Summary: Research suggests that cognitive problems linked to schizophrenia may originate from altered thalamic activity during adolescence, a critical window for brain maturation.
Source: Columbia University
Researchers at Columbia University report evidence that disruptions in thalamic activity during adolescence can lead to long-lasting cognitive impairments in adulthood, offering new insight into mechanisms that may underlie cognitive deficits in schizophrenia and related neurodevelopmental disorders.
Published May 19 in Nature Neuroscience, the study focuses on how the thalamus shapes the maturation of the prefrontal cortex during a sensitive developmental period. The findings point to the thalamus as a potential target for interventions aimed at improving prefrontal-dependent cognition in disorders characterized by executive dysfunction.
“Cognitive deficits are a core feature of schizophrenia, yet the circuit-level causes remain poorly understood,” said Christoph Kellendonk, Ph.D., associate professor of psychiatry and molecular pharmacology and therapeutics and senior author of the study. “Our data highlight the thalamus’ role during adolescence in guiding prefrontal cortex development, and suggest new routes for therapeutic development.”
Brain development and schizophrenia
Schizophrenia is a debilitating psychiatric condition often diagnosed in late adolescence or early adulthood. While hallmark symptoms include delusions and hallucinations, cognitive impairments—problems with planning, working memory, attention and cognitive flexibility—are central and frequently precede the onset of psychosis. Many researchers now view schizophrenia as a neurodevelopmental disorder whose abnormal trajectory is established well before symptoms appear.
The prefrontal cortex governs executive functions such as decision-making, impulse control and working memory. In adults, the thalamus serves as a hub that helps regulate prefrontal activity, but the thalamus’ influence on prefrontal maturation during adolescence has been less clear until now.
To explore how altered thalamic signaling during development affects the prefrontal cortex, first author Laura Benoit, an MD, Ph.D. graduate student at Columbia, used targeted manipulations of thalamic neurons in mice during adolescence and tracked the long-term consequences for prefrontal circuit structure, physiology and behavior.
Key findings: adolescent thalamic activity shapes adult cognition
The team found that transient inhibition of mediodorsal and midline thalamic regions during adolescence produced persistent reductions in thalamo–prefrontal projection density and weakened excitatory input to prefrontal neurons. Behaviorally, these animals displayed deficits in attentional set shifting, a measure of cognitive flexibility that is commonly impaired in schizophrenia.
Importantly, the researchers demonstrated that increasing thalamic activity in adulthood—during cognitive testing—restored prefrontal network correlations, task outcome encoding and performance on cognitive tasks in mice that had experienced developmental thalamic suppression. In contrast, inhibiting the thalamus in adulthood did not produce long-lasting deficits, indicating that adolescence represents a sensitive window for thalamocortical circuit maturation.
“Even when cortical maturation is disrupted during development, enhancing thalamic function later in life can reverse cognitive deficits,” said Sarah Canetta, Ph.D., assistant professor of psychiatry and co-leader of the study. “These results support a model in which the thalamus actively shapes prefrontal network formation and suggest that targeted modulation of thalamic activity could have translational relevance for cognitive symptoms in schizophrenia.”
The study was conducted in collaboration with Columbia’s Zuckerman Mind Brain Behavior Institute Center for Theoretical Neuroscience. Stefano Fusi, Ph.D., professor of neuroscience, and postdoctoral researcher Lorenzo Posani contributed to the experimental and theoretical work that supported the conclusions.
About this schizophrenia research news
Author: Press Office
Source: Columbia University
Contact: Press Office – Columbia University
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Original Research: Closed access.
“Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function” by Laura J. Benoit et al., Nature Neuroscience
Abstract
Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function
Impaired cortical maturation is a proposed mechanism underlying neurodevelopmental conditions, including schizophrenia. In sensory cortex, thalamic activity during a postnatal sensitive period is essential for proper maturation. Whether similar thalamic-driven processes shape prefrontal development has been unclear.
This study shows that transient inhibition of mediodorsal and midline thalamic regions in adolescent mice produces a long-lasting reduction in thalamo–prefrontal projection density and diminished excitatory drive onto prefrontal neurons. These structural and physiological changes are associated with adult deficits in prefrontal-dependent cognition, disrupted prefrontal neuronal correlations and impaired encoding of task outcomes.
By contrast, inhibiting the thalamus in adulthood did not elicit enduring effects. Crucially, enhancing thalamic activity during a cognitive task in adulthood rescued prefrontal network dynamics, task encoding and cognitive performance. These results identify adolescence as a sensitive period for thalamocortical circuit maturation and suggest that boosting thalamic activity may offer a therapeutic strategy to improve cognitive function in neurodevelopmental disorders.