Stress hormones drive female-specific brain rewiring following ketamine anesthesia

A recent study found that female mice, but not males, experience a surge in a stress hormone during recovery from ketamine anesthesia, prompting immune cells in the brain to reshape neuronal connections. This points to profound sex differences in how the brain regains function after being anesthetized. The findings were published in Science Advances.

Recovery from anesthesia is a complex biological process required to resume normal bodily and brain functions. Ketamine is unique among anesthetics because it targets specific inhibitory systems in the brain. It is normally viewed as a standard anesthetic that causes a temporary and fully reversible loss of consciousness.

Recent observations suggest ketamine can actually reinstate juvenile-like plasticity, or the brain’s ability to rewire and form new connections, and induce mild anxiety in female animals. This aligns with other work showing that biological sex plays a role in anesthesia responses. For instance, a study covered by PsyPost in 2024 indicated that females tend to regain consciousness and cognitive function faster than males following exposure to general anesthetics.

Microglia, the resident immune cells of the brain, are known to interact with neuronal networks and respond to environmental changes, shaping how neurons fire. However, their specific role in anesthesia recovery, particularly regarding potential sex differences, has remained largely unexplored.

The research, led by Alessandro Venturino and Sandra Siegert, a professor at the Institute of Science and Technology Austria, aimed to see if microglia behave differently in male and female brains during anesthesia recovery.

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“We were interested to investigate which consequences ketamine anesthesia had on microglia,” said Siegert, who leads the Siegert Group. “Microglia are known to respond to neuronal activity and anesthesia alters the brain activity, which led us to hypothesize that microglia might respond to it.”

To test this, the team administered a single dose of a ketamine-based anesthesia mixture to adult male and female mice. They then examined the primary visual cortex, an area of the brain where ketamine is known to induce structural changes.

Looking at the brain tissue four hours after the injection, the scientists noticed a distinct difference between the sexes. Female mice exhibited increased levels of a protein called CD68 in their microglia, indicating heightened cellular activity. The physical shape of the female microglia also changed, and they formed prolonged contacts with the branching structures of nearby neurons. Male microglia did not show these pronounced changes.

To see if these cellular contacts altered brain function, the team recorded the electrical activity of the neurons in slices of brain tissue. They found that the frequency of spontaneous electrical impulses increased in the female mice, suggesting enhanced neural plasticity and synaptic function. When the researchers chemically depleted the microglia in a separate group of female mice before administering the anesthesia, this boost in electrical activity did not occur. This provides evidence that the immune cells are necessary for the observed neural changes.

The researchers then used genetic sequencing to figure out what was driving this female-specific response. They found that female microglia selectively increased the expression of a gene called Fkbp5. This gene produces a protein involved in the body’s response to stress hormones, particularly corticosterone.

Blood tests confirmed that two hours after the ketamine injection, female mice had corticosterone levels nearly three times higher than their baseline. In contrast, male corticosterone levels remained relatively flat. To test the role of this hormone, the team surgically removed the adrenal glands, which produce corticosterone, in a group of female mice.

Without the adrenal glands, the ketamine-induced changes in microglial activity and neuron interaction vanished. When these mice were given a direct injection of corticosterone, the microglia rapidly resumed their active state and began contacting neurons again. This indicates that the stress hormone directly drives the immune cells to remodel neural connections.

The findings are in line with research covered by PsyPost in 2026, which detailed how recovering from ketamine anesthesia triggers a female-specific surge in corticosterone that activates microglia to promote new neural connections.

“It was fascinating to see that not the typical suspicious candidates for sex differences, namely the sex hormone estrogen, is the main driver of this effect but that the effect is mediated through the stress-response via the hormone corticosterone,” Siegert said.

A general reader might assume these findings mean human women will experience identical brain remodeling after receiving ketamine. The authors note that the study was conducted in mice, and human biological responses to anesthetics and stress hormones can differ. The experimental design also focused on a single time point of four hours post-anesthesia, meaning the long-term persistence of these new neural connections is currently unknown.

The anesthetic dosage used in the experiment also differs from how the drug is sometimes applied in psychiatry. The researchers gave the animals a dose sufficient to reach a level of anesthesia deep enough to perform surgery without pain or movement. “It’s important to say that we used an anesthetic dosage of ketamine, in combination with other drugs commonly used to ensure surgical plane for animal surgery,” Siegert noted. “How much our results can be translated to dosages commonly used for treating depression requires a follow-up study.”

Despite these caveats, the results highlight how biological sex can fundamentally alter the body’s response to pharmacological treatments. “Medication can have different effects and consequences between sexes,” Siegert explained. “In the case of ketamine, we know surprisingly little about sex-differences, even though it is frequently used. Our data suggests that females are more sensitive to the effects of ketamine.”

Beyond hormones, other factors such as the neurotransmitter noradrenaline appear to fluctuate differently between the sexes during recovery and might interact with the stress response. Future research could explore how different types of anesthetics, which act on different brain receptors, might influence these immune-driven changes.

More broadly, the team hopes to continue unraveling the mysteries of these immune cells and how they interact with glial cells, the supportive, non-neuronal cells that protect and maintain the brain. “Our main research focus is on identifying which role microglia have in the adult healthy brain,” Siegert said. “They are highly active but we still have only a rudimentary understanding of their daily role on how they act on neurons and other glial cells in the brain.”

The study, “Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia,” was authored by Alessandro Venturino, MohammadAmin Alamalhoda, Thomas Negrello, Kelly Jin, Cindy T. J. van Velthoven, Ryan John A. Cubero, Jake Yeung, Peter Koppensteiner, Bosiljka Tasic, and Sandra Siegert.