ABOVE: A mouse brain section highlighting the hippocampus (green) is overlaid with the molecular structures of the anesthetics isoflurane (purple), medetomidine/midazolam/fentanyl (orange), and ketamine/xylazine (red).

After general anesthesia, a common problem that shows up in older adults is cognitive deficits, particularly memory loss, but it’s not clear why or how they happen. In a study published today (April 1) in PLOS Biologyresearchers have taken a step toward understanding how anesthetic drugs affect the hippocampus, a brain region involved in memory formation and storage. They tested three anesthesia treatments in mice and determined that isoflurane, an inhaled anesthetic commonly used by itself in animal studies and sometimes in combination with other drugs in people, was the least disruptive to hippocampal neurons and didn’t affect memory formation and consolidation.

The authors “not only looked at the onset of the effects and the changes during the acute phase...

The work began when Simon Wiegert, a neuroscientist at the Center for Molecular Neurobiology Hamburg in Germany, and colleagues set out to image the connections between neurons in the hippocampus to figure out how individual synapses contribute to memory formation. Before looking closely at small structures in mice, researchers typically anesthetize the animals so they’re not moving, which allows much more precise and efficient imaging. “We wondered, when we do this under anesthesia, whether this would affect the activity or the stability of the synapses themselves,” he says.

When the researchers combed through previously published work for clues about how activity patterns in the brain are altered during anesthesia, they realized that while there were some studies that looked at a particular anesthetic, there wasn’t any systematic work on the effects of different anesthetics on hippocampal activity. The team picked three common anesthetic regimes: inhaled isoflurane; a combination of the sedative medetomidine, the anti-anxiety medication midazolam, and the pain reliever fentanyl (MMF, which is used in animals); and ketamine and xylazine together, which are given to both animals and human patients. While commonly used solo in animal studies, isoflurane is not usually administered by itself in people, due to its potential to irritate the respiratory tract and cause low blood pressure in some patients.

The researchers administered each anesthetic to adult mice and then took electrophysiological recordings of overall activity in the hippocampus. They also visualized the region’s electrical activity with calcium imaging, which provides a precise look at single cells, but with more limited temporal resolution. “Therefore, we could do this comparison of hippocampal activity with microscopy and electrophysiology and the two techniques complement each other,” Wiegert tells The Scientist. 

The authors found that isoflurane exerted the mildest effects on activity in the hippocampus, even when applied for up to four hours. But animals treated with either ketamine–xylazine or MMF showed disrupted hippocampal activity and deficits in both memory formation and consolidation—in the case of MMF, for up to six hours after another drug was given to antagonize the anesthetic and wake the animals up. The mice “wake up within a couple of minutes, and they’re pretty mobile, and they look like they really recovered from the anesthesia,” explains Wiegert. “Even though the animal is awake, the brain activity is not as it was before.”

“The most potent effects of general anesthetics relate to memory systems but these amnesic effects have been relatively understudied to this level of detail in the hippocampus,” writes George Mashour, an anesthesiologist and neuroscientist at the University of Michigan who was not involved in the study, in an email to The Scientist. In terms of next steps, “two of the three anesthetic combinations tested in this study are used primarily in animal experiments,” he adds. “Additional investigation using experimental models that include other anesthetic regimens commonly used in humans and that also include a surgical intervention will help translate these findings to clinical care.”

“The most important [next step] is to document that these deficits occur [and] understand the behavioral domains that are most vulnerable,” says Orser. “That will help us understand the receptors and networks that are involved, and then obviously develop from there prevention and mitigation strategies. Right now, there are precious few.”

W. Yang et al., “Anesthetics fragment hippocampal network activity, alter spine dynamics, and affect memory consolidation,” PLOS Biol, doi:10.1371/journal.pbio.3001146, 2021.

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