HHMI-Funded Brain Bank Yields New Clues to Brain Development
In one region of the human brain, new cells are generated only until 18 months of age.
The creation of brain cells doesn’t end at birth, but it has been hard to pin down how long the brain continues to create new, specialized cells. Now a study led by Howard Hughes Medical Institute (HHMI) investigator David H. Rowitch and colleague Arturo Alvarez-Buylla concludes that in one region of the human brain, new cells are generated only until 18 months of age. The work relied on a new collection of specially prepared brain samples that Rowitch established with HHMI support. The new brain bank has also provided clues to why the brain can’t reverse the cellular damage that results from certain diseases.
Throughout development, new brain cells are made in an area of the brain called the subventricular zone (SVZ). The cells don’t stay there, however. They follow a torrent of moving cells, called the rostral migratory stream (RMS) that migrates toward the olfactory bulb, the part of the brain that processes smell. Studies of animal brains have suggested that cells continue to be produced in the SVZ of adults and move along the RMS throughout life.
These results are different than what’s been seen in rodents and birds, and it could explain some of the complexity of the human brain.
David H. Rowitch
“Most of what we know about the RMS comes from studies of non-human systems such as rats, mice, and birds,” says Rowitch. “There was relatively little known about the human RMS.”
Rowitch and his colleagues at the University of California, San Francisco, wanted to find out whether the results in animals also held true in humans. “We decided to look longitudinally at brain development starting at the time of birth and continuing through adulthood,” says Rowitch.
But to visualize cells in the RMS, the researchers would need brains in good condition, from all ages, to which they could add fluorescent markers. Rowitch and his team hit a roadblock. Most human brains in existing collections are preserved in a chemical that prevents fluorescent markers from working. So they decided they’d have to create their own collection of brains, preserved with a different chemical. HHMI provided the funds to do so.
“HHMI provided the ability to create a new neuropathology center at UCSF, a new brain bank where we could start collecting samples,” says Rowitch. “Now we have better quality samples so to ask new questions.”
With 55 brains collected from deceased humans aged from birth through 84 years old, the researchers were able to see how the SVZ and RMS changed over the human lifespan. They found evidence that the generation of new cells in the SVZ stopped around 18 months of age. The RMS disappeared by seven years of age. They also found that some cells produced in the SVZ didn’t follow the RMS all the way to the olfactory bulb. Instead, they moved in a different stream of cells toward a separate area of the brain, something never seen in mice. The results are published in the September 29, 2011, issue of Nature.
“These results are different than what’s been seen in rodents and birds,” says Rowitch. “And it could explain some of the complexity of the human brain.”
Understanding the normal patterns of cell creation and movement in the developing human brain will allow Rowitch’s lab group to understand how this process might be affected in diseases such as cerebral palsy and other neurological injuries. The researchers plan to compare the RMS of normal brains to those of children with brain damage.
In addition to this study, Rowitch’s team is using the brain bank to learn about other aspects of healthy and damaged brains. In separate work published in the August 2011 issue of Nature Neuroscience, Rowitch used brains from the new bank to better understand the nature of white matter injury in the newborn brain and multiple sclerosis. The brain’s so-called white matter is made up of the long tentacles, or axons, of brain cells that make connections between different parts of the brain and stretch out to the rest of the body. Axons are coated in a white, protective material called myelin.
Rowitch discovered that when brain damage occurs, the Wnt pathway is activated, inhibiting the brain from making more myelin. This slows down the repair of injured axons in diseases including multiple sclerosis and cerebral palsy. After making this finding in the human brains from the brain bank, Rowitch tested whether a drug blocking Wnt could speed up brain repair in rodents. In mice with injuries to their white matter, blocking Wnt sped up the creation of new myelin by 30 percent, he found.
“This is a potential approach we could use to enhance myelin repair in the brain after injury,” says Rowitch.