Chemogenetic disruption of monkey perirhinal neurons projecting to rostromedial caudate impairs associative learning.

Primates, including humans, use stimulus-reward associations to guide foraging. We previously showed that both rhinal cortex (Rh) and rostromedial caudate (rmCD) of rhesus monkeys play causal roles in assigning value to visual stimuli. Layer 5 neurons in Rh project to rmCD. Here, we reversibly interrupted this layer 5 connection in two male monkeys by combining a unilateral Rh lesion with contralateral expression of an inhibitory DREADD delivered using a retrograde lentivirus (FuG-E) injected into rmCD. Interruption of projection neurons from Rh to rmCD had little effect on already learned stimulus-reward associations but impaired the learning of new associations. The learning impairment appeared when the projection neurons from perirhinal cortex (PRh) to rmCD were silenced using microinjections of deschloroclozapine (DCZ) into PRh. The pathway-specific silencing led to a significant deficit in learning new stimulus-reward associations. These results suggest that the learning, but not retrieval, of visual stimulus-reward associations involves projection neurons from PRh to rmCD.Significance Statement Primates use stimulus-reward associations to guide foraging. Both Rh and rmCD play a causal role in visual-stimulus-reward associations in non-human primates. There is a strong anatomical projection from Rh to rmCD. This connection was reversibly interrupted by combining a unilateral Rh lesion with contralateral expression of an inhibitory DREADD via a retrograde lentivirus (FuG-E) injected into rmCD. Interruption of this connection had little effect on already learned stimulus-reward associations but impaired the learning of new associations. We further localized the source of this learning impairment to neurons projecting to rmCD from the Rh, i.e., PRh. Our findings emphasize the significance of this circuit in adaptive behavior and indicate that learning and retrieval depend on different neural pathways.