Halassa, M. | bioRxiv Science

bioRxiv2024

Enhancement of Mediodorsal Thalamus Rescues Aberrant Belief Dynamics in a Novel Mouse Model for Schizophrenia

Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to 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 and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral 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.

neuroscience↗

bioRxiv2023

Modulation of prefrontal couplings by prior belief-related responses in ventromedial prefrontal cortex

Humans and animals can maintain constant payoffs in an uncertain environment by steadily re-evaluating and flexibly adjusting current strategy, which largely depends on the interactions between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). While the ventromedial PFC (vmPFC) represents the level of uncertainty (i.e., prior belief about external states), it remains unclear how the brain recruits the PFC-MD network to re-evaluate decision strategy based on the uncertainty. Here, we leverage nonlinear dynamic causal modeling on fMRI data to test how prior belief-dependent activity in vmPFC gates the information flow in the PFC-MD network when individuals switch their decision strategy. We show that the prior belief-related responses in vmPFC had a modulatory influence on the connections from dorsolateral PFC (dlPFC) to both, lateral orbitofrontal (lOFC) and MD. Bayesian parameter averaging revealed that only the connection from the dlPFC to lOFC surpassed the significant threshold, which indicates that the weaker the prior belief, the less was the inhibitory influence of the vmPFC on the strength of effective connections from dlPFC to lOFC. These findings suggest that the vmPFC acts as a gatekeeper for the recruitment of processing resources to re-evaluate the decision strategy in situations of high uncertainty. Author SummaryPrefrontal cortex (PFC) together with the mediodorsal thalamus (MD) jointly establish computations critical for behavioral adaptations. While the task uncertainty (i.e., prior belief) was represented by the ventromedial PFC (vmPFC), it remains unclear how the PFC-MD network reallocates the processing resources to re-evaluate decision strategy under uncertainty. Here we filled this gap by leveraging the Bayesian hierarchical modelling and nonlinear dynamic causal modelling in an associative learning task. We found that in situations of high uncertainty, the prior belief-related responses in vmPFC significantly strengthened effective connectivity from the dorsolateral PFC to the orbitofrontal cortex, but not to the MD. The findings provide evidence for the role of vmPFC in driving the re-evaluation of the decision strategy during behavioral adaptations in situations of uncertainty.

neuroscience↗