocampus.Results1.The effect of HSP on depression-like behavior in ratsBefore and after HSP,the sugar water preference test and the open field test were performed respectively,and the paired sample T-test was performed on the data before and after HSP.The results show that the percentage of sucrose preference after HSP is significantly reduced,and the spontaneous movement distance is significantly reduced in the open field experiment.The above results indicate that the PPD model induced by HSP is relatively reliable.Specifically,the SPT results showed that compared with the Sham group,the percentage of sucrose preference in PPD rats was significantly reduced.The OFT results showed that compared with the Sham group,the total moving distance,the number of grids crossing,the spent time in the central area,and the number of grooming behaviors of PPD rats in the open field were significantly reduced,while the immobility time was significantly prolonged.The EMP results showed that compared with the Sham group,the total distance of horizontal movement and the number of vertical activities of PPD rats on the elevated plus maze were significantly reduced,and the number of times to enter the open arms and the time spent in the open arms were significantly reduced.The FST results showed that compared with the Sham group,PPD rats had a significantly reduced immobility time in the forced swimming tube and the number of times that they climbed the wall of the tube was significantly reduced;however,there was no statistical difference in the number of underwater swimming in PPD rats.The above results show that HSP causes obvious depression-like behavior in ovariectomized rats,which indicates that the violent fluctuation of ovarian hormones is sufficient to cause depression,and proves that the PPD model based on ovarian hormone fluctuations is reasonable.2.Effects of low-dose Es-ketamine on depression-like behavior in PPD ratsSPT results showed that low-dose S-ketamine treatment significantly increased the percentage of sucrose preference in PPD rats.The OFT results showed that compared with the PPD group,the movement distance,the time spent exploring in the central area,and the number of grooming behaviors of the rats in the L group were significantly increased;the immobility time in the open field was significantly reduced.EPM results showed that lowdose S-ketamine treatment significantly increased the movement distance of PPD rats and significantly prolonged the time and frequency of exploration in the open arm.The results of FST showed that compared with PPD rats,the immobility time of rats in the L group was significantly reduced and the number of climbing times was significantly increased.The above results indicate that low-dose S-ketamine treatment can significantly improve the depression-like behavior of PPD rats.3.Different manifestations of the effects of high and low doses of S-ketamine on the behavior of PPD ratsAnalysis of behavioral indicators showed that high-dose S-ketamine improved depression-like behaviors while also accompanied by more anxiety-like behaviors.Specifically,it was found in OFT that rats in group H had significantly less active time in the central area than rats in group L,and produced more vertical movements and licking behaviors and the number of feces.At the same time,in EPM,compared with the rats in the L group,the rats in the H group had significantly less time and time to explore in the open arm,and produced more vertical activities and licking behaviors.The above results indicate that although high-dose S-ketamine has antidepressant activity,it has a stronger anxiety-causing effect than low-dose S-ketamine.4.Effects of low-dose S-ketamine on synaptic plasticity in PPD ratsThe depressive effect of HSP on rats is mediated by impairing hippocampal synaptic plasticity.Specifically,in WB,compared with Sham group,the content of synapseassociated protein(BDNF,PSD-95,Syn-1)in PPD group was significantly reduced;in Golgi-Cox staining,dendritic spine density was significantly reduced;in TEM,the thickness of the postsynaptic compact,the curvature of the synaptic interface,and the length of the synaptic active area are significantly reduced,and the width of the synaptic gap was significantly increased;in the electrophysiological experiment,the LTP of the hippocampal Schaffer-CA1 area of PPD rats is significant reduce.Low-dose S-ketamine treatment can have a beneficial effect on the PPD model by increasing hippocampal synaptic plasticity.Specifically,in WB,compared with the PPD group,the total BDNF,PSD-95,and Syn-1 content in the hippocampus of the L group increased significantly.In Golgi-Cox staining,compared with the PPD group,the dendritic spine density in the hippocampal CA1 area of the L group increased significantly.In transmission electron microscopy experiments,compared with PPD rats,the thickness of postsynaptic compacts and the length of synaptic active area in hippocampal CA1 area of L group rats increased significantly,and the width of synaptic gap decreased significantly.In electrophysiological experiments,compared with PPD rats,LTP in the Schaffer-CA1 area of the hippocampus of rats in the L group increased significantly.Conclusion:1.HSP caused depression-like behavior in PPD rats by reducing hippocampal synaptic plasticity.2.Low-dose S-ketamine can significantly improve depression-like behaviors,and compared with high-dose S-ketamine,it has a smaller effect on anxiety-like behaviors in rats.3.Low-dose S-ketamine can increase the content of synapse-related structural proteins,increase the number of dendritic spines,repair damaged synaptic structure,and enhance synaptic transmission efficiency to improve depression-like behavior in PPD rats. |
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