A “herculean” genetic study just found a new way to treat ADHD
Attention disorders such as ADHD occur when the brain has trouble separating meaningful signals from constant background input. The
Attention disorders such as ADHD occur when the brain has trouble separating meaningful signals from constant background input. The brain continuously processes sights, sounds, and internal thoughts, and focus depends on its ability to ignore distractions while responding to what matters. Most current treatments improve attention by increasing activity in brain circuits that control focus, especially in the prefrontal cortex.
A new study suggests a different solution. Instead of increasing brain activity, the research points to reducing baseline activity as a way to lower mental noise and improve attention.
A Gene Linked to Calmer Focus
In research published in Nature Neuroscience, scientists report that a gene called Homer1 plays an important role in attention by shaping how quiet or noisy the brain is at rest. Mice with reduced levels of two specific forms of this gene showed calmer brain activity and performed better on tasks requiring focus.
These findings may represent an early step toward new treatments aimed at calming the mind rather than stimulating it. The implications extend beyond ADHD, since Homer1 has also been linked to disorders involving early sensory processing differences, including autism and schizophrenia.
“The gene we found has a striking effect on attention and is relevant to humans,” says Priya Rajasethupathy, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition at Rockefeller.
An Unexpected Genetic Target
When the research team began exploring the genetics of attention, Homer1 was not an obvious candidate. Scientists have long known the gene for its role in neurotransmission, and many interacting proteins of Homer1 have appeared in genetic studies of attention disorders, but Homer1 itself had not previously stood out as a key driver.
To investigate more broadly, the researchers analyzed the genomes of nearly 200 mice bred from eight different parental strains, including some with wild ancestry. This approach was designed to reflect the genetic diversity seen in human populations and allowed subtle genetic influences to emerge.
“It was a Herculean effort, and really novel for the field,” says Rajasethupathy, who credits PhD student Zachary Gershon for leading the work.
A Large Genetic Effect on Attention
This large-scale genetic analysis revealed a clear pattern. Mice that performed best on attention tasks had much lower levels of Homer1 in the prefrontal cortex, a brain region essential for focus. The gene was located within a stretch of DNA that explained nearly 20 percent of the variation in attention among the mice.
“[That’s] a huge effect,” Rajasethupathy says. “Even accounting for any overestimation here of the size of this effect, which can happy for many reasons, that’s a remarkable number. Most of the time, you’re lucky if you find a gene that affects even 1 percent of a trait.”
Timing Is Critical During Brain Development
Further analysis showed that not all forms of Homer1 contributed equally. Two specific versions, known as Homer1a and Ania3, were responsible for the attention differences. Mice that excelled at attention tasks naturally had lower levels of these versions in their prefrontal cortex, while other forms of the gene were unchanged.
When researchers experimentally reduced Homer1a and Ania3 during a brief developmental period in adolescent mice, the effects were striking. The animals became faster, more accurate, and less distractible across several behavioral tests. Making the same changes in adult mice produced no benefit, showing that Homer1 influences attention during a limited early-life window.
How Quieting the Brain Improves Focus
The most unexpected insight came from examining how Homer1 affects brain cells. Lowering Homer1 levels in prefrontal cortex neurons caused those cells to increase GABA receptors — the molecular brakes of the nervous system.
This change reduced unnecessary background firing while preserving strong, focused bursts of activity when important cues appeared. Instead of responding constantly, neurons conserved their activity for moments that required attention, leading to more accurate responses.
“We were sure that the more attentive mice would have more activity in the prefrontal cortex, not less,” Rajasethupathy says. “But it made some sense. Attention is, in part, about blocking everything else out.”
A Calmer Way to Think About Attention
For Gershon, who lives with ADHD, the findings felt intuitive. “It’s part of my story,” he says, “and one of the inspirations for me wanting to apply genetic mapping to attention.”
He was also the first in the lab to notice that lowering Homer1 improved focus by reducing distractions. In his view, the results align with common experiences. “Deep breathing, mindfulness, meditation, calming the nervous system — people consistently report better focus following these activities,” he says.
Rethinking Future Treatments
Current treatments for attention disorders typically increase excitatory signaling in prefrontal brain circuits using stimulant medications. The new findings point toward a different possibility: therapies that improve attention by calming neural activity instead of amplifying it.
Because Homer1 and its interacting proteins have been linked to ADHD, schizophrenia, and autism, further research may reshape how scientists understand multiple neurodevelopmental conditions.
Future studies from the Rajasethupathy lab will focus on refining the genetic understanding of attention, with the goal of developing therapies that precisely adjust Homer1 levels.
“There is a splice site in Homer1 that can be pharmacologically targeted, which may be an ideal way to help dial the knob on brain signal-to-noise levels,” Rajasethupathy says. “This offers a tangible path toward creating a medication that has a similar quieting effect as meditation.”
