Effects Of Enriched Environment On Depression And Anxiety-like Behavior Induced By Maternal Separation In Different Periods

Objective: Brain development is a prolonged process and is sensitive to environment during critical periods.Stress in early life is believed to increase the vulnerability of depression,while enriched environment(EE)presents beneficial effects on neural plasticity and depression.In this research,we compared the therapeutic effect of EE during different periods on depression induced by early life stress,and also investigated the role of BDNF and AKT in the effect of EE.Plasma corticosterone level was also detected to evaluate the reactivity of hypothalamic-pituitary-adrenal axis.Methods: C57BL/6 mice were subjected to a 4-hour(10:00-14:00)maternal separation(MS)procedure during postnatal day 2-21.After separation,all male pups were assigned to standard environment groups(SE),enriched environment in early period groups(3-8 weeks,EEE)and enriched environment after adult groups(8-13 weeks,EEA).At about 14-week age,depression and anxiety behavior were evaluated using sucrose preference test(SPT),open field test(OFT),elevated plus maze test(EPM)and forced swimming test(FST).The plasma corticosterone was quantified utilizing enzyme-linked immunosorbent assay.Hippocampus BDNF,AKT/p-AKT were detected using western blot.Results: The results shown that MS increased depression and anxiety level,while EE in both two intervention periods alleviated the symptoms of depression and anxiety induced by MS.Compared to EEA group,the EEE group showed better effects on anhedonia(P=0.035)and presented better effect on anxiety in OFT(P=0.012)and EPM(P=0.026).The difference of despair behavior between EEE and EEA groups was not significant in FST(P=0.785).MS increased plasma corticosterone level(P<0.001),while EE decreased corticosterone level in both intervention periods.MS decreased BDNF expression and Akt phosphorylation,while EE increased BDNF expression and p-AKT/AKT ratio.Compared with enriched environment in adulthood,early enriched environment intervention increased BDNF(P=0.020)and p-AKT/AKT(P=0.026)more significantly.Conclusion: EE can alleviate the depression and anxiety behavior induced by MS.Compared with EE in adulthood,EE in early development period was more effective in alleviating depression and anxiety induced by early lie stress.BDNF and its downstream PI3K-AKT pathway might play a significant role in the effect of EE,and further researches are needed to explore the detailed neurobiological mechanisms.