Scientists Discover Why the Brain Gets Stuck in Schizophrenia

Why do some people struggle to adapt to new information and stay locked into outdated beliefs?

Scientists at MIT may have found a key reason. A newly identified gene mutation appears to disrupt a brain circuit that helps us update our understanding of the world. When this system fails, the brain may cling to old ideas even when reality changes.

In experiments with mice, researchers showed that this mutation interferes with the brain’s ability to adjust decisions based on new input, a problem that closely mirrors cognitive symptoms seen in schizophrenia.

The mutation occurs in a gene called grin2a, previously linked to schizophrenia in large genetic studies. The findings suggest that targeting this circuit could eventually help improve cognitive function in some patients.

“If this circuit doesn’t work well, you cannot quickly integrate information,” says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT. “We are quite confident this circuit is one of the mechanisms that contributes to the cognitive impairment that is a major part of the pathology of schizophrenia.”

Feng and Michael Halassa, an associate professor of psychiatry and neuroscience at Tufts University, are the senior authors of the study published in Nature Neuroscience. Tingting Zhou and Yi-Yun Ho led the research.

A Brain That Can’t Update Itself

Schizophrenia has long been known to have a strong genetic basis. About 1 percent of people develop the condition, but the risk rises to 10 percent if a close family member is affected and up to 50 percent for identical twins.

Over the years, researchers have identified more than 100 genetic variants linked to schizophrenia. Many of these are found in regions of DNA that do not directly code for proteins, making their role difficult to interpret.

To get clearer answers, scientists turned to whole-exome sequencing, which focuses on protein-coding genes. By analyzing about 25,000 people with schizophrenia and 100,000 without, they identified 10 genes where mutations significantly raise risk.

One of those genes is grin2a.

This gene helps form part of the NMDA receptor, which plays a central role in brain signaling and learning.

Why the Brain Gets “Stuck”

To understand how this mutation affects behavior, researchers engineered mice with the same genetic change.

While mice cannot experience hallucinations or delusions (loss of contact with reality), they can model related problems, such as difficulty adjusting to new information.

For years, scientists have suspected that schizophrenia may involve a breakdown in how the brain updates beliefs.

“Our brain can form a prior belief of reality, and when sensory input comes into the brain, a neurotypical brain can use this new input to update the prior belief. This allows us to generate a new belief that’s close to what the reality is,” Zhou says. “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, so the new belief is detached from reality.”

The Experiment That Revealed the Problem

To test this idea, the researchers designed a decision-making task.

Mice had to choose between two levers. One offered a small reward and required multiple presses, while the other delivered a larger reward with fewer presses.

At first, all mice preferred the better option. But over time, the effort required to get the larger reward increased.

Healthy mice adapted. As the task became less efficient, they switched to the easier option and stuck with it.

Mice with the grin2a mutation struggled. They kept switching back and forth and took much longer to settle on the better choice.

“We find that neurotypical animals make adaptive decisions in this changing environment,” Zhou says. “They can switch from the high-reward side to the low-reward side around the equal value point, while for the animals with the mutation, the switch happens much later. Their adaptive decision-making is much slower compared to the wild-type animals.”

The Brain Circuit Behind Flexible Thinking

The researchers traced the problem to a specific brain region called the mediodorsal thalamus. This area connects to the prefrontal cortex, forming a circuit that supports decision-making and flexible thinking.

Neurons in this region appeared to track how valuable each option was, helping guide choices. The team also observed different patterns of activity depending on whether the mice were exploring options or committing to a decision.

Reversing the Effects

In a striking result, the researchers were able to reverse the behavioral problems.

Using optogenetics, they engineered neurons in the mediodorsal thalamus to respond to light. When these neurons were activated, the mice began behaving more like normal mice.

This suggests that the circuit itself plays a direct role in the symptoms.

What This Means for Schizophrenia

Only a small percentage of schizophrenia patients carry mutations in grin2a. However, the researchers believe this circuit may represent a shared pathway that contributes to cognitive impairment across different forms of the disorder.

If so, it could become a promising target for new treatments aimed at improving thinking and decision-making.

The team is now working to identify specific parts of the circuit that could be targeted with drugs.

Reference: “Reduced mediodorsal thalamus activity underlies aberrant belief dynamics in a genetic mouse model of schizophrenia” by Tingting Zhou, Yi-Yun Ho, Nolan D. Hartley, Ray X. Lee, Amanda B. Fath, Kathleen He, Xun Yuan, Sam Merrow, Jonathan Scott, Navdeep Bajwa, Jonathan Wilde, Xian Gao, Cui Li, Evan Hong, Zhanyan Fu, Matthew R. Nassar, Ralf D. Wimmer, Tarjinder Singh, Michael M. Halassa and Guoping Feng, 18 March 2026, Nature Neuroscience.
DOI: 10.1038/s41593-026-02237-9

The research was funded by the National Institutes of Mental Health, the Poitras Center for Psychiatric Disorders Research at MIT, the Yang Tan Collective at MIT, the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, the Stelling Family Research Fund at MIT, the Stanley Center for Psychiatric Research, and the Brain and Behavior Research Foundation.

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