Global vs regional knockdown of GPR83 differentially regulates anxiety‐like behavior in female mice

Abstract

Anxiety disorders, prevalent in our society, represent a burden for those suffering with these disorders. Recent studies have shed light onto the brain circuits involved in generating anxiety and there are pharmaceutical treatments for anxiety‐disorders. Despite this, patients still suffer, highlighting the need to investigate new targets involved in the etiology of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, was first identified due to its regulation by the glucocorticoid agonist dexamethasone, suggesting that GPR83 may be involved in stress‐responses that underlie anxiety. Subsequent studies identified that GPR83 null mice were resistant to stress‐induced anxiety, however, these studies did not investigate sex differences or specific brain regions. In the present studies, global loss of GPR83 in knockout mice resulted in reduced anxiety‐related behaviors which were more evident in male mice. Additionally, our studies identified that GPR83 is expressed on parvalbumin‐positive neurons in the basolateral and central amygdala. Furthermore, dexamethasone induced sex‐ and brain region dependent regulation of GPR83 expression with a consistent decrease in GPR83 expression in the nucleus accumbens and amygdala of female mice. Therefore, we sought to determine the effect of local GPR83 knockdown in the basolateral amygdala, central nucleus of the amygdala, and nucleus accumbens of female mice. We uncovered that female mice with local GPR83 knockdown in the basolateral amygdala displayed more anxiety‐related behaviors. Overall, our studies uncovered a significant role for GPR83 in the regulation of anxiety‐related behaviors.