IntroductionVolatile anesthetics, such as isoflurane, generate a state of unconsciousness and analgesia across the animal kingdom and are widely used in clinical settings. Yet, anesthetic mechanisms are poorly understood: the volatile anesthetics are so profligate in their potential effects that it has proven difficult to determine which actions are most causal at the systems level.MethodsTo test if specific cellular targets mediate the anesthetic effect across a complete, intact nervous system, we imaged neuron activity in the Caenorhabditis elegans head ganglia at cellular resolution. We measured the effect of increasing anesthetic concentrations across a range of identified neurons within the C. elegans nervous system.ResultsHowever, rather than dramatic effects on any particular neuronal class, we measured uniform suppression of both neuron activity and connectivity with increasing isoflurane across the nervous system. We find the degree of activity suppression to be proportional to the baseline activity of the neuron in the awake state. Within this context, highly connected neurons, specifically neurons with high in-degree connectivity, are inherently active and display large activity suppression. These include hub interneurons within the C. elegans command locomotory circuit that control behavioral crawling states and contribute to system-wide coherence of neuron dynamics. By analyzing the effect of isoflurane on the activity of two specific hub interneuron classes, AVA and AVE, we show that the large degree of suppression observed in these neurons corresponds to high baseline activity.DiscussionExploiting the small size, simplicity and optical accessibility of C. elegans, our results demonstrate that isoflurane anesthesia globally suppresses activity and connectivity across a wide range of neuron types, and suggest a model of anesthesia in which proportional suppression of activity results in disruption of highly connected, highly active, hub loci that are critical to nervous system coordination and state dynamics.
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