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.

Dementia and sensitivity to anesthetics

“…Traditionally, this has been considered a pharmacokinetic phenomenon, but more recent data support the hypothesis that emergence from anesthesia is under distinct neurobiological control. [22][23][24] These findings bear on the present question. Even if we assume no difference in anesthetic sensitivity between demented and non-demented patients at the beginning of the anesthetic effect, there may nonetheless be significant differences at its end.…”

“…Cela a été traditionnellement considéré comme étant un phénomène pharmacocinétique, mais des données plus récentes étayent l'hypothèse que l'émergence de l'anesthésie relève d'un contrôle neurobiologique distinct. [22][23][24] Ces constatations sont pertinentes pour la question présente. Même si nous supposons qu'il n'y a pas de différence de sensibilité aux anesthésiques entre les patients atteints de démence et les patients indemnes de MA au commencement de l'effet des anesthésiques, il pourrait néanmoins y avoir des différences significatives quand cet effet prend fin.…”

Brainstem node for loss of consciousness due to GABAA receptor-active anesthetics

“…Its mediation by dedicated brain circuitry therefore suggests that in clinical use GABA A -R active anesthetics substitute for the neurotransmitter GABA much as in endogenous pain control circuitry morphine substitutes for enkephalins and endorphins. It follows that the switching circuitry itself serves an adaptive functional role, presumably in the realm of natural sleep and perhaps also in the realms of syncope (fainting), anti-predator immobility and concussion (Franks, 2008;Hayes et al, 1984;Joiner et al, 2013;Sandoval-Herrera et al, 2011). If so, MPTA neurons might contribute to state switching in these functions as well.…”

Distinctive Recruitment of Endogenous Sleep-promoting Neurons by Volatile Anesthetics and a Nonimmobilizer

“…17,44,50,53,54 Studies across phyla as distinct as invertebrates and mammals have demonstrated that anesthetic drugs are capable of activating endogenous sleep-promoting neural systems. 18-22,55,56 Hence, we believe that exploring the commonalities and recognizing the key differences in the genesis of these states will be critical to advance our understanding both of anesthetic mechanisms as well as sleep neurobiology.…”

“…22 Studies in drosophila have shown that mutations in single genes can lead to large changes in sleep as well as crucial alterations in anesthetic sensitivity. 55,77 Moreover, increased synaptic activity specifically in sleep-related drosophila neurons alters responsiveness to isoflurane, unveiling a common neural pathway for sleep and anesthetic sensitivity. 56 However, circuits and genes affecting sleep do not exclusively map onto those regulating anesthetic responsiveness, as demonstrated by our results with halothane in the MnPO.…”