Anesthetic loss of consciousness induced by chemogenetic excitation of mesopontine effector neurons.

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

“…An interesting aspect of the EEG signature observed during microinjection-evoked anesthesia is that it features alternating epochs of NREM-like, delta-wave dominant EEG and REM-like (wake-like) EEG. This pattern, which we call “paradoxical anesthesia,” differs markedly from the uniform delta-wave dominant EEG pattern normally seen during systemic-induced GABAergic anesthesia ( Figure 2 ; Supplementary Video 1 ; Avigdor et al, 2021 ; Baron et al, 2022 ). This supports the notion that via axonal projections we are tapping into natural sleep-wake circuitry that is located nearby, within the reticular formation and at a distance.…”

“…It is premature, however, to rule out the possibility that some of this excitation reflects a direct drug action mediated by GABA A -R expressing neurons in the presence of a reversed Cl –1 gradient, rather than by network effects such as disinhibition ( Wagner et al, 1997 ; Ben-Ari, 2002 ; Price et al, 2005 ). Although MPTA effector-neurons lack the most common GABA A -R isoforms, we cannot rule out the possibility of less studied GABA A -R isoforms being expressed by these neurons ( Sinkkonen et al, 2000 ; Baron et al, 2022 ).…”

“…These observations formed the basis of a model of MPTA functioning that sees GABA and GABAergics as suppressing the activity of spontaneously active GABA-sensitive inhibitory interneurons. This suppression removes inhibition from putative “effector-neurons” in the MPTA whose ascending and descending axonal projections bring about the individual components of anesthesia ( Figure 3 ; Devor et al, 2016 ; Baron et al, 2022 ). The last step in the model has direct observational support.…”

“…Simultaneously, activation of descending bulbo-spinal inhibitory pathways, both descending inhibitory pathways to the spinal cord (SC), and pathways relayed through the rostro ventromedial medulla (RVM) induce atonia and analgesia. Modified from Baron et al (2022) . For interpretation of the references to color in the figure, the reader is referred to the web version of this article.…”

“…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 ).…”