Mesopontine Switch for the Induction of General Anesthesia by Dedicated Neural Pathways

Sukhotinsky, Inna; Minert, Anne; Soja, Peter J.; Devor, Marshall

doi:10.1213/ane.0000000000001489

Cited by 19 publications

(12 citation statements)

References 78 publications

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“…by tail pinch) is a prime example. Reanimation can also be evoked by activation of central pain pathways (Schiff et al, 2007;Brischoux et al, 2009;Anaclet et al, 2014;Roeder et al, 2016;Taylor et al, 2016;Morales and Margolis, 2017). It is not clear whether arousal by pain-provoking stimuli is mechanistically linked to mesopontine sleep-wake and anesthesia circuitry or is more general in nature.…”

Section: Indwelling Cannula Versus Bonus Time Methodsmentioning

confidence: 99%

“…In addition to their size, the larger cells tended to be flatter (smaller aspect ratio and form factor) and had a more tortuous circumference (lower roundness) than the smaller cells. A considerable amount is known about the afferent and efferent connectivity of neurons in the MPTA area and on other cellular characteristics (Sukhotinsky et al, 2016), but further analysis is needed with respect to the MPTA's common core.…”

Section: Critical Mass Of Neurons and Neuronal Characteristicsmentioning

confidence: 99%

“…A subset of neurons in the MPTA are known to express GABA A -R subunits. These are presumably the neurons that are sensitive to GABAergic anesthetics (Sukhotinsky et al, 2003(Sukhotinsky et al, , 2007(Sukhotinsky et al, , 2016.…”

Section: Nuclear Designationmentioning

confidence: 99%

“…A significant advance toward defining the locus of anesthetic action was the discovery that an anesthesia-like state is induced rapidly and reversibly by microinjecting GABA A -R agonists into a circumscribed, bilaterally symmetrical region in the upper brainstem, the mesopontine tegmental anesthesia area (MPTA) (Devor and Zalkind, 2001;Voss et al, 2005; see video at http:// links.lww.com/AA/B466). This state closely resembles systemic anesthesia by behavioral, electrographic, and functional criteria and can be sustained by repeated microinjections Abulafia et al, 2009;Namjoshi et al, 2009;Devor et al, 2016;Sukhotinsky et al, 2016). Anesthesia comes on much too rapidly to permit drug diffusion to distant brain regions (seconds to a few minutes) and effective doses are far too small to survive dilution during vascular redistribution.…”

Section: Introductionmentioning

confidence: 99%

“…No comparable anesthetic-sensitive structure has been found despite systematic searching and, if another exists, engaging it is apparently insufficient because anesthesia cannot be induced in MPTAlesioned animals at clinically relevant doses. The intrinsic properties of MPTA neurons and their connectivity makes them both sufficient and necessary for GABAergic anesthetic induction (Sukhotinsky et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness

2017

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The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss of consciousness) and to the spinal cord (for atonia and antinociception). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. Previously, we documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABA-receptor agonists into an upper brainstem region named the mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesioning this area rendered animals resistant to systemically delivered anesthetics. Here, using rats of both sexes, we applied a modified microinjection method that permitted localization of the anesthetic-sensitive neurons with much improved spatial resolution. Microinjected at the MPTA hotspot identified, exposure of 1900 or fewer neurons to muscimol was sufficient to sustain whole-body general anesthesia; microinjection as little as 0.5 mm off-target did not. The GABAergic anesthetics pentobarbital and propofol were also effective. The GABA-sensitive cell cluster is centered on a tegmental (reticular) field traversed by fibers of the superior cerebellar peduncle. It has no specific nuclear designation and has not previously been implicated in brain-state transitions. General anesthesia permits pain-free surgery. Furthermore, because anesthetic agents have the unique ability to reversibly switch the brain from wakefulness to a state of unconsciousness, knowing how and where they work is a potential route to unraveling the neural mechanisms that underlie awareness itself. Using a novel method, we have located a small, and apparently one of a kind, cluster of neurons in the mesopontine tegmentum that are capable of effecting brain-state switching when exposed to GABA-receptor agonists. This action appears to be mediated by a network of dedicated axonal pathways that project directly and/or indirectly to nearby arousal nuclei of the brainstem and to more distant targets in the forebrain and spinal cord.

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Section: Indwelling Cannula Versus Bonus Time Methodsmentioning

confidence: 99%

Section: Critical Mass Of Neurons and Neuronal Characteristicsmentioning

confidence: 99%

Section: Nuclear Designationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness

2017

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No cognitive processing in the unconscious, anesthetic‐like, state of sleep

Vertes

Linley

2020

J of Comparative Neurology

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We review evidence challenging the hypothesis that memories are processed or consolidated in sleep. We argue that the brain is in an unconscious state in sleep, akin to general anesthesia (GA), and hence is incapable of meaningful cognitive processingthe sole purview of waking consciousness. At minimum, the encoding of memories in sleep would require that waking events are faithfully transferred to and reproduced in sleep. Remarkably, however, this has never been demonstrated, as waking experiences are never truly replicated in sleep but rather appear in very altered or distorted forms. General anesthetics (GAs) exert their effects through endogenous sleep-wake control systems and accordingly GA and sleep share several common features: sensory blockade, immobility, amnesia and lack of awareness (unconsciousness). The loss of consciousness in non-REM (NREM) sleep or to GAs is characterized by: (a) delta oscillations throughout the cortex; (b) marked reductions in neural activity (from waking) over widespread regions of the cortex, most pronounced in frontal and parietal cortices; and (c) a significant disruption of the functional connectivity of thalamocortical and corticocortical networks, particularly those involved in "higher order" cognitive functions. Several (experimental) reports in animals and humans have shown that disrupting the activity of the cortex, particularly the orbitofrontal cortex, severely impairs higher order cognitive and executive functions. The profound and widespread deactivation of the cortex in the unconscious states of NREM sleep or GA would be expected to produce an equivalent, or undoubtedly a much greater, disruptive effect on mnemonic and cognitive functions. In conclusion, we contend that the unconscious, severely altered state of the brain in NREM sleep would negate any possibility of cognitive processing in NREM sleep.

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Anesthesia in mice activates discrete populations of neurons throughout the brain

Yatziv

Yudco

Vaso

et al. 2021

J of Neuroscience Research

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The brain undergoes rapid, dramatic, and reversible transitioning between states of wakefulness and unconsciousness during natural sleep and in pathological conditions such as hypoxia, hypotension, and concussion. Transitioning can also be induced pharmacologically using general anesthetic agents. The effect is selective. Mobility, sensory perception, memory formation, and awareness are lost while numerous housekeeping functions persist. How is selective transitioning accomplished? Classically a handful of brainstem and diencephalic "arousal nuclei" have been implicated in driving brain-state transitions on the grounds that their net activity systematically varies with brain state. Here we used transgenic targeted recombination in active populations mice to label neurons active during wakefulness with one reporter and neurons active during pentobarbital-induced general anesthesia with a second, contrasting reporter. We found 'wake-on' and 'anesthesia-on' neurons in widely distributed regions-of-interest, but rarely encountered neurons labeled with both reporters. Nearly all labeled neurons were either wake-on or anesthesia-on. Thus, anesthesia-on neurons are not unique to the few nuclei discovered to date whose activity appears to increase during anesthesia. Rather neuronal populations selectively active during anesthesia are located throughout the brain where they likely play a causative role in transitioning between wakefulness and anesthesia. The widespread neuronal suppression reported in prior comparisons of the awake and anesthetized brain in animal models and noninvasive imaging in humans reflects only net differences. It misses the ubiquitous presence of neurons whose activity increases during anesthesia. The balance in recruitment of anesthesia-on versus wake-on neuronal populations throughout the brain may be a key driver of regional and global vigilance states.

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Mesopontine Switch for the Induction of General Anesthesia by Dedicated Neural Pathways

Cited by 19 publications

References 78 publications

Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness

Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness

No cognitive processing in the unconscious, anesthetic‐like, state of sleep

Anesthesia in mice activates discrete populations of neurons throughout the brain

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