Thalamic projections sustain prefrontal activity during working memory maintenance

The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC) and decreased MD-PFC connectivity is observed in schizophrenia patients. Patients also display cognitive deficits including impairments in working memory, but a mechanistic link between thalamo-prefrontal circuit function and working memory is missing. Here, using pathway-specific inhibition we found directional interactions between MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially-tuned neurons and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for the MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea we found that enhancing MD excitability was sufficient to enhance task performance.