Reduced mediodorsal thalamus activity underlies aberrant belief dynamics in a genetic mouse model of schizophrenia

Belief updating is thought to be impaired in schizophrenia, leading to delusions. The neural substrates underlying belief updating are unknown, in part due to a lack of appropriate animal models and behavior readouts. We generated mice bearing a schizophrenia-associated point mutation in Grin2a (Grin2a^Y700X+/-) and developed a computationally trackable foraging task to assess belief-driven decision strategies in mice. Grin2a^Y700X+/- mice performed less optimally than their wild-type (WT) littermates, due to unstable cognitive states related to noisy representation of dynamic task values. We identified the mediodorsal (MD) thalamus as being hypofunctional in Grin2a^Y700X+/- mice and showed that MD neurons encode dynamic task values and cognitive states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2a^Y700X+/- mice and enhancing MD activity rescued task deficits in Grin2a^Y700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction and a potential target for future therapeutics.