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

Abstract

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.

Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

“…Subcortical action is further supported by microinjection experiments showing that highly localised drug application to some mesopontine/midbrain regions can, on their own and without direct cortical effects, cause an anesthesia-like state 18,35,36 , as well as studies showing that stimulation of dopaminergic VTA can hasten arousal from anesthesia in rodents 37 . Devor and colleagues have shown that anesthetic microinjection into a highly localised region of the upper brainstem called the mesopontine tegmental anesthetic area (MPTA) induces a reversible state of unconsciousness 38 , along with associated anesthesia-like changes in the electroencephalogram 35 . Investigation of fos expression suggests that general anesthesic cortical action may be attributable to effects at subcortical neuromodulatory sites 39 .…”

Reduced Repertoire of Cortical Microstates and Neuronal Ensembles in Medically Induced Loss of Consciousness

“…Despite its fundamental importance, the neural circuit and network mechanisms underlying LOC have remained unclear. Several brain areas have been implicated in causing the loss or recovery of consciousness, such as the hypothalamus (Herrera et al, 2016), thalamus (Castaigne et al, 1981), basal ganglia and claustrum (Crick and Koch, 2005;Mhuircheartaigh et al, 2010), or the brain stem (Minert et al, 2017;Moruzzi and Magoun, 1949;Penfield and Jasper, 1954). Although thalamocortical connections have been central in LOC research (Flores et al, 2017;Herrera et al, 2016;Penfield and Jasper, 1954;Steriade, 2003), the role of the cortex itself remains debated (Merker, 2007).…”

Reduced repertoire of cortical microstates and neuronal ensembles in medically-induced loss of consciousness

“…Despite its fundamental importance, the neural circuit and network mechanisms underlying LOC have remained unclear. Several brain areas have been implicated in causing the loss or recovery of consciousness, such as the hypothalamus (Herrera et al, 2016), thalamus (Castaigne et al, 1981), basal ganglia and claustrum (Crick and Koch, 2005;Mhuircheartaigh et al, 2010), or the brain stem (Minert et al, 2017;Moruzzi and Magoun, 1949;Penfield, 1954). Although thalamocortical connections have been central to research on LOC (Flores et al, 2017;Herrera et al, 2016;Penfield, 1954;Steriade, 2003), the role of the cerebral cortex itself remains controversial (Merker, 2007).…”