Research shows how visual stimulation turns up genes to shape the brain

BOSTON--Scientists have long known that brains need neural activity to mature and that sensory input is most important during a specific window of time called the "critical period" when the brain is primed for aggressive learning. Vision, hearing and touch all develop during such critical periods, while other senses, such as the olfactory system, maintain lifelong plasticity. The visual system provides an exemplary model for studying developmental plasticity, however, because of the pioneering work of Nobel prize-winning HMS researchers David Hubel and Torsten Wiesel describing the visual system's structure, prerequisite knowledge for investigating its flexibility. Although visual plasticity has been studied for over 40 years, exactly how sensory experience interacts with the built-in machinery that permits the brain to change its circuits is only beginning to be understood.

A new study focusing on the molecular roots of plasticity has found that visual stimulus turns up the expression of some genes and turns down the expression of others, somewhat like a conductor cueing the members of an orchestra. The study also found that during different stages of life in rodents, distinct sets of genes spring into action in response to visual input. These gene sets may work in concert to allow synapses and neural circuits to respond to visual activity and shape the brain, reports the May issue of Nature Neuroscience.

The investigators' identification of many distinct sets of activity-dependent genes follows a shift in neuroscience research toward a more holistic view of the role of genes in neural development and plasticity. "What we found opens science up to a more global look at genes, from studying one gene at a time to looking at families of genes acting together," said first author Marta Majdan, HMS research fellow in neurobiology. These findings suggest that genetic therapies for neurodegenerative diseases, some of which are largely limited to treatment focused on a single gene, will require more extensive knowledge of molecular pathways and gene interactions to be successful

Majdan and co-author Carla Shatz, HMS Nathan Marsh Pusey Professor of Neurobiology, studied rodents during the critical period in which visual input stimulates aggressive plasticity, shaping the mesh of neural connections in the cortex and tuning the strengths of messages relayed by synapses. In mice, this period begins shortly after they open their eyes and begin to see. Previous research had determined that visual activity changes the level of expression of, or regulates, individual genes such as Brain-derived neurotrophic factor (Bdnf).

To determine whether vision regulates other genes in these rodents, Majdan and Shatz imposed abnormal visual experiences on the rodents at a variety of ages including the critical period by removing one eye and leaving the other intact. They then compared gene expression profiles of the cortex supporting the open eye to that of the missing eye. They found that Bdnf is not alone--visual input changes the levels of expression of ten additional genes, dubbed the "common set," at all ages investigated. By chemically inhibiting a MAP kinase already known to be linked to several common set genes, they found that this kinase acts as a relay, regulating these genes in response to visual activity.

The researchers found other sets of genes superimposed on this core pathway, but these sets are turned on and off by vision at specific ages before, during and after the critical period and into adulthood. "This suggests that sensory experience regulates different genes in your brain depending on your age and past experience," said Shatz. "Thus, nurture, our experience of the world via our senses, acts through nature, sets of genes, to alter brain circuits."

These discoveries may lead to new ways of thinking about genetic therapies to correct early vision disorders. Because the brain is so altered by abnormal vision, restoring vision to a child afflicted with cataracts or strabismus, an eye misalignment which can impair vision, may not be enough to correct the damage. Nor will treatment involving single gene replacement. "We need to try to find the major switches that turn on genes in the downstream network as opposed to looking at each element of the network and designing therapy based on each gene," said Shatz.

This study helps explain why it is that children learn so quickly and easily, and it lends credence to the idea that, in adults, mental activity leads to mental agility. "It is amazing that, even in our oldest mice we saw genes regulated by vision. Genes in the brain change with experience at every age, forming a basis for our ability to learn and remember even in adulthood," said Shatz.

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This research was supported by grants from the U.S. National Institutes of Health to Shatz, and by Canadian Institutes of Health Research and Harvard Medical School Berenberg Fellowships to Majdan.

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