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U. study: Could gene manipulation be a boost to the brain?

SALT LAKE CITY — A newly published study from University of Utah researchers suggests there are ways to improve the adaptability of brains in mice even after the naturally occurring window for such flexibility has closed.

Specifically, the component of the brain responsible for sight — called the visual cortex — regained adaptability in middle-age mice subjects following the manipulation of a gene called arc, said Jason Shepherd, professor of neurobiology and anatomy at the U. and the study's lead investigator.

The findings could potentially have implications for aging humans, though more research on the subject needs to be done, Shepherd said.

"Just through normal aging, there's cognitive decline in humans, as well as in response to injury to the brain," he told the Deseret News. "If we could figure how to boost that gene in that context, we could boost recovery."

Shepherd said future studies may focus on whether the arc gene can also promote improvements in other cognitive functions in mice, including memory retention and learning new information.

"The question is — can we boost plasticity in other areas of the brain?" he asked. "We're going to use similar approaches to look at other aspects of behavior in these mice."

Cognitive adaptability, frequently referred to as "brain plasticity," has been shown to generally decline as humans age, which "explains why certain eye conditions such as lazy eye can be corrected during early childhood but not later in life," said University of Utah Health spokeswoman Julie Kiefer.

Mice likewise have a "critical window" earlier in life, in which they have a high amount of brain plasticity, according to prior research. Shepherd's research, Kiefer said, shows "arc rises and falls in parallel with visual plasticity" and that those two variables "peak in teen mice and fall sharply by middle age."

A previous study by Shepherd indicated that depriving young mice of the arc gene hurts their ability to productively adapt to vision loss, compared to their peers for whom the gene was not taken away.

In Shepherd's newly released study, published Tuesday in Proceedings of the National Academy of Sciences scientific journal, he tested the arc gene's effect on the brain's visual plasticity in two ways. First, he and study co-author Harohiko Bito, a University of Tokyo professor, tested mice whose high levels of the arc gene were prolonged into middle age.

Those mice "responded to visual deprivation as robustly as their counterparts," showing a strong ability to adapt with that part of their brain, Kiefer said.

Other factors besides explicitly manipulating the arc gene have been shown to lengthen the critical window in which mice can maintain high brain plasticity, she said, including highly stimulating surroundings and the use of the antidepressant drug fluoxetine.

But Shepherd explained that the new study's second method of testing led to the more unique finding that the mice subjects' visual cortex adaptability could be reignited by the arc gene after their critical window of brain plasticity had closed. Under that method, middle-age mice whose period of plasticity had ended, as is typical for mice of that stage of life, were reintroduced to the arc gene. Viruses were used as the delivery method to bring the gene back again.

Kiefer said that "even though the window had already shut, arc enabled it to open once again."

“It was incredible to see that in adult mice, who have gone through normal development and aging, simply overexpressing arc with a virus restored plasticity,” Kyle Jenks, a graduate student working in Shepherd's lab who is listed as "co-first author" in the study, said in a statement.

Shepherd concluded that the study suggests "it's unclear if the changes that you see in the adult brain (must be) permanent or not." Even if the window of plasticity has passed in a mouse, he said, "the brain has the capacity to be plastic — it just has to have all the right buttons."

The Massachusetts Institute of Technology also played a role in the study. Financial backers of the research included the Maryland-based Howard Hughes Medical Institute, MIT's Picower Institute Innovation Fund, the E. Matilda Ziegler Foundation for the Blind and the National Institutes of Health.