MIT Neuroscientists Identify Genetic Mutation and Brain Circuit Responsible for Cognitive Detachment in Schizophrenia

Neuroscientists at MIT identify a gene mutation in the mediodorsal thalamus that prevents the brain from updating beliefs, explaining reality loss in schizophrenia.

By: AXL Media

Published: Mar 18, 2026, 9:56 AM EDT

Source: Information for this report was sourced from Massachusetts Institute of Technology

Identifying the Genetic Roots of Cognitive Rigidity

One of the most debilitating aspects of schizophrenia is the struggle to incorporate new information, a deficit that can lead to a profound loss of contact with reality. Using whole-exome sequencing on a massive scale—analyzing 25,000 sequences from patients and 100,000 controls—scientists at the Broad Institute of Harvard and MIT identified 10 genes that significantly increase disease risk. Among these, the grin2a gene stood out. This gene is responsible for encoding a protein that forms part of the NMDA receptor, which handles glutamate signaling on the surface of neurons. By creating a mouse model with this specific mutation, MIT researchers were able to observe exactly how this genetic flaw translates into the cognitive symptoms seen in human patients.

The Failure of Belief Updating and Adaptive Decision Making

In a neurotypical brain, prior beliefs are constantly updated by incoming sensory data to generate a perception that closely matches reality. However, in patients with schizophrenia, the brain often weighs prior beliefs too heavily, ignoring current inputs. To test this in mice, researchers designed a reward-based experiment where animals had to switch between a high-effort, high-reward lever and a low-effort, low-reward option. While healthy mice transitioned to the easier option as the "cost" of the high reward increased, mice with the grin2a mutation remained "stuck," switching much later and struggling to make adaptive decisions. This suggests that the mutation directly slows the integration of new environmental information into the brain's decision-making process.

Locating the Circuitry of Executive Control

Using functional ultrasound imaging and electrical recordings, the MIT team traced these behavioral impairments to the mediodorsal thalamus. This brain region connects directly to the prefrontal cortex, forming a thalamocortical circuit essential for executive control and decision-making. The study found that in neurotypical animals, neuronal activity in the mediodorsal thalamus accurately tracks the changing value of different options. In the mutated mice, this circuit dysfunction prevents the brain from shifting between an exploratory state and a committed state, effectively "blunting" the neural signals that should signal a change in reality or reward value.