Chronic Stress Causes GABA_A(?)R Hypofunction In Hippocampus-projecting Amygdala Neurons To Increase The Anxiety-like Behavior In Mice

Exposure to persistent stress leads to multiple mental diseases such as anxiety disorders and depression.Amygdala is one of the kernel brain regions responsible for regulating emotion and it plays indispensible role in fear and anxiety.Meanwhile,chronic stress has an effect on the structure and function of amygdala.Under resting condition,the amygdala maintains highly inhibitory tone.However,upon severe and/or prolonged stress exposure,the amygdala becomes disinhibited and manifests hyperactivity which is designated as a pivotal neurobiological basis underlying mental diseases.Similar to other brain regions,GABAergic inhibition in amygdala is mediated by GAB AARs and GABABRs.GAB AARs are localized at both synaptic and extrasynaptic sites,mediating phasic and tonic inhibition,respectively.Our latest study has been demonstrated that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress in our previous study.However,how chronic stress affects the individual amygdala neuron with distinct connectivity and functionality to downregulate tonic GABAAR current remains unclear.In addition,little is known about which GABAAR(s)mediate regulation of chronic stress towards tonic inhibition and whether they are involved in chronic stress induced excessive anxiety.Here,by establishing a mice model of chronic social defeat stress(CSDS)and identifying the neurons with distinct connectivity with retrograde probe,we observed that CSDS markedly reduced the tonic GABAAR current in basolateral amygdala(BLA)projecting neurons(PNs)targeting ventral hippocampus,but increased that in those terminating in BNST with little influence on both phasic GABAAR and GABABR currents in both.The opposite changes of tonic inhibition in the two populations led to the loss-and gain-of-function of GABAergic suppression of neuronal activity in BLA?vHPC and BLA?BNST PNs respectively.Furthermore,it was the inhibition downregulated in BLA?vHPC PNs but not that upregulated in BLA?adBNST ones that correlated with the increased anxiety in CSDS mice.We found that GABAA(?)R was involved in the loss of tonic inhibition in BLA?vHPC PNs and increasement of tonic inhibition in BLA?adBNST PNs.Further investigation revealed hypofunction of GABAA(?)R accounted for CSDS-induced loss of tonic inhibition in BLA?vHPC PNs and reversing the lost inhibition in this population sufficed to prevent the anxiogesis by CSDS.In summary,chronic stress causes hypofunction of GABAA(?)R in hippocampus-projecting amygdala neurons to decrease tonic inhibition,leading to loss of GABAergic suppression of neuronal excitability,thereby inducing anxiety-like behavior in mice.Our findings thus revealed a project-specific regulation of tonic inhibition in amygdala neurons for stress.