New ways to manipulate neural plasticity–the brain’s ability to rewire itself–could make adult brains as facile as young ones, at least in part. Drugs that target these mechanisms might eventually help treat neurological disorders as diverse as Alzheimer’s, stroke, schizophrenia, and autism. But first scientists will need to figure out how to harness this rewiring capacity without damaging vital neural circuitry.
“Once we understand the mechanisms behind plasticity, we can design therapies to tap into it more specifically,” says Joshua Sanes, a neuroscientist at Harvard Medical School.
The brain experiences a “critical period” of heightened malleability during development, when outside experiences–such as sights and sounds–are necessary for different brain systems to develop normally. Infants and toddlers between the ages of one and three need regular visual stimuli, for example, in order for their visual systems to form the appropriate neural circuits. If one eye is impaired during this time, such as with lazy eye (also called amblyopia), vision may be permanently faulty.
Studying the equivalent of lazy eye in rodents, Takao Hensch and his colleagues at Children’s Hospital Boston discovered two mechanisms that control this critical period. While some drugs were already known to accelerate the onset of this critical period–for example, valium, an anxiety drug that targets the brain’s inhibitory signaling system–Hensch’s work helps explain why and provides specific targets for new treatments.
Like children, rodents with one eye covered during their critical period never recover normal sight. Scientists use this fact to measure treatments that affect the timing of developmental neural plasticity. Treatments that extend the critical period, for example, allow adult animals reared with only one functioning eye to regain normal sight. Hensch’s group has previously shown that a specific cell type, called a large basket cell, triggers the onset of neural plasticity. These cells are surrounded by molecular nets. “The critical period ends when the net wraps around [the cells] very tightly,” says Hensch. So molecularly severing the nets with an enzyme called chondroitinase can restore plasticity in adults.
Hensch and his collaborators have now found that basket-cell development is controlled by a protein called Otx2. Overexpressing this protein can trigger a critical period of plasticity, while removing Otx2 halts it. While the findings are specific to the visual system, Hensch notes that different sensory systems also possess basket cells, and those might function the same way.
A second mechanism for manipulating neural plasticity in adults is blocking inhibitory molecules that the nervous system produces to stop neural growth. “The nervous system is hostile to growing new axons [the long neural projections that connect cells], which is why recovery after spinal-cord injury is so challenging,” says Hensch.
Myelin cells, which form an insulating layer around axons, secrete some of these inhibitory molecules. By experimenting with certain drugs that loosen myelin, Hensch and his collaborators found they could make the normally stable visual system of adult rodents become plastic again, allowing amblyopic rodents to recover. (However, the drug used in the study is toxic, making it unlikely to be a useful therapy.)
Given the usefulness of recapturing the neural facility of youth–the ability to quickly learn a new language, for example–it may seem odd that the brain would have evolved multiple mechanisms for preventing major rewiring in adults. But the capacity to easily overhaul neural circuits could have a downside, perhaps erasing memories. “You might lose the identity you’ve built,” says Hensch. “We want you to be able to keep what you know.”
To successfully co-opt the plasticity of youth, scientists will likely need to target treatments very precisely. “Maybe we can do a careful release of the critical period,” says Alison Doupe, a neuroscientist at the University of California, San Francisco, who was not involved in Hensch’s research. For example, “maybe you could turn on [plasticity] only when learning Russian.”
In addition to suggesting ways to enhance mental agility in old age, the findings may provide a new explanation for developmental disorders, such as autism.
Scientists have recently discovered that several strains of mice genetically engineered to mimic rare inherited forms of autism have an imbalance in levels of excitatory and inhibitory neural signals. Hensch’s previous research suggests that this kind of imbalance can throw the critical period out of whack. “Maybe different brain regions become plastic too early or too late [in autism],” says Hensch. That might also explain why disruptions to such different molecules can trigger similar symptoms, he says. “Maybe they have a common wiring problem.”
The researchers are now studying these imbalances in greater detail. For example, they found that mice from one of the strains, genetically engineered to show symptoms of autism, have too many neural connections in a specific part of the brain, although each connection is individually weak. “That could lead to too much variability,” says Hensch. “Maybe we can use that property to repair the circuit.”