Using Genetics to Unravel the Mysteries of the Brain

The impact of genetics on neuroscience has been profound, generating new insights into brain function and the roots of mental and neurological diseases. That was true even before researchers completed the human genome sequence — a milestone they hit last month, partly due to new methods developed by researchers at the Kavli Institute at Rockefeller University. In fact, the majority of research highlighted in this month's roundup wouldn't have been possible without the genomics revolution. In one study, researchers at Yale uncover risk genes for congenital hydrocephalus, a disorder in which the brain's cavities fill with fluid, upending the dominant view of the disease. Another study from researchers at John Hopkins University takes advantage of tools that can turn genes on and off to study how the brain executes complex, sequential movements. And at the Salk Institute, a geneticist is connecting the dots between genes and behavior in fruit flies, with the ultimate goal of understanding the interplay between nature and nurture.

A complete sequence of the human genome

Twenty years after scientists released the initial rough draft of the human genome, the sequence is finally complete. Researchers worldwide have contributed to the Human Genome Project, including Erich Jarvis at Rockefeller University, who played a crucial part in filling in the remaining 8 percent of the genome that had remained unsequenced and unstudied. That 8 percent is primarily non-coding DNA — stretches of As, Cs, Gs, and Ts that don't give rise to proteins, the building blocks of cells. "You would think that, with 92 percent of the genome completed long ago, another eight percent wouldn't contribute much," Jarvis told Rockefeller News. "But from that missing eight percent, we're now gaining an entirely new understanding of how cells divide, allowing us to study a number of diseases we had not been able to get at before." Jarvis and his team developed sequencing methods that have helped scientists survey hard-to-read stretches of the genome and piece them together. The methods stem from his experience leading the Vertebrate Genomes Project, a kind of "genome ark" of the world's vertebrate species. Researchers aim to generate complete genomes of more than 50,000 species to support research and conservation. Jarvis is a member of the Kavli Neural Systems Institute at Rockefeller.

Clues to the cause of "water on the brain"

About 1 in 1,000 children are born with hydrocephalus, a disorder in which cerebral spinal fluid (CSF) builds up in the brain's cavities. Neurosurgeons usually operate to drain the excess fluid. Still, many children with the disorder continue to have neurodevelopmental problems, including epilepsy and intellectual disability. Over the past decade, researchers at Yale University and Massachusetts General Hospital (MGH) have been studying the genetic roots of the disease in children with congenital hydrocephalus. Their findings, the latest published in Nature Neuroscience, show that hydrocephalus isn't the result of a plumbing problem in the brain. Instead, some forms of the disorder may be due to changes to neural stem cells, which give rise to neurons and macroglia — the two major classes of brain cells. Specifically, the researchers uncovered dozens of mutations associated with the disease affecting TRIM71, a gene that regulates neural stem cell growth and differentiation. In a news article, co-lead author Duy Phan said, "This began to hint to us that rather than affecting fluid circulation, hydrocephalus gene mutations may be disrupting the earliest processes of human brain development to cause hydrocephalus." The findings suggest more children with the disorder should undergo genetic testing. According to the researchers, the children may also benefit from therapies that support neurodevelopment. Phan is an M.D./Ph.D. student at the Yale School of Medicine, co-supervised by MGH neurosurgeon Kristopher Kahle and Yale neuroscientist Nenad Sestan. Phan, Sestan, and co-author Pasko Rakic are members of Yale's Kavli Institute for Neuroscience.

Micromanaging movement

Daniel O'Connor, a member of the Kavli Neuroscience Discovery Institute at Johns Hopkins University, studies the neural circuits underlying touch perception to learn how those circuits give rise to our sensory experience of the world. In a new study published in Nature, O'Connor and his team pinpoint the higher brain regions in mice that flexibly control their ability to perform complex, sequential movements. That flexibility is essential to our survival, yet it is poorly understood how the brain adapts and sends out new orders when a complex movement is interrupted. In the new study, O'Connor found that three cortical areas play distinct roles in guiding the animals' movements. The primary motor and primary somatosensory areas control the mice's immediate movements. The premotor area guides the sequence of movements and how mice adjust the sequence when disturbed. "The results provide a new picture of how a hierarchy among neural networks in the sensorimotor cortex are managing sequential movements," O'Connor explained in a news article. "The more we learn about these interacting neural networks, the better positioned we are to understand sensorimotor dysfunction in humans and how to correct it."

How the brain might influence lifespan

Kenta Asahina studies how genes drive behaviors like aggression and the escape response in fruit flies, as well as genetic commonalities between fruit flies and mammals that could provide insights into mental and neurological illnesses. In a Q&A with Inside Salk magazine, Asahina discusses his path to science, his affinity for insects, and a fascinating set of experiments on the brain and health, including how social isolation influences lifespan and aging. "While food, exercise, and sleep are all important for a healthy life, experiments in the fly may tell us something about how mental health can impact health and longevity," said Asahina, a member of the Kavli Institute for Brain Science at the Salk.

The ripple effect on vision

Waves of neural activity travel through the brain day and night, but their function isn't always understood. In a new study in Science Advances, neuroscientist Thomas Albright and his collaborators describe how brain waves contribute to our ability to see the world around us. Their findings add to our understanding of the role of brain waves in information processing. The team observed the activity of more than 100 neurons in an animal model to better understand how the cells coordinated their response to visual stimuli. Next, they developed and tested a mathematical model that described the neurons' behavior. To their surprise, only a wave model of neural activity could explain their observations. The researchers showed that visual stimuli provoke microscopic brain waves that interact to create patterns throughout the visual cortex. Peaks of high activity and troughs of low activity directly influence our ability to discriminate textures and other visual features. "When you're out in the world, there are many, many inputs and so all these different waves are generated," said Albright in a news article. "The net response of the brain to the world around you has to do with how all these waves interact." Albright is a member of the Kavli Institute for Brain and Mind at the Salk Institute. His collaborators were Salk staff scientist Sergei Gepshtein and Sergey Savel'ev of Loughborough University.