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

The mediodorsal thalamus (MD) is essential for learning and higher-order cognitive functions. While the role of MD projections to the medial prefrontal cortex in cognitive functions is well established, how MD projections to the orbitofrontal cortex (OFC) contribute to learning remains unclear. Using a Go/No-Go olfactory discrimination task in male mice, we found that inactivating MD projections to the OFC impaired learning but did 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, the MD input, via PV interneuron-mediated feedforward inhibition, dynamically supports associative learning by shaping both cue and outcome selectivity in the OFC.