Individual Mesopontine Neurons Implicated in Anesthetic Loss-of-consciousness Employ Separate Ascending Pathways to the Cerebral Cortex

Lellouche, Yair; Minert, Anne; Schreiber, Caterin; Aroch, Ilil; Vaso, Kristina; Fishman, Yelena; Devor, Marshall

doi:10.1016/j.neuroscience.2020.02.022

Cited by 4 publications

(4 citation statements)

References 53 publications

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“…A considerable fraction of MPTA projection neurons that innervate the RVM also send collaterals to the spinal cord. Moreover, a majority that projects to one segment of the spinal cord also sends collaterals to other segments ( Figure 4 ; Sukhotinsky et al, 2006 ; Reiner et al, 2007 ; Goldenberg et al, 2018 ; Lellouche et al, 2020 ; Baron et al, 2022 ).…”

Section: The Mesopontine Tegmental Anesthesia Area (Mpta)mentioning

confidence: 99%

“…MPTA neurons with descending projections to the hindbrain and spinal cord show a considerably greater degree of collateralization to multiple targets. Modified from Lellouche et al (2020) .…”

Section: The Mesopontine Tegmental Anesthesia Area (Mpta)mentioning

confidence: 99%

“…Irrespective of the evolutionary reasons for the four-way association of LOC, or the occasional dissociation of pain, movement, memory and consciousness, the hardware required is in place. The MPTA features ascending and descending projections where single neurons project to unique functional relays ( Figure 4 ; Reiner et al, 2007 ; Lellouche et al, 2020 ).…”

Section: Summary and Perspectivementioning

confidence: 99%

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From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery

Baron¹,

Devor²

2023

Front. Mol. Neurosci.

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The canonical view of how general anesthetics induce loss-of-consciousness (LOC) permitting pain-free surgery posits that anesthetic molecules, distributed throughout the CNS, suppress neural activity globally to levels at which the cerebral cortex can no longer sustain conscious experience. We support an alternative view that LOC, in the context of GABAergic anesthesia at least, results from anesthetic exposure of a small number of neurons in a focal brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA). The various sub-components of anesthesia, in turn, are effected in distant locations, driven by dedicated axonal pathways. This proposal is based on the observations that microinjection of infinitesimal amounts of GABAergic agents into the MPTA, and only there, rapidly induces LOC, and that lesioning the MPTA renders animals relatively insensitive to these agents delivered systemically. Recently, using chemogenetics, we identified a subpopulation of MPTA “effector-neurons” which, when excited (not inhibited), induce anesthesia. These neurons contribute to well-defined ascending and descending axonal pathways each of which accesses a target region associated with a key anesthetic endpoint: atonia, anti-nociception, amnesia and LOC (by electroencephalographic criteria). Interestingly, the effector-neurons do not themselves express GABAA-receptors. Rather, the target receptors reside on a separate sub-population of presumed inhibitory interneurons. These are thought to excite the effectors by disinhibition, thus triggering anesthetic LOC.

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Section: The Mesopontine Tegmental Anesthesia Area (Mpta)mentioning

confidence: 99%

Section: The Mesopontine Tegmental Anesthesia Area (Mpta)mentioning

confidence: 99%

Section: Summary and Perspectivementioning

confidence: 99%

See 1 more Smart Citation

From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery

Baron¹,

Devor²

2023

Front. Mol. Neurosci.

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“…Some of this drive could be direct, via axons that descend to the spinal cord or ascend to the prefrontal cortex (Sukhotinsky et al, 2005(Sukhotinsky et al, , 2006(Sukhotinsky et al, , 2007. The bulk of the drive, however, is likely mediated by relay nuclei in the brainstem and diencephalon which receive afferent input from the MPTA (Goldenberg et al, 2018;Lellouche et al, 2020). Within the widely scattered target structures modulation could be effected directly by axon terminals of neurons resident in the MPTA or its relay nuclei.…”

Section: Neun-ir Densitymentioning

confidence: 99%

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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Paradoxical anesthesia: Sleep-like EEG during anesthesia induced by mesopontine microinjection of GABAergic agents

Avigdor

Minert

Baron

et al. 2021

Experimental Neurology

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Individual Mesopontine Neurons Implicated in Anesthetic Loss-of-consciousness Employ Separate Ascending Pathways to the Cerebral Cortex

Cited by 4 publications

References 53 publications

From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery

From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery

Anesthesia in mice activates discrete populations of neurons throughout the brain

Paradoxical anesthesia: Sleep-like EEG during anesthesia induced by mesopontine microinjection of GABAergic agents

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