Interaction of cholinergic disruption and age on cognitive flexibility in rats

Healthy aging is associated with a functional reduction of the basal forebrain (BF) system that supplies the neurochemical acetylcholine (ACh) to the cortex, and concomitant challenges to cognition. It remains unclear how aging and ACh loss interact to shape cognition in the aging brain. We used a proactive interference (PI) odor discrimination task, shown to depend on the BF in young adults, wherein rats acquired new associations that conflicted with past learning or associations that did not conflict. This manipulation allowed independent assessment of encoding alone vs. encoding in the face of interference. Adult (9.8 ± 1.3 months) or aged male Long-Evans rats (20.7 ± 0.5 months) completed the PI task with systemic administration of a muscarinic cholinergic antagonist, scopolamine, or a pharmacological control. Aged rats were less able to resolve PI than adult rats. Moreover, while scopolamine reduced efficient PI resolution in adult rats, this cholinergic antagonism had no additional effect on aged rat performance, counter to our expectation that scopolamine would further increase perseveration in the aged group. Scopolamine did not impair encoding of non-interfering associations regardless of age. These data suggest that natural aging changes the effect of cholinergic pharmacology on encoding efficiency when past learning interferes.