Estrogen has been named as the middleman following its beneficial effect on the brain - a finding which raises hopes of developing drugs based on the beneficial action of this hormone.
A split-personality chemical, estrogen is thought to protect neural circuits and boost learning and memory, while at the same time increasing cancer risk when taken in high doses.
In a new study, neuroscientists at USC and the Western University of Health Sciences show that estrogen sometimes acts through another chemical.
They conducted experiments on mice and verified that the hormone stimulates parts of the brain dedicated to learning and memory.
"We show very clearly that it does activate the same machinery that is activated during learning and memory," said Michel Baudry, professor of neurobiology at the USC College of Letters, Arts and Sciences.
However, the researchers also found that estrogen acts through calpain, a protein considered crucial to learning and memory since a seminal paper in 1984 by Baudry and Gary Lynch of the University of California, Irvine on the biochemistry of memory.
He said that estrogen acting through calpain does not work as a slowly diffusing hormone, but as a neurotransmitter with a more powerful and nearly immediate effect on the brain.
He compared estrogen to adrenalin, a substance that acts like a hormone in most of the body but as a neurotransmitter in the brain.
"It's not a hormonal effect. It's a synaptic modulator. It completely changes the way we look at estrogen in the brain," said Baudry.
The change may lead to better drugs against Alzheimer's and other neurodegenerative diseases, according to USC graduate student and lead author Sohila Zadran.
"Estrogen is critically involved in learning and memory," she said, and the study shows that its effects "critically involve calpain."
In the future, drug developers may choose to target calpain directly, which could possibly avoid the risks associated with hormone therapy.
The study was published online in the Proceedings of the National Academy of Sciences (PNAS).