title: A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia.
abstract: One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Eliot B
authors.initials: EB
authors.lastname: Friedman
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Jason T
authors.initials: JT
authors.lastname: Moore
authors.forename: Hsiao-Tung
authors.initials: HT
authors.lastname: Hung
authors.forename: Qing Cheng
authors.initials: QC
authors.lastname: Meng
authors.forename: Priyan
authors.initials: P
authors.lastname: Perera
authors.forename: William J
authors.initials: WJ
authors.lastname: Joiner
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
authors.forename: Max B
authors.initials: MB
authors.lastname: Kelz
mesh_terms: D000777:Anesthetics / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D002490:Central Nervous System / Q000187:drug effects; D004330:Drosophila; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014474:Unconsciousness / Q000139:chemically induced*; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D000777:Anesthetics