Feed-forward inhibitory circuit from the anterior cingulate cortex regulates periaqueductal gray’s panic-like responses

Threatening events elicit panic responses characterized by rapid movement, sympathetic arousal, and negative emotions—critical, instantaneous reactions that can determine survival in moments of acute danger. This study elucidates the neural circuit architecture underlying these responses, focusing on projections from the anterior cingulate cortex (ACC) to the dorsolateral periaqueductal gray (dlPAG) in male mice. We demonstrate that a subpopulation of GABAergic neurons (^ACC→dlPAG neurons) in the dlPAG receives direct glutamatergic inputs from the ACC and provides feed-forward inhibition to surrounding dlPAG neurons, serving as crucial intermediaries in regulating PAG output. Optogenetic suppression of ^ACC→dlPAG neurons elicited immediate and robust flight responses and pupil dilation. Moreover, the inhibition of ^ACC→dlPAG neurons produced aversive states, as evidenced by conditioned place aversion and modified Pavlovian fear conditioning paradigms. Our findings reveal that ^ACC→dlPAG neurons function as a gate for panic-like emotional and behavioral responses. This circuit architecture might allow for fine-tuned control of defensive behaviors, balancing the need for rapid action in genuine threat scenarios with the suppression of inappropriate responses in non-threatening situations.