When the Brain Doesn't Update Reality: New Discovery Explains Why Delusions Persist in Schizophrenia

The study investigated why the brain has difficulty updating beliefs in schizophrenia. Using mice with a genetic mutation associated with the disorder, researchers observed deficits in decision-making and identified reduced activity in the mediodorsal thalamus. Experiments that directly manipulated this region confirmed its central role in the problem. The results suggest that dysfunction in this area may explain the cognitive rigidity and delusions characteristic of the disease, pointing to new avenues for treatment.

Schizophrenia is a complex mental disorder that affects how a person thinks, interprets reality, and makes decisions. One of its most striking symptoms is delusions, firm beliefs that do not correspond to reality and that persist even in the face of contrary evidence.

Scientists have long suspected that these delusions are related to a difficulty in the brain updating beliefs based on new information. However, understanding exactly which brain mechanisms are involved in this process has always been a challenge.

The study presented seeks to answer this question by investigating how specific changes in the brain can lead to this cognitive "freeze."

In our daily lives, we are constantly adjusting our beliefs based on new experiences. For example, if something unexpected happens, the brain re-evaluates predictions and changes strategies. This process involves internal calculations that assess probabilities, rewards, and consequences.

In schizophrenia, it is believed that this system is impaired, causing the brain to maintain erroneous interpretations even when they no longer make sense. This can result in a distorted perception of reality.

To investigate this phenomenon, researchers used genetically modified mice with a mutation in a gene associated with schizophrenia. This gene is related to communication between neurons, especially in receptors important for the transmission of signals in the brain. Alterations in this type of receptor can directly affect how information is processed, learned, and updated over time.

Scientists developed an experimental task that simulates expectation-based decision-making. Mice had to search for food in different locations, learning over time which options were most advantageous.

Most interestingly, this task was designed to allow for a detailed analysis of the mental process behind the choices, using computational models. This means that the researchers not only observed the final behavior but also inferred how the animals' "thinking" evolved during the task.

During the experiments, the scientists analyzed the activity of a specific brain region called the mediodorsal thalamus. This area acts as an integration center, connecting different regions involved in cognition and decision-making.

In healthy mice, the neurons in this region clearly represented the values ​​of the available choices and cognitive states, that is, they helped the animal maintain a coherent understanding of what was happening. In mice with the mutation, this activity was reduced and disorganized.

To confirm the role of this region, the researchers used a technique called optogenetics, which allows them to control the activity of neurons with light. When they temporarily "switched off" the mediodorsal thalamus in healthy mice, these animals began to behave similarly to those with the genetic mutation, with inconsistent decisions and difficulty in updating strategies.

On the other hand, when they increased the activity of this region in the altered mice, there was a significant improvement in performance. This demonstrated a direct relationship between this area of ​​the brain and the observed problem.

Optogenetic Technique

The study revealed that the difficulty in updating beliefs, a central characteristic of schizophrenia, may be linked to inadequate functioning of the mediodorsal thalamus. When this region does not function correctly, the brain begins to represent information in a "noisy" and unstable way, making it difficult to make coherent decisions. In other words, the brain loses the ability to adjust its interpretations based on new evidence.

These findings help to understand why people with schizophrenia can get "stuck" in certain beliefs. The problem lies not only in the content of thought, but in how the brain processes and updates information.

By identifying the mediodorsal thalamus as a key point in this process, the study opens the way for new therapeutic approaches that can focus on restoring the activity of this region and improving cognitive flexibility.

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

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 

Nature Neuroscience. 18 March 2026

DOI: 10.1038/s41593-026-02237-9

Abstract:

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 (Grin2aY700X+/−) and developed a computationally trackable foraging task to assess belief-driven decision strategies in mice. Grin2aY700X+/− 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 Grin2aY700X+/− 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 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.