In emergencies, when more common anesthetics aren’t an option, paramedics and other health professionals often turn to ketamine to relieve pain and quickly induce unconsciousness. Unlike most anesthetics, ketamine works by temporarily disrupting communication between brain cells, creating its distinctive dissociative effects.
Now, researchers from the Institute of Science and Technology Austria (ISTA), working with scientists at the Allen Institute in Seattle, have found that female brains in mice recover from ketamine differently than male brains. Their study, published in Science Advances, shows that female mice release a stress hormone during recovery that makes their brains temporarily more adaptable, a trait known as plasticity.
The findings add to growing evidence that drugs can affect female and male brains differently, an important consideration given that ketamine is also used to treat depression.
“It’s astonishing how readily people assume that men and women respond to drugs in the same way — when clearly they do not,” said study co-author Sandra Siegert from ISTA in a statement.
Ketamine Triggers Brains to Rewire — But Only in Females
The discovery builds on earlier work from Siegert's lab, which found that male and female mice respond differently to ketamine anesthesia.
The researchers used a tiny window implanted in the skull to watch living brain cells under a microscope as mice recovered from anesthesia. They focused on microglia, the brain's resident immune cells, which help protect the brain while also monitoring and maintaining connections between neurons.
As female mice woke up, the microglia formed prolonged contacts with neurons, coinciding with the rewiring of neural connections that underlies brain plasticity. The same effect didn't occur in males, and it disappeared entirely in mice that lacked microglia.
“What was fascinating, was that we observed this plasticity — the brain’s ability to change, adapt, and in this case recover — only in females,” said the study's first author, Alessandro Venturino, in the news release.
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Stress Hormones May Cause Brain Plasticity
“I’ve always believed that women have greater brain plasticity,” added Siegert. “Alessandro and I just couldn’t let it go — we wanted to know why.”
The answer appears to involve corticosterone, a major stress hormone in mice. As the animals recovered from ketamine, corticosterone levels rose. In females, the hormone activated a stress-response gene called Fkbp5 in microglia, prompting the cells to interact with neurons and drive the observed brain changes.
“These results clearly show that corticosterone triggers this reaction in female mice,” said Venturino. “They also remind us that stress is not always harmful — stress hormones are essential for certain processes in the brain,” added Siegert.
The researchers still don't know why the same response wasn't seen in males. It's possible that male brains rely on a different mechanism or simply recover on a different timeline.
Sex-Specific Differences of Drugs Matter
The researchers speculate that greater brain plasticity may have offered females an evolutionary advantage by helping them adapt more quickly to changing environments and social demands. But they note that this flexibility can also come with a downside.
“If this plasticity becomes too frequent or too intense,” said Sieger, “It can increase the risk of depression. We also know that psychiatric disorders are more prevalent in women than in men.”
The researchers also found surprisingly little previous research on ketamine's effects in females. “There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia,” added Siegert.
Given that the drug is increasingly used to treat depression as well as for anesthesia, they argue that understanding these sex-specific differences will be essential for developing safer and more effective treatments.
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- This article references information from a study published in Science Advances:Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia