Chemogenetic modulation of PAC1-expressing neurons in the bed nucleus of the stria terminalis (BNST) alters anxiety-related behaviors in male mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) is a highly conserved neuropeptide that plays essential roles in numerous physiological functions, and central PACAP signaling has been associated with mechanisms regulating stress-induced psychopathologies. PACAP binds to several receptor subtypes, including PAC1 (ADCYAP1R1), VPAC1 (VIPR1), and VPAC2 (VIPR2), to activate several signaling cascades that can alter neuronal excitability and enhance indices of neuroplasticity, and much of our prior work has suggested that the anxiogenic effects of bed nucleus of the stria terminalis (BNST) PACAP depend on the activation of PAC1 receptors. To complement our previous work that evaluated the roles of BNST PACAP expression and secretion in anxiety-related responses, we employed in the current work chemogenetic approaches in male PAC1-Ires-Cre mice to directly and specifically modulate the activities of BNST PAC1 receptor-expressing neurons. Inhibition of BNST PAC1 receptor neuron activity with clozapine-N-oxide significantly increased open arm exploration without reducing total locomotor activity; conversely, stimulating BNST PAC1 receptor function significantly reduced open arm exploratory activities. In sum, these data are consistent with our prior work suggesting a key role for BNST PACAP receptor activation in anxiety and stress; further, these observations importantly clarify the neural circuits involved in anxiety-like behaviors. (PsycInfo Database Record (c) 2025 APA, all rights reserved).