Chronic Stress Differentially Regulates Tonic Inhibition In Two Subsets Neurons In Amygdala Based On Thy-1 Expression

It is well known that persistent stress exposure is an important cause of mental illness such as anxiety disorder,a process closely related to the excessive activation of amygdala.Recent studies have amply demonstrated that the projection neurons in the amygdala exhibit a high degree of heterogeneity in many aspects,such as gene expression,structural connection and physiological function.Different projection neurons make synaptic connections with different brain regions and play different and even opposite functions in the related functions of the amygdala.It is thus of great theoretical and practical significance to reveal the specific roles of different types of amygdala neurons in the pathogenesis of the mental disease,which may help to develop effective and precise methods for treatment of mental diseases.Recently,some scholars used Thy1 as molecular markers and found that activating Thy1 positive neurons in the basal amygdala region inhibited fear expression,while activation of Thy1 negative neurons promoted fear expression.However,little is known about the pathological and physiological functions of these neurons,including their roles in anxiety disorders induced by chronic stress.The disinhibition of amygdala neurons by chronic stress is an important mechanism for raising the activity of amygdala.Our previous studies have shown that chronic stress has selectively reduced the tonic inhibitory current mediated by the extrasynaptic GABA_ARs,but has no significant effect on the phasic inhibitory current mediated by the intrasynaptic GABA_ARs.But how it affects the inhibitory current of Thy1+and Thy1-neurons in the amygdala is unclear.To this end,we intend to use Thy1-GFP transgenic mice to establish the chronic social defeat stress model to observe the possible effects of chronic stress on Thy1+and Thy1-neurons.The results showed that the chronic social defeat stress significantly increased the tonic inhibition of the Thy1+neurons of amygdala,but reduced the tonic inhibition of the Thy1-neurons.On the contrary,stress had no significant effect on the phasic inhibition current of these two groups of neurons.Feeding the mice with corticosteroids for 10 consecutive days readily mimics the effect of chronic stress on the tonic inhibition current of Thy1+and Thy1-neurons.Further studies have shown that chronic stress enhances the inhibitory effect of GABA on the excitability of Thy1+neurons,and reduces the inhibitory effect of GABA on the excitability of Thy1-neurons.Based on the above results,we speculate that chronic stress enhances the inhibitory effect of GABA by increasing the tonic inhibition current on Thy1+neurons,to inhibit the Thy1+neurons’function of“fear inhibition”,and at the same time,it weakens the inhibitory effect of GABA by reducing the tonic inhibition current on Thy1-neurons,to enhances its function of“fear facilitation”.Our research provides an experimental basis for elucidating the neural circuits mechanism of chronic stress regulating the activities of amygdala,and provides a new potential research target for the prevention and treatment of anxiety disorder diseases.