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During ketamine anesthesia the brain’s nerve cells fall silent, and as consciousness returns, they begin to reconnect. A study in mice by researchers at the Institute of Science and Technology Austria (ISTA) and colleagues at Allen Institute for Brain Science in Seattle, has now for the first time shown that immune cells in the brain play a critical role in this process, and indicates that there are differences between female and male brains.

Senior and corresponding author Sandra Siegert, PhD, at ISTA, reported on their findings in Science Advances, in a paper titled “Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia,” in which they concluded “Our study uncovers significant sex-specific differences in neuronal adaptation during recovery from ketamine anesthesia, driven by microglia.”

Recovery from anesthesia is critical for resuming normal physiological and neuronal functions, but the mechanisms involved remain elusive, the authors wrote. “Ketamine distinguishes itself from other anesthetics by its unique pharmacological properties as an N-methyl D-aspartate (NMDA) receptor antagonist, which preferentially targets GABAergic inhibitory interneurons.”

And 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. “…  ketamine anesthesia induces mild anxiety behavior phenotypes, interestingly, only in females,” the team continued, “suggesting inherent sex differences in anesthesia recovery with neuronal consequences that extend beyond the immediate sex-dependent metabolic processing described for low-dose ketamine.”

Working with mice, Siegert, together with Alessandro Venturino, PhD, and their colleagues at ISTA, and researchers at the Allen Institute, now offer the first answers to some of these questions. 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. “Ketamine, across different dosages, affects microglia, which are embedded within the neuronal network,” the team explained. “Locally, microglia influence the synaptic machinery and neuronal firing properties by responding to environmental changes.”

As early as 2017, Siegert’s group at ISTA noticed that male and female mice respond differently to ketamine anesthesia, and more precisely, their microglia do.

For the newly reported study, 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.”

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 said 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 explained. “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.”

The authors further noted, “Mechanistically, we found that female microglia selectively up-regulated the cochaperone Fkbp5/FK506-binding protein 51 (FKBP51), which is a key intermediary in the corticosteroid-induced stress response … Our findings underscore that microglia serve as a relevant interface between the endocrine stress response and the brain -immune cell system.”

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,” said Venturino.

Siegert added, “They also remind us that stress is not always harmful—stress hormones are essential for certain processes in the brain.” In their paper the investigators commented, “The selective hypothalamic activation and elevated blood plasma corticosterone levels during the recovery phase in females shape the microglia-neuron interactions, highlighting a link between the endocrine and the brain-immune axes.”

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 noted.

From an evolutionary viewpoint, she speculates, females may have faced greater demands for social, emotional, and multitasking adaptability—for example, in childcare, food gathering, or coordinating group activities. The female brain, therefore, had to adapt and respond more swiftly. “That’s a good thing,” Siegert added “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.”

Siegert further pointed 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 stated. 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 stressed.

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. “Our findings contribute to a growing body of evidence recognizing sex-specific differences in brain function and immune responses, the latter of which is already well known for increased susceptibility to infection and autoimmune diseases,” the team pointed out. “Our results identified a link between microglia-specific Fkbp5 expression and ketamine action, warranting a reevaluation of assumptions that ketamine is a general anesthetic and fully reversible across sexes.”

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.

The post Ketamine Triggers Sex-Specific Brain Recovery Responses appeared first on GEN – Genetic Engineering and Biotechnology News.