Seeing Guides Multiple Paths of Brain-shaping Growth

Gene Networks Underlie Plasticity, May Inform Future Genetic Therapies

Scientists have long known that brains need neural activity to mature and that sensory input is most important during a specific window of time, the “critical period,” when the brain is primed for intensive learning. The visual system offers an exemplary model for studying the critical period due to the pioneering work of Nobel Prize–winning HMS researchers David Hubel and Torsten Wiesel, who elucidated the structure of the system. Although visual plasticity has been studied for more than 40 years, exactly how sensory experience interacts with the machinery that permits brain circuits to change is only beginning to be understood.

A new study focusing on the molecular roots of plasticity has found that visual activity turns up and down the expression of different genes through a single enzyme that acts somewhat like a conductor cuing an orchestra. The study, which appears in the May Nature Neuroscience, also found that during different stages of life in rodents, other 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.

Photo by Graham Ramsay

Carla Shatz and Marta Majdan (not pictured) have found evidence suggesting that in response to visual experience, different sets of genes work in concert to equip the visual cortex with the ability to remodel its circuits.

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. Their work helps open up the science to a more global view of 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. The findings suggest that genetic therapies for neurodegenerative diseases, some of which are focused on a single gene, will likely involve entire molecular pathways and many gene interactions to be successful.

Core Genes
Majdan and co-author Carla Shatz, the Nathan Marsh Pusey professor of neurobiology and chair of that department at HMS, studied rodents during the critical period, in which visual input stimulates aggressive plasticity. The rapid growth shapes the mesh of neural connections in the cortex and tunes the strength of messages relayed by the synapses. In mice, this period begins shortly after they open their eyes and start to see.

Previous research had determined that visual activity 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 blinding one eye and leaving the other untouched. They then compared gene expression profiles of the cortex supporting the seeing eye to that supporting the blinded eye. They found that Bdnf is not alone—visual input changes the levels of expression of 10 additional genes, dubbed the “common set,” at all ages investigated. By chemically inhibiting a MAP kinase, MEK1/2, known to be linked to several common-set genes, they also showed that visual activity regulates this set of genes through the kinase.

The plasticity switch. The act of seeing causes activity in nerve cells that triggers the MAP kinase MEK1/2 to activate gene transcription in the nucleus, turning up the expression levels of core genes that permit the brain to form and strengthen neural connections. When vision is disrupted or when MEK1/2 is experimentally disabled, expression levels of these genes drop, reducing plasticity. Illustration by Rachel Eastwood

Age-specific Networks
The researchers found other sets of genes superimposed on this core pathway, but these genes 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.”

The roles that these age-specific gene sets play in developmental and adult plasticity are not yet understood, but Majdan and Shatz hypothesize that these sets work in concert to drive plasticity. They envision a model in which the common set of genes “permits plasticity,” making the visual system adaptable throughout life. The researchers theorize that during the critical period, when this system needs provisions for aggressive plasticity, the age-specific genes may adjust the fundamental plasticity provided by the common set, dampening or enhancing it as needed throughout development.

The investigators also observed that long-term visual deprivation resulted in molecular missed opportunities—developmental opportunities that come only once during extremely short periods of time. In dark-reared mice, deprived of all visual stimuli, many of the age-specific genes stopped responding to visual input, even when Majdan restored vision within a few days of a specific period. Though these genes were present at normal levels, they were never able to respond to visual experience the way they would in a normal brain. Moreover, visual deprivation itself turned up or down entirely different sets of genes not regulated at all in normal mice. “The deprived cortex was not frozen in an immature state,” said Majdan. Dark-rearing changed the molecular signature, yielding a brain that was “different, completely and unexpectedly different from a young brain.”

“People used to think of dark-rearing as a paradigm for maintaining plasticity,” said neuroscientist Elly Nedivi of MIT. “But this shows clearly that at a molecular level, that’s not true.”

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 that can impair vision, may not be enough to correct the damage. And treatment involving single-gene replacement may also fail. “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.

More generally, 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,” said Shatz. “Genes in the brain change with experience at every age, forming a basis for our ability to learn and remember even in adulthood.”

—Elizabeth Dougherty

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