DREADD-mediated inhibition of anterior retrosplenial cortex: Effects on novelty recognition of objects, locations, and object-in-place associations in male and female Long Evans rats.

Previous research suggests ionotropic glutamate receptors in anterior retrosplenial cortex (aRSC) are important for short-term (1-hour) object-in-place (OiP) novelty recognition, indicated by enhanced interaction with novel object-location pairs during OiP test phases. Here, male and female rats were repeatedly tested in three 1-hour delay novelty recognition tests: object recognition (OR), object location (OL), and OiP. Prior to behavioral testing, control (AAV5-CaMKIIα-mCherry) or active (AAV5-CaMKIIα-hM4D(Gi)-mCherry) viral vectors were bilaterally infused into the aRSC of male (8 control, 13 active) and female (8 control, 13 active) Long Evans rats, enabling selective inhibition of aRSC neurons with the hM4D agonist Compound 21 (C-21). Following recovery from surgery, rats were repeatedly tested in recognition tests following injection of either saline or C-21 (1.0 mg/kg; i.p.) ∼45-min prior to test phases (6 tests/rat). Analyses of exploration times indicated that total object interaction times did not differ between phase, sex, or treatment. Further analyses revealed that C-21 treatment of rats infused with the active vector reduced novelty recognition in the OR test yet had no influence in the OL test, regardless of sex. Interestingly, C-21 also reduced novelty recognition in OiP recognition test phases, an effect only observed in male rats infused with the active vector. Findings highlight a nuanced influence of aRSC neurons in supporting novelty recognition which varies by sex and type of stimuli assayed.