Coordinated excitatory and inhibitory circuits governing unpredictable threat-induced anxiety

Anxiety is elicited by excessive apprehension about unpredictable threats. However, the neural circuit governing unpredictable threat induced anxiety remains unclear. Here, we found ventral bed nucleus of the stria terminalis (vBNST) GABAergic neurons displayed selective activation to unpredictable threats through coordinated excitatory input from insular cortex glutamergic neurons and inhibitory input from the lateral nucleus of the amygdala (CeL) somatostatin neurons. Using activity-dependent neuronal tagging technology, we found that unpredictable threat responsive cells in vBNST drive freezing and anxiety via projections to ventral lateral periaqueductal gray (vlPAG) and median nucleus of the amygdala, respectively. Finally, we identified that potassium voltage-gated channel subfamily Q member 3 (KCNQ3) plays an essential role in hyperactivity of vBNST GABAergic neurons induced anxiety. These data revealed a forward inhibitory circuit that determines the selective activation of vBNST in unpredictable threat and anxiety, and suggest that the KCNQ3 channel is a promising target for the treatment of anxiety disorders after unpredictable stress.