Ketamine Anaesthesia Changes Brain Structures Only in Female Mice, Study Finds

Despite 170 years of clinical use and the countless people who ‘go under’ each day, the effects of anaesthesia remain poorly understood.

While clinicians steadily unravel its mechanisms and mysteries, they continue to find fresh questions about whom it affects and in what ways.

Ketamine anaesthesia and female mouse brains

A new study in mice, published in Science Advances, has reported an unexpected finding: anaesthesia with ketamine remodels brain tissue, but only in females.

"We didn't expect to see this; it was a surprising finding," says Sandra Siegert, a neurobiologist at the Institute of Science and Technology Austria (ISTA) and the study’s senior author.

Examining the brains of mice given ketamine anaesthesia, the team found that microglia - the nervous system’s main immune cells - extended their arm-like projections to ‘embrace’ neurons, the brain cells underlying everything we do, think and are.

In vivo imaging of the mouse visual cortex, with a graph of interactions between microglia and neurons. (Venturino et al., Science Advances, 2026)

This close contact boosted the creation of synapses, the junctions between brain cells that transmit chemical and electrical signals.

The recovery phase after anaesthesia, which may continue for as long as 48 hours, therefore appears to support brain remodelling, also known as plasticity.

An illustration of neuronal communication, with the synapse shown in detail in the inset. (Christy Krames, MA, CMI, for US National Institutes of Health, National Institute on Aging/Wikimedia Commons)

"What was fascinating," says Alessandro Venturino, a neurophysiologist and research scientist at ISTA and the study’s first author, "was that we observed this plasticity – the brain's ability to change, adapt, and in this case recover – only in females."

Microglia drive the post-anaesthesia response

To establish when this plasticity emerged and whether it was sex-specific, the researchers tracked brain changes in vivo through a cranial window, allowing them to look into the brains of living mice.

Roughly an hour after ketamine was administered, microglia in female mouse brains began making significantly more contact with neurons.

However, when the mice were given a specially formulated chow during the week before anaesthesia, microglial density in the brain was dramatically reduced. This stopped the anaesthesia-triggered effect.

Microglia (green) embedded across different brain layers (orange) in the mouse visual cortex. (Siegert group/ISTA)

By sequencing almost 37,000 brain cells and assessing activity changes in 2,000 genes, the researchers identified a particular gene-hormone interaction.

"During recovery from anesthesia, corticosterone levels rise," Venturino says.

"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."

Injecting an antagonist that inhibits Fkbp51 blocks the microglial response and plasticity in female mouse brains. Knocking out, or inactivating, this gene in a specialised mouse line had a similarly suppressive effect. (Venturino et al., Science Advances, 2026)

Lastly, the researchers removed the mice’s adrenal glands, the body’s principal source of corticosterone.

This weakened the ketamine response of microglia. Injecting corticosterone restored it, reinforcing the hormone’s role as a key pathway.

Why male mice apparently do not show this adaptive brain response remains unclear. The response may be delayed, or males might rely on another mechanism for reshaping the brain.

The researchers say that circulating sex hormones contribute, but cannot fully account for the effect.

From an evolutionary perspective, Siegert compares this with the distinct selection pressures experienced by females over history. These included rapidly adapting to varied challenges involving childcare, food gathering and organising groups of people, among other things.

What the findings could mean for ketamine treatment

The results require substantially more investigation, including detailed research into sex-dependent clinical differences.

Earlier research found that ketamine anaesthesia induced anxiety traits, again exclusively in female mice.

It is therefore just as important to investigate how this work may translate to humans.

"There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia," Siegert notes.

Limiting ketamine’s effects is consequently crucial when determining which therapeutic approach to take.

Related: Ketamine Can Treat Depression as Effectively as Electroconvulsive Therapy

"How drug effects differ between males and females is important to know in order to offer the best treatment," Siegert adds.

As ketamine is also used to treat depression, the findings underscore a double-edged sword: brain plasticity can help, yet either too much or too little may contribute to neuropsychiatric disorders.

"How can you modify and modulate this plasticity but in a positive way?" asks Bosiljka Tasic, a neurobiologist at the Allen Institute for Brain Science in Seattle and one of the study’s co-authors.

"Many of the major plasticity-inducing drugs have become quite interesting, especially as treatments for depression, but we still don't know how they work."

This research was published in Science Advances.

This article was fact-checked by Clare Watson and edited by Peter Dockrill. Although we take pride in our process, we are only human. If you spot an error, please let us know.