| Postpartum depression (PPD) is one of the most common mental disorders in the puerperium. Due to the special connection between mother and child, PPD mothers will have a negative impact on their children’s physical and mental development. These children may be easier to show abnormal behaviors, have more suicidal thoughts and become depression patients at early age. PPD may lead to increased susceptibility to depression in the childeren as an early life adversity. PPD increase the risk of children suffering depression and bring heavy burdens to the family and community. Therefore, it has become a serious issue to know how to prevent and treat depression affected by the PPD mothers. Based on the clinical and pathogenic characteristics, offspring depression has been considered to be "depression" in Chinese medicine, "deficiency and depression (or stasis)" is the key pathogenesis. The treatment should be treating deficiency syndrome with tonifying menthod and promoting Qi circulation for removing the stasis. Yueju pill and Ganmaidazao decoration are classic formulas to alleviate these sydromes, so this study combined with two medicines and observe rapid the antidepression-like effect of the Yuejuganmadazao decoration and analysis the mechanism of depression in PPD offspring.Objective:To observe the rapid antidepressant effect of Yuejuganmaidazao decoction (YG) on the treatment of depression of the offspring and its mechanism, provide theoretical and experimental support for YG in treating offspring depression, and further explore methods of traditional Chinese medicine in the preventionand treatment of offspring depression.Methods:Female mice were randomly divided into stressed and non-stressed groups. The stressed mice received a three week chronic mild stress procedure:daily 6 hr restraint stress in a 50 ml centrifuge tube, combined with overnight illumination twice a week for 3 weeks. Four days later, the females were mated with a male. About 4 weeks after, prepregancy stressed females gave birth offspring, which started from 1 week and lasted at least for 3 weeks postpartum. The offspring of prepregancy stressed females were defined as the F1 of PPD mice, PPD-F1. In contrast, the offspring ofprepregancy non-stressed females were defined as the F1 of control mice, or CTL-F1. The two group offspring were housed with their mother until 3 weeks postnatal. When adult, PPD-F1 and CTL-F1 were bred to naive wide-type females to produce F2 offspring. F2 mice were reared in normal conditions and were never exposed to maternal postpartum depression. The experiment may be divided into six parts:1. The adverse effect of maternal postpartum depression on the depress ion-like behaviors in PPD-F1 at adolescence and adulthood. By measuring body weight, sucrose preference test, forced swimming test and novelty suppressed feeding test, we observed the depression-like behavior of PPD-F1 at adolescence and adulthood.2. The effect of maternal postpartum depression on the AKT-mTOR signaling in the hippocampus of PPD-F1 at adolescence and adulthood. By using the western blot method to measure the expression of phosphorylation and total AKT and mTOR, phosphorylation of p70S6K,4EBP-1 and DISC1 in the hippocampus of PPD-F1, we observed the effects of postpartum depression on mTOR pathway in the hippocampus of PPD-F1 at adolescence and adulthood.3. The adverse effect of maternal postpartum depression on the depress ion-like behaviors and hippocampal AKT-mTOR signaling in PPD-F2. Through behaviors tests and Western blot methods, we tested the depression-like behaviors and hippocampal AKT, mTOR, and p70S6K expression in PPD-F2.4. Hippocampal DNA methylation analysis sinificantly associated with depression at early life of PPD-F1. Using RRBS sequencing methods, we tested gene methylation in the hippocampus of PPD-F1 and profiled molecular pathways and gene networks significantly related to depression.5. The rapid antidepressant effects of Yuejuganmaidazao decoction. The F1 offspring are divided into:PPD-F1 treated with saline (Veh), PPD-F1 treated with YG (YG) and PPD-F1 treated with ketamine (Ket). By the behaviors tests, we test the rapid antidepressant effect of YG in PPD-F1 after drug administration.6. The rapid antidepressant effects of YG on the AKT-mTOR signaling in the hippocampus of PPD-F1 at adulthood. Using the western blot method, we tested the expression of AKT, mTOR, p70S6K and DISCI in hippocampus of PPD-F1 while adult.Results:1. PPD-F1 had lower weight than CT-F1 group at postnatal 3-4 week (3rd week: p<0.001,4th week:p<0.01). PPD-F1 also showed significantly decreased sucrose preference (SPT, p<0.001), increased immobility time in forced swimming test (FST, p<0.01), longer latency to feed (p<0.001) and less food intake (p<0.01) in novelty-suppressed feeding test (NSF) at adolescence. While adult, PPD-F1 showed significantly decreased sucrose preference (p<0.001), less food intake (p<0.001), and increased immobility time in the TST (p<0.001) and FST (p<0.001) compared with CTL-F1 group.2. At adolescence, PPD-F1 had significantly decreased the phosphorylation of m-TOR (p-mTOR) in the hippocamus (p<0.05), while total mTOR expression did not change. Consequently, the ratio of p-mTOR/mTOR significantly decreased (p<0.05).AKT phosphorylation (p-AKT) was significantly reduced (p<0.01), and total AKT expression didn’t change (p>0.05), and thus the ratio of p-AKT/AKT decreased (p>0.05). Meawhile, S6K phosphorylation (p-p70S6K) decreased significantly (p<0.05) and DISCI expression increased significantly (p<0.05). However,4EBP-1 phosphorylation levels didn’t change (p>0.05). While adult, there was a significant decrease inAKT phosphorylation(p<0.01),while total AKT expression didn’t change (p>0.05), and the ratio of p-AKT/AKT decreased significantly(p< 0.05).The phosphorylation of m-TOR (p-mTOR) in the hippocamus was decreased (p<0.05), while total mTOR expression did not change and the ratio of p-mTOR/mTOR significantly decreased (p<0.05). Meawhile, S6K phosphorylation (p-p70S6K) decreased significantly (p<0.05) and DISCI expression didn’t change.3. PPD-F2 showed longer latency to feed and less food intake in NSF test (p<0.05), and reduced sucrose intake in SPT (p<0.05). Moreover, the hippocampal phosphorylation of AKT (p<0.01) phosphorylation of m-TOR (p<0.05), total m-TOR (p<0.05) and phosphorylation of S6K (p<0.01) were significantly reduced.4. Gene methylations closely associated with depression were significantly changed, such as Adcyapl, Mapks, Pik3c, Grinl (NMDAR1), Grin2d (NMDAR2d), Grml (GluRl) and calmodulin gene family (Camk2b, and Camk2g, and Camk2nl). Meanwhile, the methylation of genenetwoks and signalings related to depression also changed, such as MAPK signaling pathway, mTOR signaling pathway and Wnt signaling pathway.There are 267 DMRs in MAPK signal pathway,53 in mTOR signaling pathway and 152 in the Wnt signaling pathway.5. YG rapidly increased the sucrose preference (p<0.001) and food consumption (p<0.001), decreased the immobility time in TST and FST (both p<0.001).6. YG rapidly raised the expression of hippocampal p-AKT, p-mTOR and p70S6K (all p<0.05). However, the expression of DISCI didn’t changed.Conclusion:1. Maternal postpartum depression has adverse effect on the F1 offspring which can start at adolescence and adulthood.2. PPD-F1 showed hippocampal AKT-mTOR signaling deficiency at adolescence and adulthood which may be associated with the depression-like phenotypes.3. The adverse effects of maternal postpartum depression may even transfered to PPD-F2. PPD-F2 shows significant depression-like behavior and deficiency in hippocampal AKT-mTOR signaling.4. There were significant methylations changes in genes and networks associated with depression, which may lead to the abnormal expression of genes, and thus increased the susceptability of depression. 5. YG rapidly alleviated the depressive-like behaviors in PPD-F1.6. YG rapidly reversed the deficiency of mTOR signaling which may further strengthen the synaptic plasticity, thus playing crucial role in the antidepressant effect. |
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