Researchers at ISTA found that during recovery from ketamine, microglia in female mice make prolonged contact with neurons and remodel synapses, a response triggered by the stress hormone corticosterone.
General anesthesia is one of medicine’s great tools, but what happens in the brain as a patient wakes up remains surprisingly poorly understood. Anesthetics such as ketamine quiet neural activity, and as their effects fade, neurons must reestablish their connections and restore normal function.
A study in mice from the Institute of Science and Technology Austria (ISTA) suggests that this recovery process differs between the sexes. Writing in Science Advances, researchers report that in female mice, immune cells in the brain called microglia actively remodel connections between neurons as the animals recover from ketamine. Male mice did not show the same response.
“What was fascinating,” said Alessandro Venturino, a researcher at ISTA, “was that we observed this plasticity—the brain’s ability to change, adapt, and in this case recover—only in females.”
A long-running hunch
The project grew out of an observation Sandra Siegert’s group made in 2017, when the team noticed that male and female mice responded differently to ketamine, specifically in their microglia. Microglia are the brain’s resident immune cells. Beyond defending against infection, they constantly survey their surroundings and help prune and reshape synapses, the junctions through which neurons communicate.
“I’ve always believed that women have greater brain plasticity,” said Siegert, a professor who leads the group at ISTA. “Alessandro and I just couldn’t let it go—we wanted to know why.”
Watching microglia at work
To observe the cells directly, the team used a cranial window, a transparent implant that allows researchers to look into the brain of a living mouse, combined with fluorescent labels that made microglia and neurons visible under a microscope.
Synapses are not fixed. They strengthen, weaken, form and disappear throughout life, a property that underlies learning and memory. Microglia contribute by engulfing unneeded synaptic material and by releasing signals that influence how connections develop. Watching them in living animals makes it possible to see these changes as they happen rather than inferring them after the fact.
During recovery from ketamine anesthesia, microglia in female mice formed prolonged contacts with neurons. Those contacts coincided with synaptic remodeling, changes in the structure of the connections between nerve cells. In male mice, the researchers did not see this pattern.
To test whether microglia were responsible, the team studied mice that lacked microglia. Those animals showed no such synaptic remodeling during recovery, indicating that microglia drive this form of plasticity.
A stress hormone as the trigger
The researchers then looked for what sets the process in motion. They focused on corticosterone, the main stress hormone in rodents and the equivalent of cortisol in humans.
“During recovery from anesthesia, corticosterone levels rise,” Venturino said. “In female mice, this specifically activates the stress‑response gene Fkbp5 in microglia. The gene encodes the protein FKBP51, which helps the cell manage stress signals—and apparently prompts microglia to interact with neurons.”
To confirm the link, the team removed the adrenal glands, which produce corticosterone. Without them, the microglia no longer made extended contact with neurons during recovery. “These results clearly show that corticosterone triggers this reaction in female mice,” Venturino said.
Siegert said the results offer a more nuanced view of stress. “They also remind us that stress is not always harmful—stress hormones are essential for certain processes in the brain,” she said. “Microglia enable rapid adaptation, and these cells in females are likely more sensitive to specific stress signals.”
A double-edged plasticity
Greater plasticity may help the brain recover, but it can also carry risks. “That’s a good thing,” Siegert said. “But if this plasticity becomes too frequent or too intense, it can increase the risk of depression. We also know that psychiatric disorders are more prevalent in women than in men.”
The findings are particularly relevant because ketamine is used not only as an anesthetic but also, at lower doses, as a fast-acting treatment for depression. A related drug, esketamine, is approved as a nasal spray for treatment-resistant depression. Yet few studies of ketamine have included females.
Ketamine works differently from many other anesthetics. It blocks NMDA receptors, a type of receptor for the neurotransmitter glutamate, producing what is sometimes called dissociative anesthesia. Its antidepressant effects are thought to involve a burst of synaptic growth in the hours and days after a dose, which makes the plasticity seen in the new study especially intriguing.
Siegert said clinical observations hint at differences too. “There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia,” she said. “It’s astonishing how readily people assume that men and women respond to drugs in the same way—when clearly they do not.”
The broader problem is well documented. For decades, biomedical research relied largely on male animals, partly on the assumption that female hormonal cycles would make results more variable. Funding agencies in several countries now require researchers to consider sex as a biological variable.
Questions that remain
The study was carried out in mice, and it is not yet clear whether the same mechanism operates in people. The researchers also have not determined whether males use a similar process that unfolds later or more weakly, or whether their recovery relies on different mechanisms entirely.
Siegert and Venturino have also co-founded a startup, Syntropic Medical, which is exploring whether 60-hertz flickering light can make neural networks more flexible, an approach separate from the current study.
For now, the results add to growing evidence that the sexes can differ not just in how drugs act, but in how the brain responds when their effects wear off. Understanding those differences could eventually help tailor anesthesia and ketamine-based treatments to the patients receiving them.
Notes
- “Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.” Science Advances, 2026. DOI: 10.1126/sciadv.adz6517.
- Institute of Science and Technology Austria. “After anesthesia.” EurekAlert!, 31 July 2026. https://www.eurekalert.org/news-releases/1137236.
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