MIT-led researchers report that a schizophrenia-associated mutation in the gene GRIN2A reduces activity in a mediodorsal thalamus–prefrontal cortex circuit that helps the brain update beliefs using new information. In experiments, mice carrying the mutation were slower to shift choices as reward conditions changed, and optogenetic activation of mediodorsal thalamus neurons made their behavior more similar to unaffected mice, the team reports in Nature Neuroscience.
A schizophrenia-associated mutation in the gene GRIN2A disrupts activity in a brain circuit connecting the mediodorsal thalamus and the prefrontal cortex, according to a study from researchers at the Massachusetts Institute of Technology.
The work was led by Guoping Feng of MIT and Michael Halassa of Tufts University School of Medicine, who are listed as the study’s senior authors. Tingting Zhou and Yi-Yun Ho are the paper’s lead authors, MIT said.
Researchers describe the mediodorsal thalamus–prefrontal cortex pathway as part of a thalamocortical circuit involved in cognitive functions such as executive control and decision-making, including the ability to update beliefs based on incoming information.
To probe how the mutation affects behavior, Zhou designed a reward-learning experiment in which mice chose between two levers to obtain a food reward. One lever initially provided a higher reward, while the effort required to obtain that higher reward increased over time. MIT said that, as the task progressed, unaffected mice tended to adjust their choices and ultimately shifted to the lower-reward option once the cost-benefit balance changed, while mice with the GRIN2A mutation switched later and spent longer alternating between the options.
Using functional ultrasound imaging and electrical recordings, the researchers reported that the brain region most affected by the GRIN2A mutation was the mediodorsal thalamus. They also reported that neuronal activity in this region tracked changes in the relative value of the reward options.
In another set of experiments, the team used optogenetics to activate mediodorsal thalamus neurons in the mutant mice. MIT said that when those neurons were stimulated, the mice began behaving more like mice without the mutation.
Zhou described the broader hypothesis motivating the work as an impairment in how the brain balances existing expectations against new sensory input. “What happens in schizophrenia patients is that they weigh too heavily on the prior belief. They don’t use as much current input to update what they believed before,” Zhou said.
The researchers cautioned that only a small percentage of people with schizophrenia carry mutations in GRIN2A, but argued that dysfunction in this circuit could represent a shared mechanism contributing to cognitive impairment in at least some patients. The study appears in Nature Neuroscience, and the team said it is now working to identify potentially druggable targets within the circuit.
