title: Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis.
abstract: BACKGROUND
  Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep.
  
  
  RESULTS
  Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance.
  
  
  CONCLUSIONS
  Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties.
authors.affiliation: Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Moore
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Qing Cheng
authors.initials: QC
authors.lastname: Meng
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
authors.forename: Sheryl G
authors.initials: SG
authors.lastname: Beck
authors.forename: Max B
authors.initials: MB
authors.lastname: Kelz
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D006221:Halothane / Q000494:pharmacology*; D006991:Hypnosis, Anesthetic; D006993:Hypnotics and Sedatives; D007530:Isoflurane / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D011301:Preoptic Area / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D014474:Unconsciousness
chemical_list: D000777:Anesthetics; D006993:Hypnotics and Sedatives; D016760:Proto-Oncogene Proteins c-fos; D007530:Isoflurane; D011188:Potassium; D006221:Halothane