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. The role of mediodorsal thalamus inputs to the orbitofrontal cortex in learning remains unclear. Here authors show that these inputs are required for associative learning and regulate learning-dependent neural representations via feedforward inhibition.