Brain studies provide treatment clues in unexpected fields

Photo of Stanislav Zakharenko

Stanislav Zakharenko is a member of the St. Jude Children’s Research Hospital’s Department of Developmental Neurobiology.

By studying normal brain development, we can gain insights into the missteps that lead to brain disorders and catastrophic diseases, including malignant pediatric brain tumors. We also uncover clues about normal brain development that might have clinical implications and practical applications in other unexpected fields.

Take adenosine, for example. We found that limiting the supply or function of this neuromodulator in the auditory thalamus of the brain preserved the ability of mice to learn from the soundscape of their world, as young children do. Neuromodulation is the process by which a neuron uses a chemical to regulate other neurons.

This discovery points to a promising strategy through which humans can acquire language or musical ability by restoring plasticity, or the ability to change, in critical regions of the brain, possibly by developing drugs that selectively block this adenosine activity. Results of this study appeared in Science.

What we did The auditory thalamus is the brain’s relay station where sound is collected and sent to the auditory cortex for processing. Both stations rely on the neurotransmitter glutamate to communicate. Adenosine is known to reduce glutamate levels by inhibiting its release. Our study also linked adenosine to reduced brain plasticity and the end of efficient auditory learning.

A child’s brain has plasticity, but this plasticity is lost during adulthood.  For example, young children can effortlessly pick up a language by simply hearing it spoken, but adults have much harder time to learn new languages or other acoustic skills. Researchers showed that when adenosine was reduced or its A1 receptor was blocked in the auditory thalamus, the adult mouse brain regained the childhood ability to change its tuning when passively exposed to a tone. These adult mice also developed a superior and long-lasting ability to distinguish between very close tones (or tones with similar frequencies), which normal adult mice usually do not have.

What it means Among several strategies we used to inhibit adenosine activity was the experimental compound FR194921, which selectively blocks the A1 receptor. If paired with sound exposure, this compound rejuvenated auditory plasticity in adult mice.

We also linked the age-related decline in plasticity to an age-related increase in an enzyme (ecto-5'-nucleotidase) involved in adenosine production in the auditory thalamus. Mature mice had higher levels of the enzyme and adenosine in the auditory thalamus than did newborn mice. Deletion of this enzyme returned the adenosine level in adult mice to that in newborn mice.

These results support that a similar promising strategy can be used to extend the same window in humans for acquiring language or musical ability by restoring plasticity in critical regions of the brain, possibly by developing drugs that selectively block adenosine activity.

About the author

Stanislav Zakharenko, MD, PhD, is a faculty member of the Developmental Neurobiology Department and director of Neural Circuits and Behavior Division at St. Jude Children's Research Hospital. View full bio.

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