Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia

Lanir-Azaria, Sa’ar; Meiri, Guy; Avigdor, Tamir; Minert, Anne; Devor, Marshall

doi:10.1016/j.bbr.2017.12.035

Cited by 15 publications

(12 citation statements)

References 60 publications

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“…Conversely, infusion of the GABA uptake inhibitor nipecotic acid (that effectively increases GABA levels) in the pontine reticular formation promote wakefulness and retards induction of propofol or isoflurane anesthesia [60]. However, the most direct evidence for subcortical sites mediating anesthetic-induced loss of consciousness comes from the observation that localized injections of GABAergic anesthetics into the mesopontine tegmentum can induce a complete state of anesthesia [61], while lesions to this region produce insomnia [62].…”

Section: Activation Of Endogenous Sleep Circuitsmentioning

confidence: 99%

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Hemmings

Riegelhaupt

Kelz

et al. 2019

Trends in Pharmacological Sciences

185

183

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Significant progress has been made in the 21 st century towards a comprehensive understanding of the mechanisms of action of general anesthetics, coincident with progress in structural biology and molecular, cellular, and systems neuroscience. This review summarizes important new findings that include target identification through structural determination of anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical roles of neuronal networks in anesthetic effects on memory and consciousness. These recent developments provide a comprehensive basis for conceptualizing pharmacologic control of amnesia, unconsciousness, and immobility.

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Section: Activation Of Endogenous Sleep Circuitsmentioning

confidence: 99%

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Hemmings

Riegelhaupt

Kelz

et al. 2019

Trends in Pharmacological Sciences

185

183

View full text Add to dashboard Cite

show abstract

“…It seems likely that anesthesia transiently silenced a group of neurons necessary for wakefulness, and that these are the same neurons that, when silenced, produce the behavioral effects described by Bremer and others. Interestingly, however, while other GABAergic agents produce loss of arousal, neither silencing this region with lidocaine or tetrodotoxin ( Devor et al, 2016 ; Minert et al, 2017 ; Avigdor et al, 2021 ), nor ablating it caused loss of arousal ( Minert and Devor, 2016 ; Lanir-Azaria et al, 2018 ). No specific cell populations have been identified as mediating the effect of pentobarbital in this region ( Minert et al, 2017 ).…”

Section: Animal Experimentsmentioning

confidence: 99%

A Century Searching for the Neurons Necessary for Wakefulness

2022

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Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse “reticular activating system,” the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.

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“…These inhibitory effects of classical GABAergic anesthetics may be due to the direct activation of postsynaptic GABA A receptors. Indeed, localized injections of pentobarbital into the MPTA can induce a complete state of anesthesia, which appears to be mediated by a circuit of dedicated axonal projections to the nearby arousal nuclei of the brainstem and distant targets in the forebrain and spinal cord [ 81 , 84 , 85 ]; meanwhile, lesions in this region lead to insomnia [ 86 ]. These results provide direct evidence for the role of subcortical regions in mediating GABAergic anesthetic-induced unconsciousness, and MPTA may serve as the on-off switch of GABAergic anesthetic-induced anesthesia.…”

Section: Induction Of Unconsciousness By General Anestheticsmentioning

confidence: 99%

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System

Zhang

Liu

Zhu

et al. 2022

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: Although general anesthetics have been used in the clinic for more than 170 years, the ways in which they induce amnesia, unconsciousness, analgesia, and immobility remain elusive. Modulations of various neural nuclei and circuits are involved in the actions of general anesthetics. The expression of the immediate early gene c-fos and its nuclear product, c-fos protein can be induced by neuronal depolarization; therefore, c-fos staining is commonly used to identify the activated neurons during sleep and/or wakefulness, as well as in various physiological conditions in the central nervous system. Identifying c-fos expression is also a direct and convenient method to explore the effects of general anesthetics on the activity of neural nuclei and circuits. Using c-fos staining, general anesthetics have been found to interact with sleep- and wakefulness-promoting systems throughout the brain, which may explain their ability to induce unconsciousness and emergence from general anesthesia. This review summarizes the actions of general anesthetics on neural nuclei and circuits based on c-fos expression.

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Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia

Cited by 15 publications

References 60 publications

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

A Century Searching for the Neurons Necessary for Wakefulness

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System

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