Axonal Projections of Neurons in the Brainstem Mesopontine Tegmental Anesthesia Area (MPTA) That Effect Anesthesia, Enabling Pain-Free Surgery

Background/Objectives: Chemogenetic excitation of a distinct subset of “effector-neurons” in the brainstem mesopontine tegmental anesthesia area (MPTA) is pro-anesthetic. GABAergic general anesthetics are believed to engage these neurons by disinhibition, thereby inducing loss-of-consciousness (LOC) and enabling pain-free surgery. The transition from wakefulness to LOC, however, does not occur intrinsically within the MPTA. Rather, evidence indicates that LOC is brought about (effected) by ascending and descending axonal projections of MPTA effector-neurons that terminate in a variety of downstream brain targets which, together, generate the various components of anesthesia. Previously we used anterograde and retrograde tracing to delineate the overall axonal trajectories of MPTA projection-neurons, to which targets they project. Effector-neurons, however, represent only a fraction of this neuronal pool. Which of these targets are also innervated by MPTA projecting effector-neurons? Methods: Here we marked MPTA effector-neurons with the adeno-associated virus (AAV) used in the discovery of this neuronal type, with retrograde labelling from the previously identified MPTA target structures, to establish which downstream brain structures receive direct input from effector-neurons. Results: Effector-neurons proved to contribute to all six of the major MPTA projection-targets: the prefrontal cortex, basal forebrain, intralaminar thalamus, zona incerta, rostro-ventromedial medulla and spinal cord. Conclusions: We conclude that a discrete population of projecting effector-neurons, probably representing only about 6% of all MPTA neurons, drive the multiple functional endpoints of surgical anesthesia: analgesia, atonia, amnesia and LOC. Further, we propose that these same neurons, via their associated axonal pathways, may also contribute to endogenous instances of LOC such as natural sleep, fainting, concussion, coma and hibernation.