PACAP-PAC1R signaling in the PSTh mediates stress-induced anxiety-like behavior in mice

We employed an established stress paradigm to induce anxiety-like behaviors in mice and found that stress causes robust and sustained activation of glutamatergic neurons in the parasubthalamic nucleus (PSTh). Moreover, inhibition of those neurons significantly reduced anxiety-like behavior in stressed animals.

RNA sequencing revealed that the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1R, encoded by Adcyap1r1) is enriched in the PSTh. Ex vivo patch-clamp recordings showed that PACAP, an endogenous agonist of PAC1R, increases the excitability of PSTh neurons. Interestingly, pharmacological blockade of PAC1R within PSTh was sufficient to prevent anxiety by stress.