Researchers at Duke Health have uncovered a connection between an immune system gene regulator, STAT1, and hyperactive behaviors in mice. Their study, published in the journal Brain, Behavior, and Immunity, demonstrates how prolonged activation of this gene regulator in dopamine neurons disrupts brain function, suggesting a potential link to neurodevelopmental disorders such as autism and ADHD. These findings highlight a possible therapeutic target for addressing these conditions.
The immune system and brain are closely interconnected, with many immune pathways also influencing brain development and behavior. STAT1 is a gene regulator activated during immune responses, particularly in fighting infections. However, researchers have observed that its prolonged activation can negatively affect brain function.
This raised questions about whether dysregulated STAT1 activity might contribute to neurodevelopmental disorders, which often involve behavioral and cognitive challenges. Given the prevalence of immune-related abnormalities in individuals with disorders like autism and ADHD, the research team aimed to explore STAT1’s role in brain function and behavior.
“As a neuroimmunologist, there are a few main reasons we were interested in this topic,” said senior author Anthony Filiano, an assistant professor in the departments of Neurosurgery and Pathology at Duke University School of Medicine and a faculty member in the Marcus Center for Cellular Cures.
“1. There have been large studies showing a connection with maternal infection and an increased risk of neurodevelopmental disorders. 2. The interferon pathway (a classical antiviral system) was enriched in the brains of individuals with neurodevelopmental conditions. 3. We and others have shown that interferons can regulate nerve cells, but the connection is unclear.”
“Last year, we found that neurons have a unique response to interferons,” Filiano explained. “That is unlike other cells that turn the system on and off quickly, to fight infection but not cause collateral damage; neurons had a prolonged response that revolved around the activation of the downstream factor STAT1. This was very surprising since neurons cannot be replaced.”
The researchers used genetically modified mice with a STAT1 mutation to simulate prolonged activation of the gene. These mice were bred at Duke Health in collaboration with Columbia University. The STAT1 mutation was introduced into specific brain cell types, including dopamine neurons, to investigate its effects. Dopamine neurons were chosen because of their critical role in regulating motivation, motor control, learning, and reward processing.
To assess the effects of this mutation, the team conducted a series of behavioral experiments. In the open field test, the mice were placed in an enclosed area where their movement patterns were monitored to evaluate activity levels and potential anxiety-related behaviors. The marble burying test was used to gauge repetitive and compulsive tendencies by counting how many marbles the mice buried within a set period. The tail suspension test involved suspending the mice by their tails to measure hyperactivity, while the pole descent test evaluated their motor skills as they climbed down a vertical pole.
Additional observations focused on grooming behaviors, where researchers recorded the time spent grooming to identify patterns of repetition. Finally, immunohistochemistry was employed to analyze neuronal activity. This method involved staining brain tissues to detect markers like c-Fos, which indicate active neurons. These combined approaches allowed the researchers to comprehensively examine how prolonged STAT1 activation impacts both behavior and underlying neural mechanisms.
The study found that prolonged activation of STAT1 in dopamine neurons significantly altered the behavior and brain function of mice. Mice with this genetic modification exhibited hyperactive tendencies, as evidenced by increased movement in the open field test and less immobility in the tail suspension test. These behaviors suggest a heightened level of activity compared to their unmodified counterparts.
In addition to hyperactivity, the mice demonstrated repetitive and compulsive actions. This was observed in the marble burying test, where the modified mice buried more marbles within the set timeframe. Such behavior points to increased compulsivity, often linked to neurodevelopmental abnormalities.
On a neurological level, the researchers noted changes in the caudate putamen—part of the brain’s basal ganglia and a critical region for learning, memory, motivation, and motor control. This brain region showed both a reduction in neuron count and lower neural activity in the affected mice, emphasizing the role of dopamine signaling in these behavioral patterns.
Interestingly, when the STAT1 mutation was restricted to other brain cell types, such as inhibitory neurons or microglia, these behavioral and neural alterations were absent. This finding underscores the unique sensitivity of dopamine neurons to prolonged STAT1 activation and highlights their pivotal role in regulating behavior.
“We created a transgenic mouse that had a clinical mutation in STAT1,” Filiano told PsyPost. “Using genetics, we were able to specifically insert the mutation in specific cell types. We found that driving a prolonged interferon/STAT1 response, particularly in the neurons of the basal ganglia, which has been implicated in ADHD, was sufficient to cause hyperactivity in mice.”
The study provides new insight into link between the immune system and brain function. But like all research, it has some limitations. The results were derived from mice, and their applicability to humans remains uncertain. Human brains are more complex, and additional studies are needed to confirm these findings in people.
Although STAT1 is a potential target for therapies, developing treatments that specifically modulate its activity in the brain without affecting other vital immune functions is challenging.
Future research could explore the mechanisms by which prolonged STAT1 activation disrupts dopamine signaling, examine its effects on other brain regions and cell types, and develop targeted therapies to modulate STAT1 activity specifically in brain cells without compromising essential immune responses.
“In our future work, we are dissecting how and why neurons have this unique response to interferons,” Filiano said. “There are many FDA-approved drugs targeting this pathway, but the challenge is to specifically target therapeutics to the right cells.”
The study, “Prolonged STAT1 signaling in neurons causes hyperactive behavior,” was authored by Danielle N. Clark, Shelby V. Brown, Li Xu, Rae-Ling Lee, Joey V. Ragusa, Zhenghao Xu, Joshua D. Milner, and Anthony J. Filiano.
