Knockdown Of MicroRNA134 Signal Pathway In VHP Region Relieves Anxiety-and Depression-like Behaviors In Cocaine Extinction Mice

Objective:Cocaine is a kind of excitatory drugs that acts on the central nervous system(CNS).The abuse of cocaine will increase the risk of mental disorders such as anxiety and depression.Ventral hippocampal is an important region involved in the regulation of anxiety and depression,is also closely related to cocaine addiction.MicroRNA134(miR134),as a brain-specific microRNA,is abundantly expressed in hippocampus and is closely related to the regulations of synaptic plasticity and neurochemical microenvironments.In this experiment,cocaine extinction mice model was established to explore:(1)the change of miR134 signal pathway in vHP of cocaine extinction mice;(2)the effect and mechanism of knockdown miR134 signal pathway;(3)regulation the upstream of miR134,SIRT1,to observe the effect of natural products that act on abnormal behaviors of cocaine extinction mice.Methods:(1)Cocaine conditioned place preference(CPP)was used to establish cocaine extinction mice model;(2)The anxiety-and depression-like behaviors of cocaine extinction mice were evaluated by EPM(Elevated plus maze),OFT(Open field test),FST(Forced swimming test)and TST(Tail suspension experiment);(3)Golgi-staining and electron microscopy observation were applied to observe the structure of dendritic spines and synapses,western blot was used to detect the expression of synapse related proteins in vHP;(4)MiR134 in vHP was knocked down after virus transfection experiment by stereotactic surgery;(5)The expression of miR134 and downstream gene in vHP was detected by Basescope,qPCR and western blot.Results:(1)During the period of cocaine extinction,cocaine-exposed mice showed anxiety-and depression-like behaviors significantly,along with increased miR134 expression,decreased synaptic number and density of dendritic spines,neurochemical microenvironments damaged in vHP;(2)In vHP,miR134 was maiuly expressed in pyramidal neurons,rarely in glial cells;(3)Knockdown miR134 in vHP effectively relieved the anxiety-and depression-like behaviors of cocaine extinction mice,also reverse the damage of synaptic plasticity and neurochemical microenvironment caused by cocaine extinction;(4)Activation of SIRT1 by resveratrol and ginsenoside(Rgl)could not relief the abnormal emotional behavior of cocaine extinction mice.Conclusion:(1)MiR134 signaling pathway is enhanced in vHP of cocaine extinction mice;(2)Knockdown of miR134 in vHP effectively alleviated the anxiety-and depression-like behaviors of cocaine extinction mice by reversing the synaptic plasticity damage and neurochemical microenvironment disorder regulated by miR134 signaling pathway;(3)Activation of SIRT1,the upstream of miR134,may not effectively relief the abnormal emotional behaviors of cocaine extinction mice.