The Female Brain Wakes Up Differently After Ketamine Anesthesia
In a new study, researchers identified synaptic remodeling following anesthesia that is unique to the female brain.
After anesthesia, how do we wake up?
Researchers from the Institute of Science and Technology Austria (ISTA) sought to answer this question. In doing so, they identified synaptic remodeling following ketamine anesthesia that is unique to the female brain. Their work was recently published in Science Advances.
Ketamine anesthesia turns down brain communication
Ketamine is licensed for general anesthesia and sedation; depending on the dose administered and the route it is given via, effects range from loss of consciousness requiring respiratory support, to drowsiness.
Unlike other anesthetics, ketamine has a strong pain-relieving effect, and it is commonly used in emergency departments.
While ketamine has its place in general anesthesia, it is rarely the primary anesthetic used in planned surgeries and outpatient procedures. As a dissociative anesthetic, the high doses of ketamine that are required for general anesthesia can result in unwanted side effects ranging from mild confusion to vivid, unsettling hallucinations.
It can also cause dangerous changes to blood pressure and heart rate.
The dissociative effects of ketamine are due to N-methyl-D-aspartate (NMDA) antagonism. NMDA receptors play a key role in excitatory brain communication; blocking them disrupts brain networks involved in self-perception, emotion, and cognition.
While researchers have explored many ketamine-associated brain changes, they have yet to determine exactly how the brain returns to reality.
Previous research has highlighted sex-based differences in responses to anesthesia. This, alongside evidence that ketamine affects microglia—brain immune cells with sex-dependent biology—prompted ISTA researchers to investigate sex-specific microglial responses during ketamine recovery.
Watching how the brain responds to anesthesia in real time
The team began by observing real-time changes in brain activity following intraperitoneal ketamine administration in mice, focusing on the primary visual area. Microglia-mediated changes following ketamine exposure have previously been reported in this region.
Using a cranial window and fluorescence microscopy, they watched microglia–neuron interactions before and after treatment. For the first hour post-administration, there were no changes. But after the 60-minute mark, the number of connections in female brains increased.
Over the following three hours, the increased synaptic remodeling observed in female brains ceased, and the animals woke up.
Further imaging demonstrated that the frequency of small, spontaneous electrical currents in the brain also increased in females after ketamine administration, but not in males.
Researchers conducted the experiment again, this time in mice with ~80% depletion of microglia. The female-specific responses were abolished, supporting the theory that they were microglia-driven.
Dr. Sandra Siegert, study supervisor and professor at ISTA, shared her instinctive belief and a motivation to learn more: “I’ve always believed that women have greater brain plasticity. Alessandro and I just couldn’t let it go—we wanted to know why.” Dr. Alessandro Venturino, a neuroscientist at ISTA, was the study’s lead author.
From brain observations to cellular changes following ketamine
To explore specific mechanisms, the team conducted multiomic sequencing of cells in the primary visual area of the female brain following ketamine administration.
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The total dataset included over 36,000 cells. Among the gene expression changes observed, the commonality was narrowed down to glucocorticoids; genes were either implicated in their production, metabolism, or regulation.
The team homed in on a particular gene, Fkbp5, and its protein, FKBP5. FKBP5 plays a role in modulating glucocorticoid receptor activity during the stress response. Both the Fkbp5 gene and protein levels were upregulated following ketamine administration.
Previous research has found that ketamine exposure increases CD68 expression, a protein found in certain immune cells that plays a role in phagocytosis and the clearance of cellular debris.
The team at ISTA identified that loss of FKBP5 function prevented ketamine-induced CD68 upregulation in microglial cells. Additionally, the previously observed increase in the frequency of small, spontaneous electrical currents was lost.
Given FKBP5’s role in glucocorticoid modulation and the fact that corticosterone is the main glucocorticoid in mice, the researchers investigated whether corticosterone changes following ketamine exposure could explain the missing piece.
Sure enough, they identified a three-fold increase in the steroid hormone 120 minutes after ketamine exposure in females—a rise that was not seen in males.
After adrenalectomy, removal of the glands that produce corticosterone, the effects following ketamine administration disappeared. Females exhibited lower expression of both FKBP5 and CD68.
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The team finished where they started, observing that adrenalectomy also diminished ketamine's effect on microglia–neuron interactions during cranial window observations. After administering corticosterone, interactions increased.
Sex-specific neuronal adaptation occurs following ketamine anesthesia
“Our study uncovers significant sex-specific differences in neuronal adaptation during recovery from ketamine anesthesia, driven by microglia,” concluded the researchers.
Their findings suggest that the glucocorticoid pathway mediates microglial changes, facilitated by Fkbp5/FKBP51.
The study may help explain sex-specific responses to anesthesia, such as why females have a higher incidence of perioperative awareness.
The researchers highlighted the limitations, including the models used. Further investigations are required to determine whether observations from mouse models translate to human neuropharmacology.
“What was fascinating,” Venturino explained, “was that we observed this plasticity—the brain’s ability to change, adapt, and in this case recover—only in females.”
Reference: Venturinoe A, Alamalhoda MA, Negrello T, et al. Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia. Sci Adv. 2026. doi: 10.1126/sciadv.adz6517
This article is a rework of a press release issued by the Institute of Science and Technology Austria. Material has been edited for length and content.
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