Transient DREADD manipulation of the dorsal Dentate Gyrus in rats impairs disambiguation of similar place-outcome associations

The dentate gyrus subfield of the hippocampus is thought to be critically involved in the disambiguation of similar episodic experiences and places in a context-dependent manner. However, most empirical evidence has come from lesion and gene knock-out studies in rodents, in which the dentate gyrus function is permanently perturbed and compensation of affected functions via other areas within the memory circuit could take place. The acute and causal role of the dentate gyrus herein remains therefore elusive. The present study aimed to investigate the acute role of the dorsal dentate gyrus in disambiguation learning using reversible inhibitory DREADDs. Rats were trained on a location discrimination task and learnt to discriminate between a rewarded and unrewarded location with either small (similar condition) or large (dissimilar condition) separation. Reward contingencies switched after a reversal rule, allowing us to track the temporal engagement of the dentate gyrus during the task. Bilateral but not unilateral DREADD modulation of the dentate gyrus impaired the initial acquisition learning of place-reward associations, but performance rapidly recovered to control levels within the same session. Modelling of the behavioural patterns revealed that reward learning and reward sensitivity were not associated with the DREADD-dependent impairment during acquisition learning, suggesting that either the ability to encode place-reward associations, or the fine-grained coding of place were instead affected. Our study thus provides novel evidence that the dorsal dentate gyrus is acutely and bilaterally engaged during the initial acquisition learning of ambiguous place-reward associations, although the exact neural mechanisms supporting this function still need to be fully understood.