Monday, February 10, 2025
2/10/2025
Project Summary Our overarching goal is to define the molecular and cellular mechanisms underlying the actions of volatile anesthetics (VAs). Our objective in the studies proposed here, which represent the next step in pursuing this goal, is to mechanistically define the functions of astrocytes that underly their involvement in the process of emergence from anesthesia with VAs. We hypothesize, based on substantial recent and preliminary data, astrocyte mitochondrial electron transport chain (ETC) function supports normal emergence through maintenance of astrocyte calcium signaling, gliotransmitter release, and metabolic support to neurons. We further hypothesize that specific, spatially defined, populations of astrocytes within the central nervous system (CNS) drive emergence through their local support of neuronal synapses involved in emergence. Our experiments will take advantage of pure primary astrocyte cell culture, a mouse model for cell-specific disruption of mitochondrial function through cre-mediated excision of the ETC complex I protein Ndufs4, and stereotactic microinjection targeted viral delivery of an astrocyte promoter driven cre-recombinase to enable brain region-specific disruption of Ndufs4 specifically in astrocytes. These models will allow us to characterize the astrocyte functions impacted by VAs and the population of astrocytes involved in emergence. Specifically, they will allow us to: i) define the effects of VAs on astrocyte calcium signaling and mitochondrial function, and the mechanistic links between the two, in vitro; ii) characterize the effects of VAs on astrocyte gliotransmitter release; iii) characterize the impact of VAs on astrocyte metabolites which support neuronal function; iv) define the astrocyte population, defined by region, responsible for supporting emergence from anesthesia with VAs. Ultimately, this work will greatly advance our understanding of the mechanisms of VA activity and the process of emergence. Relevance Despite their prevalence, the precise targets of VAs, and the mechanisms underlying their pleiotropic effects, are largely undefined. Emergence is a daily occurrence for thousands of patients, but the process of emergence is poorly understood. Delays in emergence are associated with anxiety, confusion, resistive activity, delays in the operating room, increased risks of injury, and significant medical costs. If the mechanisms of emergence can be resolved, it may be possible to develop strategies for active promotion of recovery of consciousness.
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