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      A Conserved Behavioral State Barrier Impedes Transitions between Anesthetic-Induced Unconsciousness and Wakefulness: Evidence for Neural Inertia

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          Abstract

          One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.

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          Most cited references 61

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          Consciousness and anesthesia.

          When we are anesthetized, we expect consciousness to vanish. But does it always? Although anesthesia undoubtedly induces unresponsiveness and amnesia, the extent to which it causes unconsciousness is harder to establish. For instance, certain anesthetics act on areas of the brain's cortex near the midline and abolish behavioral responsiveness, but not necessarily consciousness. Unconsciousness is likely to ensue when a complex of brain regions in the posterior parietal area is inactivated. Consciousness vanishes when anesthetics produce functional disconnection in this posterior complex, interrupting cortical communication and causing a loss of integration; or when they lead to bistable, stereotypic responses, causing a loss of information capacity. Thus, anesthetics seem to cause unconsciousness when they block the brain's ability to integrate information.
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            General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.

            The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.
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              Molecular and neuronal substrates for general anaesthetics.

              Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABA(A)-receptor subtypes, can be revealed by genetic studies in vivo.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                30 July 2010
                : 5
                : 7
                Affiliations
                [1 ]Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                [3 ]Howard Hughes Medical Institute, Philadelphia, Pennsylvania, United States of America
                [4 ]Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                [5 ]Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [6 ]Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                [7 ]Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                Queensland Brain Institute, Australia
                Author notes

                Conceived and designed the experiments: EBF RGE MBK. Performed the experiments: EBF YS HTH QCM PP. Analyzed the data: EBF YS JTM QCM PP WJJ MBK. Contributed reagents/materials/analysis tools: EBF JTM WJJ SAT AS MBK. Wrote the paper: EBF MBK. Edited manuscript: SAT RGE AS.

                [¤]

                Current address: Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America

                Article
                10-PONE-RA-16796R2
                10.1371/journal.pone.0011903
                2912772
                20689589
                56547ad4-dc22-4e17-ac9c-43629b39ecd8
                Friedman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 9
                Categories
                Research Article
                Pharmacology
                Neuroscience/Cognitive Neuroscience
                Neuroscience/Theoretical Neuroscience
                Anesthesiology and Pain Management/Anesthetic Mechanisms

                Uncategorized

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