A pontomesencephalic PACAPergic pathway underlying panic-like behavioral and somatic symptoms in mice

Panic disorder is characterized by uncontrollable fear accompanied by somatic symptoms that distinguish it from other anxiety disorders. Neural mechanisms underlying these unique symptoms are not completely understood. Here, we report that the pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons in the lateral parabrachial nucleus projecting to the dorsal raphe are crucial for panic-like behavioral and physiological alterations. These neurons are activated by panicogenic stimuli but inhibited in conditioned fear and anxiogenic conditions. Activating these neurons elicits strong defensive behaviors and rapid cardiorespiratory increase without creating aversive memory, whereas inhibiting them attenuates panic-associated symptoms. Chemogenetic or pharmacological inhibition of downstream PACAP receptor-expressing dorsal raphe neurons abolishes panic-like symptoms. The pontomesencephalic PACAPergic pathway is therefore a likely mediator of panicogenesis, and may be a promising therapeutic target for treating panic disorder.