The Role Of BDNF And VEGF In Neuronal Injury In Chronic Stress Depression Mice And Its Mechanism

Objective:To establish depressive mice model by using chronic unpredictable mild stress(CUMS),to research the the expression of Brain derived neurotrophic factor(BDNF)and Vascular endothelial growth factor(VEGF)in CA1,CA3 and DG of hippocampus(HP)and prefrontal cortex(PFC)in depressive mice and its relationship with depression,and to explore the effects and related molecular mechanism in depression.Methods:KM mice(2 months)were randomly separated into 2 groups which are control group and stress group.To establish depressive mice models by applying CUMS,the mice in stress group were treated with 7 different stress factors(hathpace,water deprivation,fasting,oblique cage,foot shock,ice-water swim,overnight illumination,random selection of 21 days)Experiment 1.The changes of behavior and spatial learning and memory in mice were tested by Open field test(OFT),Tail suspension test(TST)and Morris water maze(MWM)test.The morphology of neurons changes and the expression of BDNF,VEGF and PI3 K in HP and PFC were detected by HE staining and immunohistochemical(IHC)method,respectively.Experiment 2.Using brain stereotaxic coordinates technique,mice were respectively injected into bilateral hippocampus with normal saline(NS)and LY294002(LY).C-ns group: Control group+intrahippocampal injections of NS,C-ly group: Control group+intrahippocampal injections of LY,S-ns group: Stress group+ intrahippocampal injections of NS,S-ly group: Stress group+intrahippocampal injections of LY.The change of behavior and spatial learning and memory were examined in mice after 24 hours intrahippocampal injections.The morphology of neurons changes and the expression of BDNF,VEGF and PI3 K in HP and PFC were detected by HE and IHC method.Result: Experiment 1.1.OFT.Compared with the control group,the number of square crossing,grooming and rearing of stress group mice reduced remarkably,and the central grid residence time was significantly increased.2.TST.The latency immobility decrease remarkably and a significantly increase in immobility time in stress group mice,compared with control group.3.MWM.The escape latency and total swimming distance of control and stress groups were shortened with the increase of training times in place navigation test,but the control group’s escape latency and the total swimming distance were prominent lower than those of the stress group,however,the residence time of the stress group in the target quadrant was significantly less than that in the control group.4.IHC.Compared with the control group,the expressions of BDNF and VEGF in DG,CA1,CA3 and PFC of stress group were significantly decreased,and the expression of PI3 K was significantly decreased in DG and PFC.Experiment 2.1.OFT.Compared with the C-ns group,the number of square crossing,grooming and rearing of C-ly group mice reduced significantly,the number of crossing and grooming in S-ns group reduced remarkably.The central grid residence time,numbers of crossing and grooming in S-ly group mice significantly decreased than S-ns group.2.TST.Compared with C-ns group,the latency immobility decrease remarkably and a significantly increase in immobility time of mice in C-ly group,and mice in S-ns group have a prominent rise in immobility time.Compared with S-ns group,the immobility time of mice in S-ly group increased significantly.3.MWM.With the increase of training times,the escape latency and the total swimming distance in place navigation test of C-ns and S-ns groups have a prominent change,but there were no significant changes in the C-ly and S-ly groups.Comparison between groups was found that the escape latency and total swimming distance of C-ly and S-ns group increase remarkably compared with C-ns group,and S-ly group mice’s escape latency and total swimming distance higher than S-ns group.The residence time of the C-ly and S-ns group in the target quadrant was significantly less than that in the C-ns group,and S-ly group mice’s residence time in target quadrant prominent less than that in the S-ns group.4.IHC.Compared with C-ns group,expression of BDNF and VEGF in DG,CA1 and CA3 of C-ly group have a significant decrease,expression of PI3 K in DG and PFC also reduced remarkably.Compared with S-ns group,expression of BDNF and PI3 K in DG,CA1,CA3 and PFC of S-ly group decrease significantly,and VEGF’s expression in DG,CA1 and CA3 reduced remarkably.Conclusions:1.CUMS can cause significant anxiety-and depression-like behavior,and learning-memory function impairment in mice,and that intrahippocampal injection of LY294002 significantly damaged the behaviors and learning-memory function in mice.2.The expression of BDNF,VEGF and PI3 K in HP and PFC of mice were decreased after CUMS,and the expression of BDNF,VEGF and PI3 K in mice was significantly reduced after injection of LY294002 in HP.3.Down-regulated expression of BDNF and VEGF in HP and PFC is closely related to depression in mice induced by CUMS,and this may be dependent on the intracellular PI3K/Akt signaling pathway in depression.