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

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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.

Vyšlo v časopise: Genetic and Anatomical Basis of the Barrier Separating Wakefulness and Anesthetic-Induced Unresponsiveness. PLoS Genet 9(9): e32767. doi:10.1371/journal.pgen.1003605
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003605

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Zdroje

1. ChatterjeeA, KaznessisYN, HuW-S (2008) Tweaking biological switches through a better understanding of bistability behavior. Curr Opin Biotechnol 19 : 475–481.

2. SaperCB, ChouTC, ScammellTE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24 : 726–731.

3. LuJ, ShermanD, DevorM, SaperCB (2006) A putative flip-flop switch for control of REM sleep. Nature 441 : 589–594.

4. Steyn-RossML, Steyn-RossDA, SleighJW, WilcocksLC (2001) Toward a theory of the general-anesthetic-induced phase transition of the cerebral cortex. I. A thermodynamics analogy. Phys Rev E Stat Nonlin Soft Matter Phys 64 : 011917.

5. VossLJ, BrockM, CarlssonC, Steyn-RossA, Steyn-RossM, et al. (2012) Investigating paradoxical hysteresis effects in the mouse neocortical slice model. Eur J Pharmacol 675 : 26–31.

6. BeecherHK (1947) Anesthesia's Second Power: Probing the Mind. Science 105 : 164–166.

7. FriedmanEB, SunY, MooreJT, HungH-T, MengQC, et al. (2010) A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia. PLoS ONE 5: e11903.

8. LuJ, NelsonLE, FranksN, MazeM, ChamberlinNL, et al. (2008) Role of endogenous sleep-wake and analgesic systems in anesthesia. J Comp Neurol 508 : 648–662.

9. FranksNP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9 : 370–386.

10. LydicR, BaghdoyanHA (2005) Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 103 : 1268–1295.

11. HemmingsHC, AkabasMH, GoldsteinPA, TrudellJR, OrserBA, et al. (2005) Emerging molecular mechanisms of general anesthetic action. Trends in Pharmacological Sciences 26 : 503–510.

12. AlkireMT, MillerJ (2005) General anesthesia and the neural correlates of consciousness. Prog Brain Res 150 : 229–244.

13. AlladaR, NashHA (1993) Drosophila melanogaster as a model for study of general anesthesia: the quantitative response to clinical anesthetics and alkanes. Anesth Analg 77 : 19–26.

14. WeberB, SchaperC, BusheyD, RohlfsM, SteinfathM, et al. (2009) Increased volatile anesthetic requirement in short-sleeping Drosophila mutants. Anesthesiology 110 : 313–316.

15. AlkireMT, AsherCD, FranciscusAM, HahnEL (2009) Thalamic microinfusion of antibody to a voltage-gated potassium channel restores consciousness during anesthesia. Anesthesiology 110 : 766–773.

16. HumphreyJA, HammingKS, ThackerCM, ScottRL, SedenskyMM, et al. (2007) A putative cation channel and its novel regulator: cross-species conservation of effects on general anesthesia. Curr Biol 17 : 624–629.

17. LeibovitchBA, CampbellDB, KrishnanKS, NashHA (1995) Mutations that affect ion channels change the sensitivity of Drosophila melanogaster to volatile anesthetics. J Neurogenet 10 : 1–13.

18. PalD, LipinskiWJ, WalkerAJ, TurnerAM, MashourGA (2011) State-specific effects of sevoflurane anesthesia on sleep homeostasis: selective recovery of slow wave but not rapid eye movement sleep. Anesthesiology 114 : 302–310.

19. MashourGA, LipinskiWJ, MatlenLB, WalkerAJ, TurnerAM, et al. (2010) Isoflurane anesthesia does not satisfy the homeostatic need for rapid eye movement sleep. Anesth Analg 110 : 1283–1289.

20. TungA, SzafranMJ, BluhmB, MendelsonWB (2002) Sleep deprivation potentiates the onset and duration of loss of righting reflex induced by propofol and isoflurane. Anesthesiology 97 : 906–911.

21. KrishnanKS, NashHA (1990) A genetic study of the anesthetic response: mutants of Drosophila melanogaster altered in sensitivity to halothane. Proc Natl Acad Sci USA 87 : 8632–8636.

22. MorganPG, CascorbiHF (1985) Effect of anesthetics and a convulsant on normal and mutant Caenorhabditis elegans. Anesthesiology 62 : 738–744.

23. LuB, SuY, DasS, LiuJ, XiaJ, et al. (2007) The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129 : 371–383.

24. WuMN, JoinerWJ, DeanT, YueZ, SmithCJ, et al. (2010) SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker. Nat Neurosci 13 : 69–75.

25. KohK, JoinerWJ, WuMN, YueZ, SmithCJ, et al. (2008) Identification of SLEEPLESS, a sleep-promoting factor. Science 321 : 372–376.

26. GompfH, ChenJ, SunY, YanagisawaM, Aston-JonesG, et al. (2009) Halothane-induced hypnosis is not accompanied by inactivation of orexinergic output in rodents. Anesthesiology 111 : 1001–1009.

27. EckenhoffMF, EckenhoffRG (1998) Quantitative autoradiography of halothane binding in rat brain. J Pharmacol Exp Ther 285 : 371–376.

28. CirelliC, BusheyD, HillS, HuberR, KreberR, et al. (2005) Reduced sleep in Drosophila Shaker mutants. Nature 434 : 1087–1092.

29. BorbélyAA (1982) A two process model of sleep regulation. Hum Neurobiol 1 : 195–204.

30. HendricksJC, LuS, KumeK, YinJCP, YangZ, et al. (2003) Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. Journal of Biological Rhythms 18 : 12–25.

31. ShawPJ, TononiG, GreenspanRJ, RobinsonDF (2002) Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417 : 287–291.

32. KumeK, KumeS, ParkSK, HirshJ, JacksonFR (2005) Dopamine is a regulator of arousal in the fruit fly. Journal of Neuroscience 25 : 7377–7384.

33. HuberR, HillSL, HolladayC, BiesiadeckiM, TononiG, et al. (2004) Sleep homeostasis in Drosophila melanogaster. Sleep 27 : 628–639.

34. Steyn-RossML, Steyn-RossDA, SleighJW (2004) Modelling general anaesthesia as a first-order phase transition in the cortex. Prog Biophys Mol Biol 85 : 369–385.

35. MitrophanovAY, GroismanEA (2008) Positive feedback in cellular control systems. Bioessays 30 : 542–555.

36. NinfaAJ, MayoAE (2004) Hysteresis vs. graded responses: the connections make all the difference. Sci STKE 2004: pe20.

37. LasloP, SpoonerCJ, WarmflashA, LanckiDW, LeeH-J, et al. (2006) Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126 : 755–766.

38. FuentealbaP, TimofeevI, BazhenovM, SejnowskiTJ, SteriadeM (2005) Membrane bistability in thalamic reticular neurons during spindle oscillations. Journal of Neurophysiology 93 : 294–304.

39. McCormickDA, BalT (1997) Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci 20 : 185–215.

40. KottlerB, BaoH, ZaluckiO, ImlachW, TroupM, et al. (2013) A Sleep/Wake Circuit Controls Isoflurane Sensitivity in Drosophila. Curr Biol 23 : 594–598.

41. JoinerWJ, CrockerA, WhiteBH, SehgalA (2006) Sleep in Drosophila is regulated by adult mushroom bodies. Nature 441 : 757–760.

42. HeurteauxC, GuyN, LaigleC, BlondeauN, DupratF, et al. (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23 : 2684–2695.

43. SingaramVK, SomerlotBH, FalkSA, FalkMJ, SedenskyMM, et al. (2011) Optical reversal of halothane-induced immobility in C. elegans. Curr Biol 21 : 2070–2076.

44. ShawPJ, CirelliC, GreenspanRJ, TononiG (2000) Correlates of sleep and waking in Drosophila melanogaster. Science 287 : 1834–1837.