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.

Fig. 1.

Vanishing bearings of individual bees in the Southern Hemisphere. Data are shown with respect to the expected homing direction to the hive (defined as 0°, gray hive symbol). Bees caught departing from a feeder to which they had been trained were translocated to a release site outside of their home range. Vanishing bearings were recorded after either 30-min anesthesia (blue circles, control; n = 80) or 6-h anesthesia (red circles, treatment; n = 108). The mean bearing of each group is represented by the white circle with 95% CI scribed by the arc.

Fig. 2.

Flight paths of individual bees tracked by harmonic radar in the Northern Hemisphere. Data are shown with respect to the expected homing direction to the hive (defined as 0°, gray hive symbol). (A) Typical flight paths of three bees from release site to hive. Each bee represents one of three experimental groups: catch and release; 30-min anesthesia (control); and 6-h anesthesia (treatment). The vector–flight is indicated by the solid line terminating at the filled circle. The remainder of the flight is shown as a broken line. (B) The distribution of vector–flights of all individual bees. The vector–flight of each bee is represented by a line indicating both the direction (angle) and duration (length) of the flight. Mean angle of orientation of each of the three groups (catch and release, n = 13; control, n = 25; treatment, n = 24) is indicated by the white circle with 95% CI scribed by the arc.

Fig. 3.

Difference in onset of foraging time between the day before anesthesia and each of 3 d after anesthesia. Blue: 30-min anesthesia (control, n = 9); red: 6-h anesthesia (treatment, n = 11).

Fig. 4.

Hive-activity rhythms and clock gene expression. (A) Hive locomotor activity before and after a 6-h daytime anesthetic and a 30-min control anesthetic. Black bars represent the activity of bees entering and leaving the hive every 5 min. Regression line through the peaks (acrophases) is shown in red. Background colors indicate level of illumination (gray: dark; white: bright light; yellow: dim light). Samples represented in B were collected during the period indicated by circled days. (B) Brain mRNA levels of clock genes cryptochrome, period, and clock from bees sampled before and after daytime anesthesia during the recording of the actogram in A. Open circles represent individual data points (n = 6 per time point); filled circles represent the geometric means ± SEM. Solid lines display a cosinor model fitted to the log-transformed data (blue: preanesthesia; red: postanesthesia); broken lines are an extrapolation of the model. (C) Hive locomotor activity before and after night anesthesia. Samples represented in D were collected during the period indicated by circled days. (D) Brain mRNA levels of clock genes cryptochrome, period, and clock from bees sampled before and after nighttime anesthesia during recording of the actogram in C.