Researchers find chemical secret to recapturing youthful brain

Los Angeles TimesMarch 8, 2013 

WASHINGTON -- Adults (especially parents) often find fault with the teenage brain. But they should admit that it is a powerful learning machine -- and that sometimes, the grown-ups wish they could recapture its nimbleness. New research, conducted by researchers at Yale University and published Wednesday in the journal Neuron, homes in on the genetic and chemical mechanics that could make that possible.

The new research, says the study's senior author, Dr. Stephen M. Strittmatter, helps point the way to therapies that might allow victims of stroke or spinal cord damage to "set back their brain's clock" to a stage of development that would foster the rapid relearning of lost skills. And, he added, it might aid those hobbled by post-traumatic stress disorder to reconfigure their relationship to painful memories and learn to live again.

The present research was done in mice, but clinical trials now in the planning stages could allow researchers to test on human adults agents that mimic the cognitive fountain of youth.

"It's about going from adulthood back to adolescence, and in general that's something we would not want to do," said Strittmatter, a neurologist who directs Yale School of Medicine's program on neuroscience, neurodegeneration and repair. "But in some cases, it could prove very helpful."

In response to the world around it, the adolescent brain is a marvel of regeneration, wiring and rewiring itself constantly as its owner learns and refines the motor, social and perceptual skills that will form the foundation of his or her adult behavior. That ability to adapt, respond and repair on a dime is called plasticity.

Having lived through these wonder years, the adult brain becomes a bit, shall we say, plodding. Its cells continue to sprout the axons and dendrites that lash neurons together in a process we call learning. But there's nothing like the mad re-creation of brain architecture -- the constant replacement of existing neuronal connections and their replacement with new ones -- that characterizes the teen brain.

The brain, says Strittmatter, "becomes cemented in place." Compared with the highly plastic adolescent brain, it is hard-wired.

The Yale team focused on a gene that programs for the production of a central nervous system protein called Nogo Receptor 1. Earlier research had established that Nogo Receptor 1 stimulates the growth of connections between neurons, and that when it is plentiful in the brain, mice do not recover as well from brain and spinal cord injuries.

But the Yale researchers essentially took time-gap photographs of groups of brain cells and the way they connected to one another in the brains of mice. When they bred mice without the gene, they documented that even into adulthood, the cells they recorded continuously arranged themselves into constantly changing configurations themselves, at the same frantic pace seen in adolescent mice. The brains of mice with normal levels of Nogo Receptor 1, by contrast, settled down to a more stately pattern of reconstitution.

Then, the Yale team tried something more audacious: When they chemically plugged up the Nogo receptors in the brains of adult mice, they found that even mice whose brains had made the transition to plodding adulthood regained the speed of an adolescent brain at wiring and rewiring itself.

Adult mice with normal levels of Nogo Receptor 1 needed to live in cages that plied them with constant stimulation if their brain cells were to show evidence they were learning new skills. But the brains of adult mice whose Nogo receptors were knocked out were showing signs of intensive learning, even when they were housed in cages that offered them little stimulation.

The two sets of mice appeared in all respects the same in early childhood and adolescence: It was only with the transition to adulthood that the protein's power to tame the brain's constant rewiring act became evident.

Did the mice actually behave any differently when their brains were "reset" to teenage mode? Even into adulthood, Strittmatter noted, tests of memory and function in both sets of mice did not differ in significant ways.

But there was one key behavioral difference between the groups: When researchers taught the mice to expect a shock when they heard a buzzer -- a process called fear conditioning -- adult mice whose brains were in "hard-wired" mode found it harder to adapt to changes intended to extinguish that fear. But fear-conditioned mice who had their Nogo receptors knocked out easily lost their fear reactions when researchers taught them they were in no danger.

This may help explain why youngsters who survive spinal cord injuries and strokes, or who live through extremely traumatic events, tend to recover lost function and move on with their lives so much faster and better than do adults who've sustained the same injuries. Strittmatter suggests that if the brains of adult patients with stroke, PTSD or spinal cord injury could recapture the plasticity of youth, they too might repair as quickly and thoroughly as youths do.

These are the kinds of advances in neuroscience that not only promise help for patients with grievous injuries, they raise a glimmer in the eyes of healthy adults bothered by the loss of cognitive agility that comes with age. Cognitive enhancement to reverse the marginal insults of aging might look awfully seductive to healthy older adults too -- probably because they don't remember the many downsides to having a teenage brain.

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