During ketamine anesthesia, the brain's nerve cells fall silent—as consciousness returns, they begin to reconnect. For the first time, researchers at the Institute of Science and Technology Austria (ISTA) have shown that immune cells in the brain play a critical role in this process—with differences between female and male brains. The findings were published in Science Advances.
"Crack." The ankle twists; the sound shoots through bone and marrow. Pain floods the body and overrides any reaction—it's almost unbearable.Paramedics arrive within moments. After a brief assessment, they decide that the patient needs emergency surgery. Ketamine is administered.
Unlike many other anesthetics, ketamine does more than induce unconsciousness. It alters how we perceive pain and form memories. It dampens communication between neurons—the very network that must later resume normal function as the patient awakens.
Exactly how this recovery process unfolds—and whether male and female brains differ in this regard—has been unclear.
Alessandro Venturino, Professor Sandra Siegert, and their colleagues at the Institute of Science and Technology Austria (ISTA)—together with researchers from the Allen Institute in Seattle, USA—now offer the first answers.
Microglia – the brain's guardians and glue
As early as 2017, Sandra Siegert's group at ISTA noticed that male and female mice respond differently to ketamine anesthesia—more precisely, their microglia do.
Microglia are specialized immune cells that constantly scan the brain and, when needed, trigger anti‑inflammatory responses. They also monitor neurons and their connections, thus helping to maintain optimal brain function.
When the brain wakes up
Using a cranial window—a surgically implanted opening that allows microscopic access to the living brain—Venturino analyzed how microglia and neurons behave while mice recover from ketamine anesthesia. Both cell types were labeled with fluorescent markers to glow under the microscope.
The researchers observed microglia processes in their dynamic action towards neurons. Surprisingly, as female mice recovered from anesthesia, microglia began forming prolonged contacts with neurons, coinciding with the onset of synaptic remodeling and plasticity.
Notably, this phenomenon was not observable in male mice. Furthermore, in mice lacking microglia, no such synaptic remodeling occurred, indicating that microglia are critical mediators of this recovery-associated plasticity.
"What was fascinating," Venturino explains, "was that we observed this plasticity—the brain's ability to change, adapt, and in this case recover—only in females."
As often happens in science, one discovery opened the door to another. Insights into the microglia response to ketamine have since inspired Siegert and Venturino to co‑found Syntropic Medical, a start‑up in ISTA's XISTA ecosystem exploring how 60 Hz flickering light can soften such neural networks in the brain.
Positive stress shapes the brain
Despite many other projects—or perhaps because of them—the researchers kept returning to their initial observation.
"I've always believed that women have greater brain plasticity," Siegert says with a smile. "Alessandro and I just couldn't let it go—we wanted to know why."
Further experiments revealed that this plasticity depends on corticosterone, one of the major stress hormones.
"During recovery from anesthesia, corticosterone levels rise," Venturino explains. "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 this link, the team removed the adrenal glands—the endocrine organs that produce corticosterone. Without them, the close contact between microglia and neurons during recovery disappeared.
"These results clearly show that corticosterone triggers this reaction in female mice," says Venturino.
Siegert adds: "They also remind us that stress is not always harmful—stress hormones are essential for certain processes in the brain."
An evolutionary hypothesis
Why this process differs between female and male mice remains uncertain; it is still unclear whether the male brain uses a similar mechanism, just delayed, or has another strategy.
"Microglia enable rapid adaptation, and these cells in females are likely more sensitive to specific stress signals," Siegert notes.
From an evolutionary viewpoint, she speculates, females may have faced greater demands for social, emotional, and multitasking adaptability—for example, in child care, food gathering, or coordinating group activities. The female brain, therefore, had to adapt and respond more swiftly.
"That's a good thing," Siegert says. "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."
Drugs for Women, Tested on Men
Siegert further points out that during the literature review, her team found very few studies in which ketamine had been tested in females.
"There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia," she says.
Given that ketamine is also used as an antidepressant, understanding how its mechanisms differ between the sexes is all the more important.
"It's astonishing how readily people assume that men and women respond to drugs in the same way—when clearly they do not," Siegert stresses.
Research like this is a step in the right direction: it highlights that medications can act differently in women and men and serves as a call to consider sex‑specific differences in future studies.
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Information on animal studies
In order to better understand fundamental processes, for example, in the fields of neuroscience, immunology, or genetics, the use of animals in research is indispensable. No other methods, such as in silico models, can serve as an alternative. The animals are raised, kept, and treated according to the strict regulations of Austrian law. All animal procedures are approved by the Federal Ministry of Education, Science, and Research.
