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Adenosine may extend learning of language and music
Learning language or music is usually a breeze for children, but that capacity declines dramatically with age. St. Jude Children's Research now has evidence that restricting a key chemical — adenosine — in the brain can help extend auditory learning much later into life.
Research revealed that limiting the supply or function of adenosine, a naturally appearing brain chemical found in the auditory thalamus of the brain, preserves the ability of adults and young mice, to learn from sounds in their world. The study appeared June 30 2017 in the journal Science.
"By disrupting adenosine signaling in the auditory thalamus, we have extended the window for auditory learning for the longest period yet reported, well into adulthood and far beyond the usual critical period in mice. These results offer a promising strategy to extend the same window in humans, in order to acquire language or musical ability by restoring plasticity in critical regions of the brain. Possibly, by developing drugs that selectively block adenosine activity."
The auditory thalamus acts as the brain's relay station, where sound is collected and sent for processing to the auditory cortex, located on either side of our brain. This pathway requires the neurotransmitter glutamate to function. Adenosine is known to reduce glutamate levels, and by inhibiting glutamate, reduces plasticity in that brain region and ends auditory retention and learning.
Researchers used a variety of methods to demonstrate how reducing adenosine, or blocking the A1 adenosine receptor — essential to the chemical messenger's function — changes how adult mice respond to sound.
Much as young children pick up language simply by hearing it spoken, researchers showed that when adenosine was reduced, or the A1 receptor blocked in the auditory thalamus, adult mice passively exposed to a tone would respond to the same tone much stronger when it was played weeks or months later. These adult mice also gained an ability to distinguish between very close tones (or tones with similar frequencies), even though mice usually don't have "perfect pitch." Researchers also noted how experimental mice retained that improved tone perception for weeks.
"Taken together, the results demonstrate that the window for effective auditory learning re-opened in mice, and that they retained the new information."
Among the strategies researchers used to inhibit adenosine activity was the experimental compound FR194921, which selectively blocks the A1 receptor. But, when paired with new sound exposure, the compound rejuvenated auditory learning in adult mice. "That suggests it might be possible to extend the window in humans by targeting the A1 receptor for drug development," Zakharenko said.
Zakharenko and colleagues also linked the age-related decline in ease of auditory learning to an age-related increase in the enzyme ecto-5'-nucleotidase which is involved in adenosine production in the auditory thalamus. Researchers found mature mice had higher levels than newborn mice of both ecto-5'-nucleotidase enzyme and adenosine in their auditory thalamus. Deleting ecto-5'-nucleotidase returned adenosine levels in adult mice to that of newborn mice. Now, researchers are looking for compounds that target ecto-5'-nucleotidase as an alternative approach for extending the window of auditory learning.
Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. Here we show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5?-nucleotidase–dependent adenosine production or A1–adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement of tone-discrimination abilities. We conclude that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.
The first authors are Jay Blundon, Ph.D., an associate scientist in Zakharenko's laboratory, and Noah Roy, Ph.D., a postdoctoral fellow in the laboratory. The other authors are Brett Teubner, Jing Yu, Tae-Yeon Eom, K. Jake Sample, Amar Pani, Seung Baek Han and Burgess Freeman III, all of St. Jude; Richard Smeyne and Pradeep Vuppala, both formerly of St. Jude; Ryan Kerekes and Derek Rose, both of Oak Ridge National Laboratory; and Troy Hackett, of Vanderbilt University School of Medicine, Nashville.
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This video captures the activity of neurons in the auditory cortex of mice listening
to tones being played. Each flash of light is a neuron firing. Scientists used a special
two-photon microscope to image the activity of the neurons, which are almost 0.5
millimeter deep within the brain. Image Credit: Jay Blundon, PhD