Opening up brain critical periods: Lynx1 and where sensory information meets context

auditory critical periods involve neurons in levels 1 and 4 of the auditory cortex
Interneurons (white) from layer 1 (L1) of the auditory cortex descend to contact parvalbumin cells (red) in layer 4. (Images courtesy Hensch Lab).

Babies’ brains are like sponges — highly tuned to incoming sensory information and readily rewiring their circuits. But when so-called critical periods close, our brains lose much of this plasticity. Classic experiments reveal this in the visual system: when kittens and mice had one eye covered shortly after birth, that eye was blind for life, even after the covering was removed. The brain never learned to interpret the visual inputs.

In 2010, a study led by Takao Hensch, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, showed that levels of a protein called Lynx1 rise just as the critical period for visual acuity closes. When the researchers deleted the Lynx1 gene in mice, the critical period reopened and mice recovered vision in the blind eye.

A new study this week in Nature Neuroscience extends Lynx1’s role to the auditory system.

“If we remove Lynx1, the auditory critical period stays open longer,” says Hensch.

Equally important, the study pinpoints the location in the brain where sensory inputs combine with another essential ingredient: what neuroscientists call context.

Giving meaning to sensory information

Context is the social component of learning that motivates our brains to pay attention. It tells the brain, “this information matters,” helping to refine brain connections.

“Even infants at the height of plasticity won’t learn without context,” says Hensch, who is also a professor of neurology at Harvard Medical School and of molecular cellular biology at Harvard University. “You can set a baby in front of a television and try to teach a foreign language with a program like Baby Einstein. But this is far less efficient than a half-hour interaction with a native speaker.”

Research in songbirds proves the point. Young zebra finches learn songs by mimicking adults — but not by listening to recordings of the songs.

In the new study, Hensch and colleagues identify the “hub” where contextual and sensory information converge to “sculpt” developing brain circuits. In this area, the outermost layer (layer 1) of the primary auditory cortex, “bottom-up” sensory information from the thalamus meets “top-down” contextual information arriving from the higher brain.

At left, projections from the medial geniculate body (MGB) in the thalamus to layers 1 and 4 of primary auditory cortex (A1). At right, a schematic of neuron electrical recordings to map brain activity.

The contextual information is supplied by neuromodulators, chemicals like serotonin, dopamine and acetylcholine that neurons release when the brain is aroused.

“Neuromodulators were already known to influence critical period plasticity, but the mechanism had not been worked out,” says Hensch.

Hear this: Measuring auditory critical periods

Hensch and colleagues turned to an auditory model of critical periods. They exposed mice to tones of a specific frequency at different times during development, then measured brain activity in response to low- versus high-frequency sound inputs.

Brainbow of interneurons in primary auditory cortex“If you hit a critical period, the brain’s auditory cortex will remap, so that other tone frequencies are less represented,” Hensch explains. “When you play back the full range of tones, the auditory system will be distorted in favor of what they grew up hearing.”

Hensch was particularly interested in tracing inhibitory interneurons in layer 1, which are known to be richly endowed with receptors for neuromodulators. To map their connections, they used Brainbow, a technique that labels individual neurons in different colors. In this image, the interneurons descend in a narrow column to meet parvalbumin cells, inhibitory neurons shown in white that reside in layer 4 of the cortex, receiving sensory input from the thalamus.

“The context in which sensory information is given is very important to learning,” says Hensch. “We now have an explanation for that. Context and sensory information are interacting together in layer 1, while layer 4 cells are determining the timing component of the critical period. This study expands what we know about how neuromodulators control critical periods of brain development.”

A second chance for learning?

These new insights could fuel interest in trying to reopen critical periods — to enhance learning in children with neurodevelopmental disorders or help us learn languages as adults. As in the visual system, it appears that can be done by deleting Lynx1.

In the visual system, deleting Lynx1 increases communication between neurons via the neuromodulator acetylcholine. Cholinesterase inhibitors such as the Alzheimer’s drug donepezil (Aricept) also boost this communication, by preventing breakdown of acetylcholine. Given to adult mice reared with one eye covered, they override Lynx1 and reopen the critical period, enabling the mice to regain vision.

Ophthalmologists David Hunter, MD, PhD, and Carolyn Wu, MD, at Boston Children’s are in the midst of a pilot study of donepezil in children with amblyopia, or vision loss in one eye. In amblyopia, the brain comes to ignore input from a weaker eye. They hope the drug will reopen a critical period and restore that eye’s vision.

Hensch thinks that overriding Lynx1 could also reopen the auditory critical period for hearing or learning a new language. In the new study, mice that received a cholinesterase inhibitor continued to alter their brain responses to tones even past the critical period.

SSRI warning?

There’s a side note here that could have implications for the use of selective serotonin reuptake inhibitor (SSRIs). These drugs, commonly prescribed for depression and other conditions, boost levels of the neuromodulator serotonin — similar to what cholinesterase inhibitors do for acetylcholine. This raises a concern when babies are exposed to SSRIs prenatally. Could these drugs open a critical period prematurely and alter brain plasticity? In a 2012 study led by the University of British Columbia, Hensch and his colleagues found that infants had accelerated “perceptual narrowing” to speech sounds in SSRI-exposed infants — meaning they more quickly lost the ability to perceive non-native speech sounds if not exposed to multiple languages from birth. How this relates to overall language development, however, remains unclear.

The fine print

Anne Takesian of Boston Children’s Hospital and Harvard University was first author on the paper. Luke Bogart and Jeff Lichtman of the Center for Brain Science at Harvard University were coauthors. The study was funded by the Nancy Lurie Marks Family Foundation, the Canadian Institute for Advanced Research, the Ellison Medical Foundation and the Silvio O Conte Center of the National Institutes of Mental Health (P50MH094271).