Control of associative learning by the mediodorsal thalamus-orbitofrontal cortex circuit

Mediodorsal thalamus (MD) projections to the prefrontal cortex are crucial for adaptive cognitive functions. Using a Go/No-Go olfactory discrimination task in male mice, we investigate how MD input to the orbitofrontal cortex (OFC) regulates associative learning and modulates cue-value and outcome representations in OFC neurons. We show that inactivating MD projections to the OFC impairs learning but does not affect performance in the well-trained phase. During learning, cue value selectivity increased and outcome selectivity was dynamically reshaped in both MD and OFC, and inactivating MD projections disrupted these learning-associated changes in OFC neurons. Furthermore, MD projections targeted OFC parvalbumin (PV) interneurons, whose inactivation attenuated the learning-related enhancement of cue value selectivity and altered outcome selectivity dynamics in OFC broad-spiking cells. Thus, MD inputs engage PV interneuron-mediated feedforward inhibition to dynamically shape cue-value and outcome selectivity in the OFC, supporting associative learning.