Waking up from surgery can be disorienting. One minute you're in an operating room counting backwards from 10, the next you're in the recovery ward sans appendix, tonsils, or wisdom teeth. And unlike getting up from a good night's sleep, where you know that you've been out for hours, waking from anesthesia feels like hardly any time has passed. Now, thanks to the humble honeybee (Apis mellifera), scientists are starting to understand this sense of time loss. New research shows that general anesthetics disrupt the social insect's circadian rhythm, or internal clock, delaying the onset of timed behaviors such as foraging and mucking up their sense of direction.
Putting insects to sleep is nothing new. Researchers have used the animals for decades to figure out how anesthetics work, because the drugs elicit the same effects, at the same concentrations, in many different organisms. "You can give the anesthetic to a monkey and a snail, and they'll fall over and stop moving," says study co-author Guy Warman, a chronobiologist at the University of Auckland in New Zealand.
The circadian rhythm's daily cycles are also common across organisms. So-called clock genes help regulate the rhythms that make us feel awake during the day and tired at night, while also prompting honeybees to search for nectar at certain times of day. External inputs, such as light, fine-tune those cycles. In our case, they keep us on a roughly 24-hour schedule.
Warman and his colleagues used the honeybee's sense of timing to study the behavioral and genetic effects of isoflurane, a common anesthetic for human surgeries. "[Honeybees] display behaviors in their everyday life that tell you exactly what time of day they think it is, which isn't possible to do [with] mammals," Warman notes.
First, the researchers tested the insects' ability to navigate back to their hive after being dosed with isoflurane for 6 hours. Honeybees use the sun's position, along with their internal clock, to determine the way home. If anesthetics interrupted that clock, the researchers expected to see a shift in the bees' headings. And indeed, when the team released the insects into novel areas in Germany and New Zealand and watched them try to fly home, post-anesthetic bees were nearly 90° off in the Southern Hemisphere and 62° off in the Northern Hemisphere. This deviation indicated a delay in the honeybees' internal clock, the researchers report online today in the Proceedings of the National Academy of Sciences.
When Warman and his colleagues studied isoflurane's effects on when honeybees started searching for nectar, they saw similar delays. Bees carrying radio frequency identification tags and trained to visit a feeder between 9 a.m. and 10 a.m. every day delayed their post-anesthesia searches by about 3 hours.
The researchers then tested the anesthetic's genetic effects. They sampled bees every 3 hours for 36 hours before and after anesthesia, measuring concentrations of mRNA—molecules carrying protein-building instructions—for three clock genes. They found that mRNA cycles from two of the genes were delayed between 4 and 5 hours after anesthesia. Movements of bees in and out of the hives were delayed by about 5 hours. When the team dosed hives at night, the anesthetic did not produce any delays in mRNA cycles.
"I think [it's] a very creative and provocative paper," adds Gene Robinson, an entomologist and neuroscientist at the University of Illinois, Urbana-Champaign. "I think they've made a compelling case that anesthesia is affecting the [circadian] clock," adds neurobiologist Ravi Allada of Northwestern University in Evanston, Illinois, who was not involved in the research. People have considered anesthesia's effects on movement and sensory perception, but no one has focused on its effects on the circadian clock, he notes.
Next up: seeing if this research will translate to humans. Warman says his team is currently looking at whether shining bright light at someone under anesthesia—a well known way to alter the circadian clock—could also reduce the procedure's disorienting effects.