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Involvement of endogenous sleep neural circuitry in volatile anesthetic induction and emergence
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Involvement of endogenous sleep neural circuitry in volatile anesthetic induction and emergence
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Involvement of endogenous sleep neural circuitry in volatile anesthetic induction and emergence
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Dissertation
Involvement of endogenous sleep neural circuitry in volatile anesthetic induction and emergence
2012
Overview
Ever since the first documented use of an anesthetic nearly 166 years ago, the mechanisms by which general anesthetics produce unconsciousness have remained elusive. Recently, the endogenous neural circuitry that underlies transitions between sleep and wakefulness has emerged as an intriguing possible mediator for the hypnotic properties of general anesthetics. Increasing amounts of evidence suggest that the \"flip-flop\" switch model for sleep—reciprocal inhibitory connections between wake-active centers such as the orexinergic neurons in the hypothalamus and sleep-active centers such as the ventrolateral preoptic nucleus (VLPO) ensure quick, stable transitions between wakefulness and sleep—could also contribute to anesthetic-induced hypnosis (Chapter 1). In Chapter 2 we demonstrate that the forward and reverse paths through which anesthetic-induced hypnosis arises and dissipates are not identical. The hysteresis that separates induction from emergence is not a pharmacokinetic side-effect, and can be manipulated with single gene mutations that are known to affect sleep and wakefulness. The processes of induction and emergence are further distinguished in Chapter 3, where we demonstrate that genetic ablation of the wake-active (and anesthetic-inhibited) orexinergic neurons in the hypothalamus delays emergence but does not affect induction. Finally, in Chapter 4, we show that the sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) play a role in induction: the sleep-active neurons—but not the neighboring state-indifferent neurons—are directly depolarized by isoflurane, and VLPO lesions produce an acute resistance to induction. Together, this work supports the emerging hypothesis that at least some general anesthetics promote unconsciousness by acting on sleep/wake circuits. We identify the orexinergic neurons of the hypothalamus as a critical component of emergence from anesthesia and the sleep-active neurons in the VLPO as a similarly key mediator of induction.
