Female Brains Wake Up from Anesthesia Differently Than Male Brains

All over the world, doctors perform more than 300 million surgeries each year.¹ While some procedures require local anesthetics, nearly 60,000 people go under general anesthesia each day in the United States alone, rendering them unconscious during surgeries.²

While doctors must ensure that patients go under anesthesia for the procedure, it is equally important that they wake up after the surgery. Researchers have previously found that male and female animals respond differently to the general anesthetic ketamine, but they did not fully understand its underlying molecular basis.³

Now, scientists led by Sandra Siegert, a neuroscientist at the Institute of Science and Technology Austria found that sex differences in ketamine recovery arise due to distinct dynamics of neurons and immune cells called microglia in male and female brains.⁴ Their findings, published in Science Advances, offer a deeper understanding of ketamine anesthesia recovery and highlight the need to study sex as a biological variable.

Siegert and others in the field had previously found that ketamine affects microglia, and that sex differences influence microglial function.^5,6 Isolating brain tissue of ketamine-treated mice indicated higher microglial activity in female brains compared with male brains.

To dig deeper, the researchers used transgenic mice with fluorescently labeled microglia and neurons. They surgically replaced a small section of the animals’ skulls with clear coverslips, offering them a window into the rodents’ brains. Using in vivo imaging, the researchers observed that ketamine treatment triggered microglia to establish significantly more contacts with surrounding neurons in female brains compared to male ones, forming new synapses to increase plasticity.

Depleting microglia suppressed the effects of such synaptic remodeling, indicating that microglia are critical for this process. To understand the molecular basis of this female-specific microglia-dependent plasticity, Siegert and her colleagues subjected female brain cells to single-nucleus sequencing.

They observed increased expression of the gene encoding FK506 binding protein 5 (Fkbp5), a stress response regulator that helps detect the stress hormone corticosterone. In vitro experiments validated that only female microglia exposed to ketamine showed a rise in Fkbp5 expression and Fkbp51 levels.

To understand how corticosterone and microglia-mediated effects are linked, the researchers measured the levels of this hormone in the mice’s blood plasma. Ketamine treatment led to a rise in corticosterone levels only in female animals, suggesting that the stress hormone spike during ketamine recovery triggers increased Fkbp51 production in microglia, which in turn increases microglial activity to increase neuroplasticity.

According to the authors, these findings underscore the importance of studying the effects of anesthesia in both male and female animals. “There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia,” said Siegert in a statement. “It’s astonishing how readily people assume that men and women respond to drugs in the same way—when clearly they do not.”