Ketamine has long been known as a powerful anesthetic, but its influence on the brain extends far beyond the operating room. Doctors also use low doses of the drug to manage pain and, more recently, to help people with treatment-resistant depression. Now, a study published in Science Advances suggests that ketamine can trigger profoundly different biological responses in male and female mice. The findings identify a previously unrecognized pathway through which the drug may promote neuroplasticity—the brain’s ability to reshape its connections—and raise important questions about how sex differences should be considered when developing and testing psychiatric medicines.
Researchers at the Institute of Science and Technology Austria, working with scientists at the Allen Institute, examined what happens in the brains of mice as they recovered from a single ketamine-induced sedation. Their most striking observation was that female mice showed a sharp increase in activity among microglia, immune cells that operate throughout the central nervous system. In contrast, the researchers did not observe the same response in male mice. The difference emerged during recovery from anesthesia, a period when the brain was undergoing significant molecular and cellular changes.
Microglia are often described as the brain’s resident immune cells, but their role is far broader than defense against infection. They constantly survey the surrounding tissue, remove damaged material, regulate inflammation, and help maintain the environment in which neurons communicate. In the female mice studied after ketamine exposure, microglia extended their thin, branch-like processes into the surrounding neural tissue. These cells began interacting more extensively with neighboring neurons and other brain cells, a behavior that appeared to alter the physical environment around synapses—the junctions through which neurons exchange signals.
The researchers found that activated microglia helped remove portions of the extracellular matrix, a complex meshwork of proteins and molecules that surrounds cells and provides structural support. Although this matrix is essential for maintaining tissue organization, it can also restrict the formation and rearrangement of synapses. By reducing elements of the matrix, microglia appeared to create additional physical space for neural connections to develop and reorganize. This remodeling may have increased the capacity of neural circuits to adapt, offering a cellular explanation for how ketamine can produce rapid changes in brain function.
The study also traced the hormonal and genetic sequence behind this sex-specific response. During recovery from ketamine anesthesia, levels of corticosterone rose in the bloodstream of the mice. Corticosterone is the principal stress hormone in rodents and is closely related to cortisol, the major stress hormone in humans. In female mice, the corticosterone surge activated the Fkbp5 gene in microglia. The gene produces FKBP51, a protein involved in regulating cellular responses to stress-related hormonal signals. According to the researchers, FKBP51 then helped drive the microglial activity associated with extracellular-matrix removal and increased neural remodeling.
To identify this molecular pathway, scientists at the Allen Institute used single-nucleus RNA sequencing. This technique allows researchers to examine gene activity in individual cell nuclei, revealing which genes are switched on in specific cell types. Rather than analyzing the brain as a uniform organ, the approach made it possible to distinguish molecular responses in microglia from those in neurons and other cells. The data showed that the Fkbp5 pathway was activated in female microglia following ketamine exposure, while the same pattern was not detected in male mice.
The discovery is significant because neuroplasticity is not automatically beneficial. The brain must balance flexibility with stability: insufficient remodeling can make it difficult to learn, recover, or adapt, while excessive or poorly regulated plasticity may contribute to maladaptive changes associated with psychiatric and neurological disorders. Ketamine is already one of the most prominent examples of a drug capable of rapidly altering neural plasticity, yet scientists are still working to understand how its effects arise. The new findings suggest that FKBP51 may function as a molecular lever that helps regulate this process, at least in female mice.
The work could eventually influence the study of depression treatments, but the researchers emphasize that the results cannot yet be directly applied to humans. Mouse corticosterone biology does not perfectly mirror human cortisol biology, and the response observed in laboratory animals may depend on factors such as age, hormonal state, dose, timing, and the specific brain region examined. The study also does not establish that the microglial changes themselves produce ketamine’s antidepressant effects. Instead, it reveals a mechanism that may help explain why the drug’s impact can differ between sexes and provides a target for future experiments.
Sex differences in immune function are already well documented. Men and women can respond differently to infections, inflammatory diseases, and immune-modulating treatments, reflecting interactions among hormones, genes, and cellular signaling pathways. Microglia share many functional characteristics with macrophages, the immune cells found throughout the body, making them plausible contributors to sex-dependent responses in the brain. The researchers say that systematically examining these differences could lead to more precise treatments, rather than assuming that a drug will produce the same biological effect in everyone.
If future studies reproduce the pathway in humans, the findings could reshape how researchers evaluate drugs that alter brain plasticity. Clinical trials may need to analyze male and female responses separately and investigate whether treatments should be adjusted according to biological sex or hormone-related factors. For now, the study offers a detailed glimpse of how ketamine can engage the brain’s immune system and remodel its neural environment. It also delivers a broader message for neuroscience: a drug’s effects may depend not only on its dose and target, but on the biological context of the person receiving it.
Subject of Research: Sex-specific effects of ketamine on microglial activity and neuroplasticity in mice
Article Title: Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia
News Publication Date: 31-Jul-2026
Web References: Science Advances article; Institute of Science and Technology Austria; Allen Institute researcher profile
References: Science Advances, DOI: 10.1126/sciadv.adz6517
Image Credits: Alessandro Venturino and Sandra Siegert, scientists at the Institute of Science and Technology Austria. Credit: Siegert group, Institute of Science and Technology Austria (ISTA).
Keywords
Ketamine, neuroplasticity, microglia, depression, neuroscience, corticosterone, FKBP51, Fkbp5, sex differences, brain immune cells, synapses, single-nucleus RNA sequencing, neural remodeling, psychiatric medicine
