Understanding the Brain's "Brake Pedal" in Neural Plasticity

You definitely want to avoid an encounter with a banded krait. A single bite from this snake delivers enough venom to spell the end for a dozen people. Working like a chemical brake, the active toxin finds its way to your neurons, and snuffs out the signals that would otherwise animate your muscles. It’s bad stuff.

Which makes it all the more surprising that the venom, or something very close, is found in our heads. Recent work from Professor Takao Hensch’s Harvard lab shows that a close molecular cousin of the krait’s toxin, called Lynx1, serves as a kind of brake in the brain. Rather than silencing neurons outright, molecules like Lynx1 help hold them in check, suppressing their tendency to grow and otherwise change with experience. In the absence of these brakes, our brains’ circuits are sprawling and adaptable, but also somewhat unstable.

When we are young, we live through a biological “critical period” -- a time when there is little braking, and the brain is extraordinarily adaptable. Certain kinds of learning seem to just happen without much special attention or practice. None of us learned our native tongue by memorizing rules and exceptions for juggling different parts of speech. Instead, our brains seemed somehow ready for the necessary information, and the information found its way in.

As the brain ages, it is much less willing to meet the world halfway. Instead of easily re-molding itself to accommodate new kinds of inputs, the older brain is more constrained - a biological truth known to anyone who’s struggled to pick up a new language later in life. While many processes contribute to this change in the brain’s learning potential, scientists believe that some of the changes are brought about by the gradual accumulation of molecules, like Lynx1, that limit the brain’s adaptability.

Of course, it might seem like a raw deal to be ‘bitten’ by your own brain, and have your neural prowess slowly snuffed out. But in fact, this is the necessary - if less exciting - second half of a process that stores knowledge in a format that’s accessible for life. Without some kind of insulation from change, the youthful neuronal clay would never set, making life’s lessons unstable and prone to degrade. So although Lynx1 and other molecules cut off our critical period by hitting the brakes on plasticity, they also help lock in knowledge for the long term.

Naturally, scientists have long been interested (reviewed here) in understanding the specifics of how these brakes work, and, perhaps one day, how to control them. With their investigation of Lynx1, the Hensch group has found what may be one of the major factors responsible for closing the door on plasticity after the critical period. In addition, they demonstrate a strategy for lifting the brake to enhance adult plasticity and repair wiring errors in the brain. This could have major implications for the treatment of developmental disorders and brain injuries, and may eventually provide ways to augment cognition in later life.

The first step in investigating Lynx1’s properties was to ask if it accumulated at the right time to function as a plasticity brake. By labeling and collecting samples of Lynx1 and its precursors from the brains of mice at different ages, the researchers tracked how its levels changed over time. Its concentration was low and steady at young ages - within the known critical period for mice -- and ramped up with age.

Of course, many molecules are expected change their concentration over the critical period, and many of them could be just going along for the ride without playing a role in critical period closure. If Lynx1 really was a brake, then letting up on it should enhance plasticity in older brains.

Using genetic engineering techniques, Hensch’s group went a step further -- they removed this brake in mice, and asked if their brains were still plastic past the usual critical period. Could these older brains be rewired by experience, in the manner usually seen only in young brains? To answer this, Dr. Hensch and his colleagues modified a classic experimental paradigm developed by Drs. David Hubel and Torsten Wiesel - the Nobel prize winning duo who did foundational work on the neurobiology of critical periods in the visual system.

The basic experimental approach is to record from neurons of the visual cortex of an animal - in this case a mouse - some time after one of its eyes has been sutured shut. As you might expect, depriving the visual cortex of half of its expected input is a major change in experience that can trigger changes in brain organization. Over time, more neural real estate is devoted to handling inputs from the good eye, at the expense of the bad eye. This is known as a change in “ocular dominance.”

The team found that, unlike control mice, which only undergo ocular dominance shifts if an eye is closed early in life, mice without Lynx1 still showed these shifts for eye manipulations well into adulthood. Thus, an old brain without Lynx1 is still plastic, as if the critical period had never closed. In another experiment, the group also showed that a brain without Lynx1 was also more adept at repairing itself.

While genetically eliminating Lynx1 is a sure-fire way to promote plasticity, this is unlikely to ever be the basis of ‘plasticity therapy’ in humans. Practically speaking, we can’t be re-engineered to lack Lynx1. However, another way of getting at a similar end - and one with more potential as a therapy - is to find out what the plasticity brake is acting on, and try to artificially boost the process being suppressed.

Using pharmacological and molecular labeling studies, Hensch and his colleagues found that Lynx1 works by blocking receptors for the neurotransmitter acetylcholine. Acetylcholine is infused broadly throughout the brain during intense concentration or arousal, and essentially delivers a wake up call to neurons that can prompt them to change their response properties and physical organization. By deafening neurons to these alerts, Lynx1 effectively cuts off the brain’s ability to change.

At the same time, this suggests that plasticity in later life can be enhanced by delivering drugs that boost acetylcholine levels. Indeed, Dr. Hensch’s group found that infusions of drugs that raise acetylcholine could make the mice’s brains more adaptable.

Although directly applying this to humans is probably still a ways off, it raises certain tantalizing possibilities. Naturally, most thoughts turn to some kind of ‘brain boosting’ that would help us learn certain kinds of skills with the same ease we enjoyed when we were younger. Who wouldn’t want a bit more neuro-mojo, or to be able to soak up a handful of new languages just by casually hanging out in countries we’ve always wanted to visit?

It’s not clear, though, that removing Lynx1 would necessarily spell happy times for learning complex skills and languages. These may be subject to additional, or simply different forms of regulation. Still, this research might also help with more immediate, if more modest, goals. It may be possible, for example, to use acetylcholine boosters to increase the effectiveness of brain training programs for staving off senescence and cognitive decline with age.

Mental Blizzard

Turkish novelist and 2006 Nobel laureate Orhan Pamuk found inspiration from daydreams for works such as Snow (2004, Knopf). In a speech titled “the Implied Author” that Pamuk gave when he received the Puterbaugh literary prize in 2006 , Pamuk declared: "I long for inspiration to come to me (as poems did to Coleridge—and to Ka, Snow's hero) in dramatic ways, preferably in scenes and situations that might sit well in a novel. If I wait patiently and attentively, my dream comes true. To write a novel is to be open to these desires, winds and inspirations, and also to the dark recesses of our minds and their moments of mist and stillness.

For what is a novel but a story that fills its sails with these winds, that answers and builds upon inspirations that blow in from unknown quarters, and seizes upon all the daydreams we've invented for our diversion, bringing them together into a meaningful whole?"

Willi Dansgaard in Memoriam

Willi Dansgaard, the great Danish paleoclimatologist, died on January 8. His passing has received remarkably little notice in the world press, though the New York Times published an appreciative obituary today. Were there a Nobel Prize in the earth sciences, he surely would have been a recipient. As it was he had to content himself with the Tyler Prize, the highest award given for environmental research, which he shared with Hans Oeschger, the Swiss glaciologist with whom his work was closely linked, and Claude Lorius, a French scientist.

It was Dansgaard who discovered that the temperature of the earth's atmosphere could be inferred from the isotopic composition of rainwater and snow, and who then realized that the past temperatures of the atmosphere could be extracted from ice cores. Oeschger made himself the world's foremost expert on the measurement of carbon dioxide and other gases found in ice cores. Their work led eventually to a complete year-by-year reconstruction of the earth's climate going back a million years, through a handful of ice ages, showing a powerful linear relationship between greenhouse gas levels and temperatures. Lorius led a team that produced an early version of that record, going back hundreds of thousands of years, based on drilling in Antarctica.

Dansgaard and Oeschger also discovered cycles in which drastic climate changes were found to occur much more rapidly than anybody had imagined--on the scale of decades, rather than hundreds or thousands of years. Though Dansgaard was a rather apolitical person, the discovery of abrupt climate change put it on the global agenda, leading to language in the Rio Framework Convention on Climate Change calling for measures to prevent "dangerous" climate change.

It's regrettable that we don't have a Nobel prize in the geosciences, and not merely for personal reasons. There's altogether too little appreciation of the fact that a revolution occurred in the earth sciences in the second half of the twentieth century, as science historian Spencer Weart has observed, and that the study of the biosphere remains one of the most dynamic of the physical sciences today. Yet earlier this week the Washington Post published an excellent article detailing how most of the major U.S. satellites dedicated to monitoring changes on the Earth's surface and in its atmosphere are behind schedule and under-funded. These include the Global Precipitation Measurement mission, the latest Landsat satellite, Hydros, and the NPOESS satellite set.