The Role And Mechanism Of Dysfunction Of BLA-vHPC Circuit In The Occurrence Of Post-Traumatic Stress Disorder

Post-traumatic stress disorder(PTSD)is a common psychiatric disorders,which is characterized by delayed and persistent anxiety disorder occurringafter the individual suffers from severe traumatic event.Excessive anxiety is the basic symptom of PTSD patients.Preclinical and clinical studies have found that the occurrence of PTSD is closely related to the dysfunction of amygdala.The amygdala is the emotioncenter of the brain which has extensive structural and functional connections with the ventral hippocampus(v HPC),prefrontal cortex and other brain regions and participates in emotional valence encoding and etiology of several psychiatric diseases.The amygdala is highly inhibited under physiological conditions,which prevents the inappropriate emotion expression.However,under a series of pathological conditions such as traumatic stress,the high inhibition state of amygdala is relieved and causes its over excitation,leading to the occurrence of mental diseases.A large number of studies have shown that the basolateral amygdala(BLA)-ventral hippocampus(BLA-v HPC)neural circuit plays an important role in the occurrence of anxiety and depression.We found that the activity of BLA neurons projected to v HPC was enhanced in stress-induced PTSD mice,how stress causes the hyperactivation of BLA→v HPC circuit through which molecular mechanism remains unknow.In this study,we established a mouse model of PTSD by simulating traumatic stress with foot shock.The role and molecular mechanism of BLA→v HPC circuit in FS induced PTSD were studied by using chemogenetic,pharmacological,behavioral and electrophysiological patch-clamp techniques.The results showed that FS significantly increased anxiety-like behavior in mice.Chemical genetic inhibition of the BLA→v HPC circuit can effectively alleviate the anxiety-like behavior induced by FS.In addition,activation of the BLA→v HPC circuit significantly increased anxiety-like behavior under physiological conditions.Further experiments showed that corticosterone levels in mice were significantly increased after FS,and corticosterone synthesis inhibitor(metyrapone)could reduce the increase in corticosterone levels and alleviate the symptoms of PTSD in mice.Then we investigated the effect of FS on the activity of BLA→v HPC PNs.To this end,we injected retrograde adeno-associated virus with green fluorescent protein sequence into v HPC,which could specifically labele BLA→v HPC PNs.Electrophysiological data showed that the intrinsic excitability and excitatory synaptic transmission of BLA→v HPC PNs were significantly enhanced after FS.Crucially,intraperitoneal injection of metyrapone in mice can effectively reverse the effects of FS.This study shows that FS enhances the activity of BLA→v HPC PNs by enhancing the synthesis and secretion of corticosterone,leading to PTSD in mice.This study elucidated the role and mechanism of hyperactivation of BLA→v HPC circuit in stress-induced PTSD,and provided a new theoretical basis for clarifying the pathological mechanism of PTSD.