A little-studied steroid that serves as a building block for hormones like estrogen and testosterone has been shown to enhance learning and memory in a new study by researchers at UC San Francisco.
The discovery could offer a new path toward treatments for neurodegeneration, schizophrenia and depression, conditions that affect millions of Americans.
The researchers found that the presence of the steroid, called ADIOL, reduces the amount of another substance in the nervous system called kynurenic acid, or KYNA, that hampers cognitive function. KYNA exists at elevated levels in the brains of people with dementia and other neurodegenerative diseases.
Until this discovery, ADIOL was largely thought to be important only for its role in making steroid hormones.
“We discovered something completely unexpected,” said Kaveh Ashrafi, PhD, senior author on the study, published in Genes and Development. “What we thought was just a little sideshow turns out to be an agent with potential to treat conditions that we have few good therapies for.”
A famous worm reveals answers
Researchers have known that increased KYNA in the brain translates to less neurological activity and less memory retention, and that reducing KYNA enhances memory and learning. How that system works and what controls it has been a mystery.
Ashrafi’s team investigated the question using C. elegans, a tiny worm that’s been a hero in bioscience, helping to reveal some fundamental biology that has garnered Nobel prizes.
The famous worm makes for a good experimental model in this case because the genetics and components involved in its learning and memory are broadly similar to ours, despite its nervous system being orders of magnitude smaller. The relative simplicity of C. elegans’ genetics allows scientists to do many experiments quickly.
“A huge advantage of C. elegans is that we can do genetics research on a scale that that wouldn’t otherwise be realistic for a single lab,” said George Lemieux, PhD, a senior researcher in Ashrafi’s lab. “It’s allowed us to find something that we otherwise wouldn’t have found, which can now be further studied in more complex organisms, and ultimately in humans.”
About a decade ago, Ashrafi and Lemieux found that KYNA plays a role in fat metabolism in C. elegans. That discovery sent them on a search for what else the molecule might be doing. They learned that the compound binds with a cell receptor associated with learning and memory.
They also found that as C. elegans ages, the levels of KYNA in its nervous system go up, which is also true in humans and other mammals. The increased KYNA is associated with a decrease in learning capacity, and a reduction in KYNA improves cognitive function.
A Pavlovian experiment
The researchers searched for potential regulator molecules and identified genes not previously known to play a role in cognition. Their analyses of these genes led to the discovery that ADIOL promotes learning and memory.
To observe its effect in C. elegans, Ashrafi’s team used an approach similar to experiments done by Pavlov, in which he rang a bell when feeding dogs. Eventually, the dogs responded to the sound of the bell in the same way they’d responded to feeding, even if no food appeared.
Rather than feeding C. elegans, Ashrafi’s team trained them by pairing butanone, a substance the worms can sense, with stimuli that they would be attracted to (or, in some experiments, repelled by). Then the researchers exposed the C. elegans to butanone on its own.
How well the worms formed an attraction to (or repulsion from) the butanone indicated their learning capacity, and the length of time the associations lasted was a gauge of memory.
When the worms were only exposed to the butanone pairing once, the association they formed with it only lasted for 1 to 2 hours. But when they were exposed multiple times, the effect lasted for several days, which is impressive for a worm with a two-week lifespan.
The higher the ADIOL levels were, the lower the amount of KYNA in the worms’ nervous systems. The C. elegans also learned more quickly and retained it longer.
Ashrafi believes ADIOL could do similar things in people with neurodegenerative disease, schizophrenia and depression, all conditions associated with high levels of KYNA.
Some pharmaceutical companies have shown interest in tempering KYNA levels as a way of treating neurodegenerative conditions. But the idea stalled because no one knew how to control those levels. Ashrafi hopes the discovery of ADIOL’s role will change that.
“The therapeutic possibilities are obvious, but it will take some work to realize them,” he said.