When we pour concrete for a sidewalk or foundation, we want the material to be as fluid as possible, so that it will easily assume the shape we have in mind. But for our structure to be durable and useful, we want the concrete to harden—quickly.
The brain’s early development is a similarly delicate balancing act between malleability and permanence. The areas of an infant’s cerebral cortex devoted to sensory systems are highly plastic, so that cortical circuits can be efficiently sculpted in response to the sights, sounds and smells that make up the baby’s world. But as soon as a baby has had enough time to acquire adequate sensory experience—a developmental window known as the “critical period”—neural circuits become hard-wired.
Fixed neural circuits ensure that cortical function is stable and reliable, but stability comes at a cost: if the brain or spinal cord is damaged by trauma, disease or stroke, it can rarely repair itself well enough to restore function.
How the brain shuts the door on plasticity and how that process might be blocked to regenerate or repair neural circuits are the focus of the laboratory of Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology.
In 2000, Strittmatter identified a protein called Nogo that suppresses self-repair in damaged axons. In order to establish whether Nogo shuts down plasticity more generally, Strittmatter and Nigel W. Daw, Ph.D., professor of ophthalmology and visual science, married genetic techniques with a classic experiment devised by Nobel prize-winning neurobiologists David H. Hubel, M.D., and Torsten N. Wiesel, M.D., in the early 1960s.
Normally the visual cortex is divided equally between inputs from each eye into regions known as ocular dominance columns, but Hubel and Wiesel showed that if one of an animal’s eyes is kept shut during the highly plastic critical period, the active eye’s inputs will appropriate a larger share of the visual region, leaving vision in the other eye irreversibly impaired. However, as reported in the September 30 issue of Science, when Strittmatter, Daw and postdoctoral fellows Aaron W. McGee, Ph.D., and Yupeng Yang, Ph.D., performed the same experiment with mice specially bred to lack a functional Nogo receptor, the cortex remained plastic after the critical period, and an active eye could usurp cortical real estate from a deprived eye well into adulthood.
Encouraged by these and other results, Strittmatter is searching for Nogo blockers that he hopes will revive the capacity for plasticity, and healing, of the damaged or diseased brain and spinal cord. “Limited nerve cell regeneration and plasticity are central to a range of neurological disorders,” he said, “including stroke, head trauma, multiple sclerosis and neurodegenerative disease.”