Genetic and Anatomical Basis of the Barrier Separating Wakefulness and Anesthetic-Induced Unresponsiveness

Abstract

A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states.

Author Summary

An annual 234 million surgical procedures are performed worldwide, making general anesthetics among the most common drugs administered to humans. Remarkably, however, we still do not understand the mechanisms by which general anesthetics render patients unconscious or the processes that re-establish consciousness upon emergence from anesthesia. We previously showed that the brain resists transitions between the wakeful and anesthesia states by generating a barrier to such transitions in both directions. We also showed that the existence of this barrier is conserved from invertebrates to mammals. In our present work, we use the genetic tractability and the simplified nervous system of the fruit fly Drosophila melanogaster to show that four genes are required to maintain this barrier. We also show that, as in mammals, there is overlap between pathways regulating natural sleep and general anesthesia. We propose that some of these shared pathways are impaired in conditions such as coma and persistent vegetative states, in which the barrier to transitioning to the waking state appears to be insurmountable.