The brain is constantly bombarded with information, and focus depends on its ability to filter out distractions and detect what matters. Attention disorders such as attention-deficit hyperactivity disorder (ADHD) involve a breakdown in our ability to separate signal from noise. Stimulant medications improve attention by boosting activity in circuits known to govern attention, such as the prefrontal cortex (PFC). A new study has now discovered a surprising potential alternative strategy, which may be to reduce background activity as a way of turning down extraneous noise.
Headed by Priya Rajasethupathy, MD, PhD, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition at The Rockefeller University, researchers showed that a gene called Homer1 plays a critical role in shaping attention in just that way. Their studies in mice showed that animals with lower levels of two specific versions of the gene experienced quieter brain activity and improved ability to focus. The team says the findings may be the first steps toward a novel therapeutic approach to calming the mind, with implications for ADHD as well as related disorders characterized by early sensory disturbances already linked to Homer1, such as autism and schizophrenia.
“The gene we found has a striking effect on attention and is relevant to humans,” said Rajasethupathy, who is senior author of the team’s published paper in Nature Neuroscience, titled “Gene that Improves Attention in Mice Could Point to Mind-Calming Therapeutic Strategies for ADHD.”
Animals are “bombarded with a constant stream of sensory inputs,” the authors wrote, yet have limited capacity with which to process them. “A mechanism for filtering, prioritizing and directing mental assets is required to prevent sensory overload and enable meaningful comprehension; this process of sensory selection and prioritization is described as attention,” they stated.
The PFC plays an important role in mediating attention control, and many ADHD medications work in the PFC to boost attention. However, the team noted, “The genetic factors and resulting neural circuit physiology driving variation in attention are poorly understood.”
For their reported study the team began by scanning the genomes of nearly 200 mice outbred from eight different parental lines (diversity outbred, DO, mice), including some with wild ancestry, to mimic the genetic diversity found in human populations. This unusually broad variation made it possible to spot genetic effects that might otherwise be missed. “It was a Herculean effort, and really novel for the field,” says Rajasethupathy, who credits PhD student and first author Zachary Gershon for pulling it off.
Using this approach, they ultimately narrowed in on their observation that high-performing mice had far lower levels of the gene Homer1 in the prefrontal cortex, the brain’s attention hub. This gene was found within a genetic locus that accounted for almost 20% of the variation in attention across the mice—”a huge effect,” Rajasethupathy says. “Even accounting for any overestimation here of the size of this effect, which can happen 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.”
Digging deeper, the team also showed that it was specifically the Homer1a and Ania3 variants of Homer1 were causing the difference. Mice that performed well on attention tasks had naturally lower levels of these variants, but not others, in their prefrontal cortex. Subsequent experiments showed that dialing down these Homer1a and Ania3 variants in adolescent mice during a narrow developmental window led to striking improvements. The mice became faster, more accurate, and less distractible across multiple behavioral tests. “… in all cases, we observed a substantial improvement in attentional performance in mice with developmental prefrontal Homer1/Ania3 knockdown compared to controls,” the team stated. The same manipulation in adult mice, however, had no effect, demonstrating that Homer1‘s influence appears to be locked into a critical early-life period.
“Notably, the effects of Homer1a/Ania3 were highly specific to attention, as there were no overall changes in the ability to learn the tasks, and perform other cognitive functions, nor were there obvious sensory-motor impairments or changes in measures of anxiety,” they stated.
The biggest surprise, however, came when the team examined what Homer1 was doing to the brain, mechanistically. They found that reducing Homer1 in prefrontal cortex neurons caused those cells to upregulate GABA receptors—the molecular brakes of the nervous system. This shift created a quieter baseline and more focused bursts of activity when cues appeared. Instead of firing indiscriminately, neurons conserved their activity for moments that mattered, enabling more accurate responses. “Mechanistically, reduced Homer1 levels resulted in an upscaling of GABA receptors and enhanced inhibitory tone in the prefrontal cortex, leading to improved neural signal to noise and attentional performance,” the investigators stated. “… it will be important to understand how Homer1 influences GABAergic receptor expression and why its effects are more prominent during development.”
Rajasethupathy added “We were sure that the more attentive mice would have more activity in the prefrontal cortex, not less. But it made some sense. Attention is, in part, about blocking everything else out.”
The results were less surprising to Gershon, who lives with ADHD. “It’s part of my story,” he said, “and one of the inspirations for me wanting to apply genetic mapping to attention.” Gershon was the first in the lab to notice that reducing Homer1 was improving focus by reducing distractions. To Gershon this made perfect sense. “Deep breathing, mindfulness, meditation, calming the nervous system—people consistently report better focus following these activities,” he commented.
Existing therapies for attention disorders amplify excitatory signals in prefrontal circuits with stimulant medications. But these new findings point toward a potential pathway for developing ADHD medication that could calm rather than stimulate. And the fact that studies have linked Homer1 and its interacting proteins to ADHD, schizophrenia, and autism suggests that further research focused on this gene may provide new frameworks for thinking about a number of neurodevelopmental disorders.
Future work from the Rajasethupathy lab will aim to better understand the genetics of attention, with a view towards potential therapeutic strategies for targeting of 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 said. “This offers a tangible path toward creating a medication that has a similar quieting effect as meditation.” In their paper the team concluded, “More broadly, genetic mapping in DO mice may be a promising approach to dissecting individual behavioral domains that together compose the complex phenotypes of neuropsychiatric disease.”
