General anesthesia alters time perception by phase shifting the circadian clock

Abstract

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87°in the Southern Hemisphere and a clockwise shift in flight direction of 58°in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.chronobiology | anesthesiology | post-operative sleep disruption E ver since "Ether Day" in 1846, when William Morton administered the first general anesthetic, anesthesia has been used to alleviate pain and enable a wide range of surgical procedures that were not previously possible. Today, an estimated 234 million operations requiring anesthesia occur around the world each year (1). Despite the ubiquity and importance of general anesthesia, the mechanisms by which anesthetics work to "put you to sleep" remain unclear. Recent evidence suggests that most general anesthetics act, at least in part, on the same brain centers as those involved in the control of sleep (2) and that they may "hijack" endogenous GABA-ergic (γ-aminobutyric acid) sleep-controlling pathways to exert their effects on consciousness (3). The effect of anesthesia on brain activity parallels some of the features of sleep (3). However, there are obvious differences. For example, a common patient response on emerging from anesthesia is disorientation and the feeling that time has not passed. This is in stark contrast to sleep, where one often wakes up just before the alarm sounds aware that time has passed during the night.Daily sleep timing relies on the endogenous circadian clock, which drives daily rhythms in biochemistry, physiology, and behavior. In animals, this clock is controlled by a set of conserved and well-char...

Measuring individual locomotor rhythms in honey bees, paper wasps and similar sized insects

“…In addition, the honey bee circadian system regulates complex physiological and behavioral processes such as sleep stages, spatiotemporal learning, sun-compass navigation, time perception, division of labor, mating and reproduction (von Frisch, 1967;Moore and Rankin, 1985;Goodwin and Lewis, 1987;Harano et al, 2007;Shemesh et al, 2007;Moore and Doherty, 2009;Johnson et al, 2010;Shemesh et al, 2010;Cheeseman et al, 2012;Eban-Rothschild and Bloch, 2012;GalindoCardona et al, 2012). Both the wide range of biological processes under circadian regulation and the extraordinary plasticity of the circadian network of these organisms potentially represent unique evolutionary challenges and solutions.…”

Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver

“…In contrast to Cheeseman et al (9) and Challet et al (10), isoflurane administration caused suppression of circadian gene expression but did not cause a shift in circadian pattern in investigated tissues. Cheeseman et al (9) kept animals in a DD cycle after anaesthesia administration, and they found a phase shift in circadian gene expression. The different effect of anaesthesia on circadian gene expression in our study may be due to light in the LD cycle.…”

“…Yoshida et al (8) found that propofol administration significantly changes the expression of circadian genes in rat whole brain, and the influence of intravenous anaesthesia also persists for 24 hours after awakening from anaesthesia. Cheeseman et al (9) investigated the effect of the time of day of general anaesthesia administration and circadian gene expression profile in the brain of a honeybee (Apis mellifera). They found that this effect is dependent on the time of day of administration, and night-time anaesthesia did not shift the clock.…”

Effect of Day and Night Desflurane Anaesthesia on Melatonin Levels in Rats

“…Cheeseman ve ark. (27) bal arılarında gündüz uygulanan izofluran anestezisinin per, cry ve CLOCK genlerini etkileyerek deneklerin zaman algılarında sapmaya neden olduğunu göstermişlerdir. SKÇ'teki GABA reseptörlerinin aktivasyonu ile CLOCK genlerin ekspresyonu baskılanabilir ve bu baskılanma anesteziklerin oluşturduğu sirkadiyan ritimdeki faz kayması oluşumu için bir mekanizma olabilir.…”