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

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Distinctive Recruitment of Endogenous Sleep-Promoting Neurons by Volatile Anesthetics and a Nonimmobilizer Distinctive Recruitment of Endogenous Sleep-promoting Neurons by Volatile Anesthetics and a Nonimmobilizer Bo Han, M.D., Ph.D., Hilary S. McCarren, Ph.D., Dan O’Neill, M.D., Max B. Kelz, M.D., Ph.D. Background: Numerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypo- thalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of γ-aminobutyric acid (GABA)ergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic nuclei remains unknown. Methods: Mice were exposed to oxygen, hypnotic doses of isoflurane or halothane, or 1,2-dichlorohexafluorocyclobutane Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/121/5/999/484850/20141100_0-00020.pdf by guest on 01 October 2021 (F6), a nonimmobilizer. Hypothalamic brain slices prepared from anesthetic-naive mice were also exposed to oxygen, vola- tile anesthetics, or F6 ex vivo, both in the presence and absence of tetrodotoxin. Double-label immunohistochemistry was performed to quantify the number of c-Fos–immunoreactive nuclei in the GABAergic subpopulation of neurons in the VLPO and the median preoptic areas to test the hypothesis that volatile anesthetics, but not nonimmobilizers, activate sleep- promoting neurons in both nuclei. Results: In vivo exposure to isoflurane and halothane doubled the fraction of active, c-Fos-expressing GABAergic neurons in the VLPO, whereas F6 failed to affect VLPO c-Fos expression. Both in the presence and absence of tetrodotoxin, isoflurane dose-dependently increased c-Fos expression in GABAergic neurons ex vivo, whereas F6 failed to alter expression. In GABAergic neurons of the median preoptic area, c-Fos expression increased with isoflurane and F6, but not with halothane exposure. Conclusions: Anesthetic unconsciousness is not accompanied by global activation of all putative sleep-promoting neurons. However, within the VLPO hypnotic doses of volatile anesthetics, but not nonimmobilizers, activate putative sleep-promoting neurons, correlating with the appearance of the hypnotic state. (ANESTHESIOLOGY 2014; 121:999-1009) HE preoptic area is home to heterogenous cell popu- What We Already Know about This Topic Tlations that regulate a variety of homeostatic func- tions. Since von Economo first demonstrated that lesions • Anesthetic-induced unconsciousness is accompanied by ac- 1 tivation of neurons in hypothalamic sleep-promoting regions. to this area produce insomnia, the preoptic area’s specific • The extent to which the same neurons are involved in both role in arousal state regulation has been repeatedly dem- sleep and anesthesia is not clear. onstrated. Localized clusters of neurons within the ventro- • Neuronal activation was evaluated after anesthetic exposure lateral preoptic (VLPO) nucleus and the median preoptic both in live mice and in ex vivo brain tissue for two nuclei inti- mately involved in sleep regulation: the ventrolateral preoptic (MnPO) nucleus increase their expression of the immediate and the median preoptic areas. early gene, c-fos, during sleep.2,3 The suggestion that these c-Fos–expressing VLPO and MnPO neurons increase their What This Article Tells Us That Is New neuronal activity during sleep has been validated using in • Within the ventrolateral preoptic area, volatile anesthetics 4,5 increased activation of γ-aminobutyric acidergic neurons. In vivo electrophysiologic unit recordings. Moreover, these the median preoptic area, neuronal activation was indepen- sleep-active neurons in the VLPO and the MnPO are dent of hypnosis. γ-aminobutyric acid (GABA)ergic and exchange mutual • Anesthetics do not activate all neurons that regulate sleep, nor inhibitory projections with a number of wake-active neu- do they universally recruit all sleep-promoting neural nuclei. ronal nuclei to regulate sleep and arousal.6–8 Finally, lesion or pharmacological modulation of VLPO or MnPO activity alters induction and maintenance of sleep, confirming their hypnosis.16,17 The active roles of the VLPO and the MnPO sleep-promoting function.9–15 in the genesis of sleep coupled with their inhibitory con- Many changes in brain activity observed during sleep nectivity to arousal-promoting structures have singled these are similar to those observed during anesthetic-induced nuclei out as potential neuronal targets of general anesthetics. The first two authors contributed equally to this work. Submitted for publication December 4, 2013. Accepted for publication June 30, 2014. From the Department of Anesthesiology and Critical Care (B.H.), Department of Pharmacology (H.S.M.), University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Anesthesiology, Weill Cornell Medical College, New York, New York (D.O.); and Department of Anesthesiology and Critical Care, Center for Sleep and Circadian Neurobiology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perel- man School of Medicine, Philadelphia, Pennsylvania (M.B.K.). Copyright © 2014, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2014; 121:999-1009 Anesthesiology, V 121 • No 5 999 November 2014 Volatile Anesthetics and Sleep-promoting Neurons Indeed, exposure to suprahypnotic doses of a variety of gen- weeks before experiments were acclimatized to a reverse 12-h eral anesthetics including barbiturates, propofol, dexme- light–dark cycle with lights on at 7 PM (zeitgeber time 0). The detomidine, chloral hydrate, isoflurane, and halothane all reversed light cycle allowed experiments to be performed induces c-Fos expression in putative sleep-promoting VLPO during the animals’ active period, when confounding induc- neurons.18–22 Although activation of the VLPO could be tion of c-Fos due to physiological sleep would be minimized. indirect, arising via disinhibition, the volatile anesthetic isoflurane directly depolarizes the subset of VLPO neurons In Vivo Anesthetic Drug Exposure and Tissue Collection that are electrophysiologically indistinguishable from those Mice were exposed to isoflurane, halothane, F6, and 100% involved in the genesis and maintenance of natural sleep.22 oxygen in custom-made controlled environmental chambers Evidence regarding the MnPO’s role in anesthetic-induced while euthermia was maintained as described previously.34,35 hypnosis is less clear. To date, only a single study has eval- In brief, each mouse was placed in a cylindrical gas-tight Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/121/5/999/484850/20141100_0-00020.pdf by guest on 01 October 2021 uated the effects of anesthetics on the MnPO. It failed to chamber submerged in a 37°C water bath. Body tempera- find c-Fos induction in the MnPO of rats after exposure to tures were maintained at 37.1° ± 0.5°C throughout the expo- pentobarbital, chloral hydrate, or ethanol.19 However, it did sure. Inhaled exposure occurred for 2 h with 1.2% isoflurane not address the functional heterogeneity of neurons in the (administered via a Drager model 19.1 isoflurane vaporizer; MnPO, in which subsets of neurons also help to regulate Drager Medical Inc., Telford, PA), 1.0% halothane (admin- blood pressure, body temperature, and endocrine signaling, istered via a Drager model 19.1 halothane vaporizer), 3.2% and might therefore have missed a selective activation con- F6 (administered via a Drager model 19.1 enflurane vapor- fined to a subset of neurons that did not increase the overall izer as previously described),28 or no drug in 100% oxygen number of c-Fos–expressing neurons. at a flow rate of 200 ml/min per chamber. Anesthetic doses In the current study, we quantify VLPO and MnPO 35 correspond to the EC99 for loss of righting reflex in mice. activation, as measured by c-Fos expression, in response to F6 was administered at the highest dose that did not induce the volatile general anesthetics isoflurane and halothane. seizures. In vivo experiments were conducted between zeit- As the sleep-promoting subsets of hypothalamic neurons geber time 14 and zeitgeber time 17 (9 AM to 12 PM). After in the VLPO and MnPO are known to be GABAergic,23 exposure, mice were rapidly overdosed with isoflurane and we hypothesized that anesthetic-induced increases in c-Fos transcardially perfused with saline followed by 4% parafor- immunoreactivity would be significant in these glutamic maldehyde. Brains were removed and postfixed for 1 to 3 h acid decarboxylase (GAD)–immunoreactive populations. at 4°C. After cryoprotection in 30% sucrose for 2 days at Moreover, we further test the hypothesis that induction 4°C, tissue was flash-frozen in liquid nitrogen. Tissue was of c-Fos would only occur with drugs capable of eliciting then sectioned at 40 μm on a 2800 Frigocut N cryostat hypnosis. Nonimmobilizers are compounds predicted to (Reichert-Jung, Depew, NY) and stored free-floating in anti- be anesthetics based on their structure and lipid solubility, freeze solution (1.75 M sucrose, 8 M polyvinylpyrrolidone, but violate the Meyer–Overton hypothesis of anesthetic 15.4 mM sodium azide, and 10.7 M ethylene glycol in 0.1 M 24,25 action. These drugs are biologically active, elicit amne- sodium phosphate buffer pH 7.2) at −20°C until staining.36 sia, and can cause seizures, but critically, they fail to produce
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