Chronic Non-predictable Stress, Hippocampal Bdnf Antidepressant Mechanism

Depression is an emotional psychiatry.It is marked by lower interest and anhedonia,and with an ascending incidence year by year along with the exacerbation of social factors,such as the accelerating pace of modern life and the increasingly fierce competition.Therefore,studies on depression are of great clinic and social significance.However,it is still unclear about the pathology and mechanism of depression.Brain derived neurotrophic factor(BDNF) is a neurotrophic family protein,protecting neuron from damage,and promoting neurogenesis,axon and dendrite growth, axon and dendrite reorganization,and synaptic formation.In recent years,researches have proven that BDNF had antidepressant action via neurogenesis,which is necessary for antidepression. Kalirin(kal) is a Rho guanine nucleotide exchange factor(GEF).Among the kal protein family, kalirin-7(kal7) is the most prevail adult isoform of kalirin and necessary for promoting and maintaining dendritic spines and branches.Basic fibroblast gowth factor(bFGF) protects neurons from excictoxicity,and selectively promotes neuron axon branching.Altogether,BDNF,kal7 and bFGF have the consistency in the aspect of promoting neural structure plasticity.Chronic unpredicted mild stress(CUMS) was used in this experiment to establish depression model and to explore whether BDNF can cure CUMS-induced depression and the mechanisms involved in the BDNF-anti-depression.Immunochemical technique was applied here to detect kal7 and bFGF expression changes after intrahippocampal infusion of BDNF,and to investigate the relevance between the behavioral variations and the expression changes.Specific results are as follows:1.CUMS-treated rats showed very significant(p＜0.01) decrease in the body growth rate after 7, 14,21 days respectively,the sugar solution preference,and rearing and grooming in the open field (OFT).And,CUMS-treated rats showed significant(p＜0.05) decrease in locomotion in OFT.2.Intrahippocampal infusion of BDNF into CUMS-treated rats prominently ameliorated depression-like behaviors.Although the body weight in these rats did not grow faster than the control rats,the sugar solution preference,locomotion and rearing and grooming in the OFT were similar between these groups.Compared with only-CUMS-treated rats,intrahippocampal infusion of BDNF very significantly(p＜0.01) increased the body weight after 7,14,21 days respectively,the sugar solution preference,and grooming in the OFT,and also significantly(p＜0.05) raised locomotion and rearing in the OFT.3.Intrahippocmapal infusion of K252a,the antagonist to TrK B receptor,to block endogenous BDNF mimicked CUMS-induced depression-like behaviors,but which were contrary to intrahippocampal-infusion-BDNF rats.4.Compared with the control,CUMS dramatically(p＜0.01) down-expressed kal7 and bFGF in each hippocampal sub-regions,CA1,CA2,CA3 and DG,however,BDNF reversed the CUMS-induced down-expression of kal7 and bFGF in hippocampus.After blocking BDNF receptor TrK B by K252a,the expression of kal7 and bFGF was similar to that in only-CUMS-treated rats, but contrary to that in intrahippocampal-infusion-BDNF rats.Therefore,CUMS induced depression-like behaviors in rats,especially the core symptom anhedonia,and leaded to the down-expression of kal7 and bFGF in all the hippocampal sub-regions. BDNF improved CUMS-induce depression-like behaviors,and reversed the CUMS-induced down-expression of kal7 and bFGF in all the hippocampal sub-regions.Blocking BDNF receptor TrK B not only produced depression-like behaviors,but also declined the expression of kal7 and bFGF in all the hippocampal sub-regions,which were similar to the behaviors induced by CUMS,on the contrary,intrahippocampal infusion of BDNF reversed the down-expression of kal7 and bFGF induced by CUMS.All the above points out that BDNF achieves the anti-depression efficacy via TrK B to modulate hippocampal kal7 and bFGF expression,and then to regulate neurogenesis and structure plasticity of newborn neurons.