Scientists ID 100 memory genes, open new avenues of brain study

Dr. Genevieve Konopka is Assistant Professor of Neuroscience with the O’Donnell Brain Institute. CREDIT UT Southwestern

Scientists have identified more than 100 genes linked to memory, opening new avenues of research to better understand memory processing in the human brain.

A study at the Peter O’Donnell Jr. Brain Institute includes the results of a new strategy to identify genes that underlie specific brain processes. This strategy may eventually help scientists develop treatments for patients with memory impairments.

“Our results have provided a lot of new entry points into understanding human memory,” said Dr. Genevieve Konopka, Assistant Professor of Neuroscience with the O’Donnell Brain Institute at UT Southwestern Medical Center. “Many of these genes were not previously linked to memory, but now any number of labs could study them and understand their basic function in the brain. Are they important for brain development; are they more important for aspects of behavior in adults?”

The study published in Cerebral Cortex stems from previous research by Dr. Konopka that linked specific genes to resting-state brain behavior. She wanted to use that same assessment to evaluate brain activity during active information processing.

To do so, she collaborated with Dr. Bradley Lega, a neurosurgeon with the O’Donnell Brain Institute conducting memory research on epilepsy patients while helping to locate the source of their seizures. Dr. Lega maps the brain waves of these patients to understand what patterns are critical for successful memory formation.

Combining their techniques, the doctors found that a different group of genes is used in memory processing than the genes involved when the brain is in a resting state. A number of them had not previously been linked to any brain process, Dr. Konopka said.

Dr. Lega is hopeful the findings can help scientists better understand and treat a range of conditions involving memory impairment, from epilepsy to Alzheimer’s disease.

He also hopes the study’s success in combining genetics and cognitive neuroscience will encourage more scientists to reach beyond their areas of expertise to elevate their research.

“This kind of collaboration is not possible unless high-quality neuroscience research and academically minded clinicians are in close physical and intellectual proximity. I don’t think either of us working or thinking independently would’ve come up with this type of analysis. Ideally, the O’Donnell Brain Institute will be a natural incubator for these sorts of collaborations for a number of neuroscience fields,” said Dr. Lega, Assistant Professor of Neurological Surgery, Neurology and Neurotherapeutics, and Psychiatry.

Forming sound memories: Autism gene plays key aspect in birdsong

Todd Roberts, Ph.D. CREDIT UT Southwestern Medical Center

Inactivating a gene in young songbirds that’s closely linked with autism prevents the birds from forming memories necessary to accurately reproduce their fathers’ songs, a new study led by UT Southwestern shows.

The findings, published online today in Science Advances, may help explain the deficits in speech and language that often accompany autism and could eventually lead to new treatments specifically targeting this aspect of the disorder.

Study leader Todd Roberts, Ph.D., associate professor of neuroscience and a member of the Peter O’Donnell Jr. Brain Institute at UT Southwestern, explains that the vocalizations that comprise a central part of human communication are relatively unique among the animal world – not just for their complexity, but in the way they’re passed down from caregivers to offspring. Songbirds such as zebra finches also learn complex vocalizations from caregivers (songs are passed on to male offspring typically from their fathers). Much like humans, these animals have intricate brain circuitry devoted to this task, found in a region of the brain in the birds often referred to as the high vocal center, or HVC.

Because of the parallels between language learning in humans and song learning in the birds, Roberts says, songbirds are often used as a scientific model for understanding speech development in people, including conditions in which vocal communication is changed.

In their research, Roberts and his colleagues used zebra finches to study the role of a gene called FoxP1, one of the genes most correlated with autism. Mutations of this gene cause a specific subtype of autism linked with severe language impairment and intellectual disability.

Roberts, a Thomas O. Hicks Scholar in Medical Research, explains that learning vocalizations for both songbirds and humans consists of two different stages: First, birds and humans must form a memory of sounds. Next, they practice the sounds through imitation. Juvenile zebra finches typically practice their fathers’ song thousands of times a day over three months, rehearsing it around 100,000 times until it’s a close match. These birds can memorize the song 20 to 60 days after hatching, but they don’t start to practice singing it until approximately 35 to 40 days after hatching.

To better understand the role FoxP1 might play in both parts of this process, the researchers separated young zebra finches into two groups: Half the birds spent their early lives in contact with their singing fathers and continued to live with them while they practiced their songs; the other half spent their early lives with their songless mothers and later joined their fathers during the practice phase. Either before the birds formed memories of the songs or before they began practicing, Roberts and his colleagues used a technique called RNA interference to “knock down” FoxP1 in the birds’ HVC, ridding cells in this brain region of the vast majority of this gene’s protein products. This technique used constructs created in the lab of Roberts’ close collaborator and study co-author Genevieve Konopka, Ph.D., associate professor of neuroscience at UT Southwestern.

When the researchers analyzed the birds’ songs in adulthood, they found that only those with active FoxP1 during the song memorization phase were able to accurately reproduce their fathers’ songs. If this gene was knocked down during the practice phase, these birds could still correctly mimic the songs. However, birds in which FoxP1 was inactivated before memorization sang haphazard songs that bore no resemblance to the ones their fathers sang.

“Our results suggest that FoxP1 is key for forming the song memories in these birds that are critical for imitation later in life,” Roberts says. “A similar deficit in humans could play a parallel role in speech development, blocking babies from forming memories of adult speech they hear around them and hindering their own communication as they grow.”

If this finding is reinforced in future studies, he adds, it could lead to new types of therapy for children with autism. Current ASD therapies centered on speech development often focus on helping children learn the motor skills necessary to produce sounds. However, Roberts says, techniques that focus on helping children form speech memories may be more important. In the future, he says, it may be possible to avoid speech deficits by replacing the missing FoxP1 protein using gene editing or altering FoxP1-regulated signaling using pharmaceuticals.

“This study is not only critical for understanding the symptoms of patients with FoxP1-related autism but also lays the groundwork for studying many other genes associated with autism using the songbird system,” adds Konopka, a Jon Heighten Scholar in Autism Research.