Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation

Beliefs drive decisions but require constant updating in order to match environmental dynamics. In schizophrenia this updating process is thought to be impaired leading to delusions, but the underlying neural substrates are unknown, in part, due to a lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/-), a gene that confers high-risk for schizophrenia identified by recent large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven decision strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, due to unstable cognitive states related to noisy representation of dynamic task values. Using functional ultrasound imaging, in vivo and ex vivo electrophysiological recording, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic task values and cognitive states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/- mice and enhancing MD activity rescued task deficits in Grin2aY700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.