In the past two decades, genetic studies have revealed mechanisms that regulate circadian and sleep neurophysiology. They promise to unveil mechanisms of anesthetic-induced unconsciousness as well. Sensitivity to anesthetics varies across a population with some individuals requiring a higher dose to achieve a given depth of anesthesia. Anesthetic resistance may present in humans as awareness under anesthesia. One form of hypersensitivity may present as delayed emergence from anesthesia and js seen in a subset of narcoleptic patients with impaired orexin signaling. The central hypothesis of this grant is that inhaled anesthetics exert specific effects upon the endogenous neural circuitry regulating sleep and wakefulness. During induction and maintenance of anesthesia, we hypothesize that inhaled anesthetics produce their hypnotic effects through activation of the ventral lateral preoptic area (VLPO), the central sleep-active region of the brain. Emergence from anesthesia should depend upon re-activation of orexinergic (Ox) neurons, a wake-promoting and sustaining region of the brain.
In aim 1 of this grant, we will map neural activation through c-Fos protein immunohistochemistry?the same methodology used initially to find arousal state- dependent nuclei. We hypothesize that c-fos mRNA and protein levels will be induced in VLPO and repressed in Ox neurons during inhaled anesthesia;and that these changes must reverse during normal emergence from anesthesia.
In aim 2, we will evaluate the contribution of Ox neurons to induction and emergence from inhaled anesthesia using behavioral (loss of righting reflex) as well as electroencephalographic (EEC) assays. We hypothesize that mice with genetically and pharmacologically impaired orexin signaling will show delayed emergence from anesthesia. Finally, in aim 3, we will demonstrate that administration of orexin agonists speeds emergence from anesthesia. We hypothesize that orexin agonists should also produce c-fos neuronal activation patterns that attenuate (or reverse) both inhaled anesthetic-induced activation of VLPO and inhibition of Ox neurons. As an anesthesiologist formally trained in neuroscience and mouse genetics, Dr. Kelz is firmly committed to a career in academic anesthesia. His ultimate career goal is to improve perioperative patient care through a better understanding of the mechanisms by which anesthetics suppress consciousness. This proposal will enhance his training toward that end by providing formal education in sleep neurobiology (including EEG and EMG acquisition and analysis), stereotactic surgerical techniques necessary for pharmacologic studies, and advanced molecular biology. His co-mentors have established records of nuturing junior faculty. Together with his current skill set, these new tools will help transition him towards becoming an independent physician-scientist by bridging the interface between sleep neurobiology and anesthetic action.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM077357-05
Application #
7799778
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$127,872
Indirect Cost
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Deutschman, Clifford S; Raj, Nichelle R; McGuire, Erin O et al. (2013) Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit Care Med 41:e368-75
Li, Rosie Q; McKinstry, Andrew R; Moore, Jason T et al. (2012) Is hydrogen sulfide-induced suspended animation general anesthesia? J Pharmacol Exp Ther 341:735-42
Hu, Frances Y; Hanna, George M; Han, Wei et al. (2012) Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine *-hydroxylase knockout mice. Anesthesiology 117:1006-17
Moore, Jason T; Chen, Jingqiu; Han, Bo et al. (2012) Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. Curr Biol 22:2008-16
Pick, Jeremy; Chen, Yihan; Moore, Jason T et al. (2011) Rapid eye movement sleep debt accrues in mice exposed to volatile anesthetics. Anesthesiology 115:702-12
Daley, Joseph T; Kelz, Max B (2010) Time in general anesthesia: depriving the homeostat? Sleep 33:1583-4
Friedman, Eliot B; Sun, Yi; Moore, Jason T et al. (2010) A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia. PLoS One 5:e11903
Bianchi, Shannon L; Caltagarone, Breanna M; Laferla, Frank M et al. (2010) Inhaled anesthetic potency in aged Alzheimer mice. Anesth Analg 110:427-30
Gompf, Heinrich; Chen, Jingqiu; Sun, Yi et al. (2009) Halothane-induced hypnosis is not accompanied by inactivation of orexinergic output in rodents. Anesthesiology 111:1001-9
Kelz, Max B; Friedman, Eliot (2009) Anesthetic sensitivity: learning to fly. Anesthesiology 111:5-7

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