By exposing mice that had been closeted in complete darkness for days to light, Italian researchers have determined why adult brains lose the plasticity of younger brains. Their findings, published in this week's issue of Neuron, provide further evidence that a certain class of drugs may one day be used to successfully treat degenerative nerve diseases like Alzheimer's and Huntington's.

The researchers primarily focused on the plasticity of the visual cortex, because there is a wealth of evidence that this part of the brain can be rewired more easily in children than in adults. For example, it is known that children—but not adults—can develop amblyopia or lazy eye (which makes it difficult to read closely spaced letters) when deprived of light or the full range normal visual stimulation.

Researchers divided mice at different stages of development into two groups, which they deprived of light for three days. One set included animals between 80 and 100 days old; the other contained mice 24 and 25 days old—the critical period of development when experience still shapes the growth of certain brain functions. They then exposed the mice to a "normally lightened environment" for either 15- or 40-minute intervals. The results: just a few minutes of exposure was enough to trigger a molecular cascade that altered a class of proteins called histones (which serve as spools for DNA chromosomes to wind around). When histones are changed, DNA becomes available to be used in the cellular action that activates the transcription of many genes.

The change only took place, however, in the younger group of animals. In adults, the initial chemical signaling took place, but the histones were not altered and there was no increased transcription.

"The first steps of the molecular cascade that normally occurs outside [of] the neuron nucleus are equally activated in young and adult mice," says study co-author Tomasso Pizzorusso, a neurobiologist at the Institute of Neuroscience of the National Research Council in Pisa, Italy. "So, the differential regulation between adult and young animals should be due to nuclear factors."

Jonathan Levenson, a neuropharmacologist at the University of Wisconsin School of Medicine and Public Health in Madison says the finding that "the brakes on the system are actually set on the level of chromatin and not the signaling pathways," which turn on immediately prior to histone activation, is unexpected. Ed Korzus, a neuroscientist the University of California, Riverside, says that whereas regulating gene transcription is not necessary for short-term brain plasticity or for acquiring information, "a new gene expression is critical … for permanent alteration of neural networks (or stabilization of memory trace)."

In a second part of their study, Pizzorusso and his colleagues gave the older mice a drug called trichostatin—a member of a class of compounds known as histone deacetylases—to activate and change their histones. There was a significant increase in the plasticity of their visual cortices. This finding indicates that trichostatin and similar compounds may be useful in treating brain lesions that heal when the brain is rewired. Wisconsin's Levenson notes that histone deacetylases—previously shown to be effective in treating neurodegenerative disorders—are currently in clinical trials. "This class of compound probably will show some kind of promise for use as cognitive enhancers," he says, cautioning that "the jury is still out on whether, at the end of the day, they'll be effective."

In addition to future therapeutic possibilities, Pizzorusso says he wants to determine whether histone alterations caused by visual stimuli are global to all DNA or occur only if specific genes are targeted. "There are techniques available to analyze histone modifications and localize them on DNA," he says, "and this would tell us the identity of the genes regulated by visual experience."

1 Comments

1. 1. cyclone001 12:09 AM 6/28/10

   Can the brain be 'trained' to overcome signals it produces (tinnitus), to make up for frequencies that the ears don't hear? When receptors are broken through loud noise ie explosions, loud music, etc or even just aging. I have a 7kHz 'scream' in my head all the time, yet on one occassion late at night, it suddenly stopped for about a minute, then came screaming back like a jet plane.

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