Location of the mesopontine neurons responsible for maintenance of anesthetic loss of consciousness

“Most notably, they support the dedicated pathways hypothesis of general anesthesia by suggesting that systemic drug administration induces immobility, analgesia, amnesia, and LOC by a primary action in the brainstem, followed by recruitment of dedicated ascending and descending axonal pathways that secondarily modulat…”

“Network actions Observations, mostly based on noninvasive imaging in humans, have highlighted large-scale network connectivity and top-down processing as central factors in conscious awareness, with thalamocortical interactions taking center stage (Brown et al., 2010; Bonhomme et al., 2012; Vijayan et al., 2013; Hudet…”

“Network actions Observations, mostly based on noninvasive imaging in humans, have highlighted large-scale network connectivity and top-down processing as central factors in conscious awareness, with thalamocortical interactions taking center stage (Brown et al., 2010; Bonhomme et al., 2012; Vijayan et al., 2013; Hudet…”

“…locus coeruleus, tuberomammillary nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et…”

“Proposals about where exactly this might occur include the locus coeruleus, tuberomammillary nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz,…”

“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).”

“Previously, we documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABAA-receptor agonists into an upper brainstem region named the mesopontine tegmental anesthesia area (MPTA).”

“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).”

“These nuclei are implicated in sleep and arousal (Fuller et al., 2011; Watson et al., 2011; Roeder et al., 2016), but all were ruled out as the location of the anesthesia-promoting MPTA neurons.”

“…where exactly this might occur include the locus coeruleus, tuberomammillary nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf…”

“Most notably, they support the dedicated pathways hypothesis of general anesthesia by suggesting that systemic drug administration induces immobility, analgesia, amnesia, and LOC by a primary action in the brainstem, followed by recruitment of dedicated ascending and descending axonal pathways that secondarily modulat…”

“This difference is potentially significant because emergence from anesthesia might be an active process, not simple reversal of induction as the anesthetic agent dissipates (Sleigh et al., 2001; Kelz et al., 2008).”

“Extrapolating based on dye spread radius (Myers, 1966; Myers and Hoch, 1978) in each case, the muscimol would likely have reached the common core.”

“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).”

“…nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et al., 2014; Weber et al., 2015).”

“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).”

“Proposals about where exactly this might occur include the locus coeruleus, tuberomammillary nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz,…”

“Network actions Observations, mostly based on noninvasive imaging in humans, have highlighted large-scale network connectivity and top-down processing as central factors in conscious awareness, with thalamocortical interactions taking center stage (Brown et al., 2010; Bonhomme et al., 2012; Vijayan et al., 2013; Hudet…”

“…nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et al., 2014; Weber et al., 2015).”

“Thus, circulating anesthetic molecules suppress the neocortex and hippocampus to bring about LOC and amnesia and the brainstem and spinal cord to cause atonia and analgesia (Lukatch and MacIver, 1996; Antognini et al., 2003; Grasshoff et al., 2005; Hentschke et al., 2005; Bonhomme et al., 2012; Raz et al., 2014).”

“…nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et al., 2014; Weber et al., 2015).”

“Network actions Observations, mostly based on noninvasive imaging in humans, have highlighted large-scale network connectivity and top-down processing as central factors in conscious awareness, with thalamocortical interactions taking center stage (Brown et al., 2010; Bonhomme et al., 2012; Vijayan et al., 2013; Hudet…”

“Most notably, they support the dedicated pathways hypothesis of general anesthesia by suggesting that systemic drug administration induces immobility, analgesia, amnesia, and LOC by a primary action in the brainstem, followed by recruitment of dedicated ascending and descending axonal pathways that secondarily modulat…”

“Clinical studies report significantly longer emergence times from propofol-induced anesthesia in men than in women when measurements begin at an equivalent anesthetic depth based on bispectral index values (Hoymork and Raeder, 2005; Choong et al., 2013).”

“However, because muscimol is a direct GABAA-R agonist, in contrast to pentobarbital, which acts at an allosteric modulatory site on the receptor (Löscher and Rogawski, 2012), and because it has a much higher affinity for the GABAA-R than pentobarbital (KD 2–10 nM), muscimol was used here as a tool to refine the functi…”

“…nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et al., 2014; Weber et al., 2015).”

“This difference is potentially significant because emergence from anesthesia might be an active process, not simple reversal of induction as the anesthetic agent dissipates (Sleigh et al., 2001; Kelz et al., 2008).”

“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).”

“Thus, circulating anesthetic molecules suppress the neocortex and hippocampus to bring about LOC and amnesia and the brainstem and spinal cord to cause atonia and analgesia (Lukatch and MacIver, 1996; Antognini et al., 2003; Grasshoff et al., 2005; Hentschke et al., 2005; Bonhomme et al., 2012; Raz et al., 2014).”

“The mMPTA approximately overlaps the rodent homolog of the “mesencephalic locomotor region” (Sherman et al., 2015), an area in which Shik et al.”

“These are presumably the neurons that are sensitive to GABAergic anesthetics (Sukhotinsky et al., 2003, 2007, 2016).”

“For example, it has been reported that muscimol delivered to the PnO promotes arousal (Xi et al., 2001; Watson et al., 2011).”

“Extrapolating based on dye spread radius (Myers, 1966; Myers and Hoch, 1978) in each case, the muscimol would likely have reached the common core.”

“Network actions Observations, mostly based on noninvasive imaging in humans, have highlighted large-scale network connectivity and top-down processing as central factors in conscious awareness, with thalamocortical interactions taking center stage (Brown et al., 2010; Bonhomme et al., 2012; Vijayan et al., 2013; Hudet…”

“Clinical studies report significantly longer emergence times from propofol-induced anesthesia in men than in women when measurements begin at an equivalent anesthetic depth based on bispectral index values (Hoymork and Raeder, 2005; Choong et al., 2013).”

“This state closely resembles systemic anesthesia by behavioral, electrographic, and functional criteria and can be sustained by repeated microinjections (Sukhotinsky et al., 2007; Abulafia et al., 2009; Namjoshi et al., 2009; Devor et al., 2016; Sukhotinsky et al., 2016).”

“It is probably also not sufficient because, after MPTA lesions with the thalamus and cortex intact, clinically relevant drug doses no longer induce anesthesia (Minert and Devor, 2016).”

“…nucleus, medial thalamus, lateral hypothalamus, and preoptic area (Correa-Sales et al., 1992; Alkire et al., 2008; Franks, 2008; Lu et al., 2008; Brown et al., 2010; Moore et al., 2012; Zecharia et al., 2012; Scharf and Kelz, 2013; Anaclet et al., 2014; Baker et al., 2014; Weber et al., 2015).”

“…state is induced rapidly and reversibly by microinjecting GABAA-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 (Sukhotinsky et al., 2007; Abulafia et al., 2009; Namjoshi et al., 2009; Devor et al., 2016; Sukhotinsky et al., 2016).”

“This is also the region where direct application of teflurane or cyclopropane were shown to induce sedation and sleep (in cats; Folkman et al., 1968).”

“These are presumably the neurons that are sensitive to GABAergic anesthetics (Sukhotinsky et al., 2003, 2007, 2016).”

“Most notably, they support the dedicated pathways hypothesis of general anesthesia by suggesting that systemic drug administration induces immobility, analgesia, amnesia, and LOC by a primary action in the brainstem, followed by recruitment of dedicated ascending and descending axonal pathways that secondarily modulat…”

“However, because muscimol is a direct GABAA-R agonist, in contrast to pentobarbital, which acts at an allosteric modulatory site on the receptor (Löscher and Rogawski, 2012), and because it has a much higher affinity for the GABAA-R than pentobarbital (KD 2–10 nM), muscimol was used here as a tool to refine the functi…”

“The improved localization will also facilitate determination of whether the flip-flop circuit associated with GABAergic anesthesia participates in other instances of transient LOC such as fainting due to hypotension (syncope), blood gas imbalance, fear, or natural sleep (Meiri et al., 2016).”

“Interestingly, projection neurons, MPTA neurons retrogradely labeled from a variety of projection targets (Reiner et al., 2008), are considerably larger than the average (188 vs 109 m 2).”

“However, in hM3Dq mice, the time was 139 ± 42 seconds after saline and 71 ± 55 seconds after CNO (group × treatment interaction, F[1, 16] = 29.”

“MPTA is sensitive to GABAergic anesthetics, including pentobarbital, propofol, and etomidate [81, 83, 84].”

“One study by Minert et al.(22) examined the role of an upper brainstem region, the mesopontine tegmental area, in anesthetic-induced unconsciousness.”

“Microinjection of GABA A -receptor agonists into an upper brainstem region, mesopontine tegmental anesthesia area (MPTA), induces rats to an anesthesia-like state [35] .”

“Correspondingly, MPTA lesions render animals resistant to anesthetic induction by direct exposure of the whole brain to clinically relevant concentrations of the anesthetic (Minert & Devor, 2016; Minert et al., 2017, 2020; Sukhotinsky et al., 2016).”

“The bottom line of the initial microinjection survey, and several follow-up studies, was the discovery of a single, small bilaterally symmetrical site located in the rat brainstem at which microinjection of minute quantities of a variety of GABAA-R agonists including PB and propofol rapidly evokes a state of surgical…”

“Specifically, microinjections of the GABAA agonist, muscimol, or the anesthetics, sodium pentobarbital or propofol, into the MPTA, but not into adjacent RF areas, rapidly induced an anesthetized state in rats (Devor et al., 2016; Minert et al., 2017).”

“In practice, the area of mesopontine tegmental anesthesia has a strong relation with individual sensitivity to anesthetics (Minert et al., 2017), but the role of adjacent areas remains unclear.”

“11,64 Briefly, the animal was initially anesthetized with a standard bolus dose of propofol.”

“The nuclei that primarily affect cerebral activity are located in the upper pons and in the midbrain, with some possible influence from lower brainstem structures, and rely on a network of nuclei families, rather than a single nucleus or family.(110,111)”

“For example, microinjection of anesthetics into a discrete portion of the upper brainstem can produce a state akin to general anesthesia [5], and isoflurane has been found to activate sleep-promoting neurons in the ventrolateral preoptic area [6].”

“From top to bottom (z-axis): 3 rats in which the retrograde tracer was AAVrg-mCherry (red) followed by 2 rats in which the tracer was FG (blue). to be pro-anesthetic (Minert et al., 2017).”

“That is, they form a rectangle bounding the region that, when exposed to small volume microinjections of the GABAergic agonist muscimol (10 or 20 nL), proved to be pro-anesthetic [28].”

“Injections elsewhere in the brain did not have this e ect [4].”

“The responsive cells were located within the reticular formation, in an area crossed by fibers of the superior cerebellar peduncle, and responded to propofol and pentobarbital [75].”