THE EFFECTS OF THE VOLATILE ANESTHETIC ISOFLURANE ON NETWORK ACTIVITY IN C. <EM>ELEGANS</EM>

Volatile anesthetics, such as isoflurane, generate a state of unconsciousness across the animal kingdom and are widely used in clinical settings. However, anesthetic mechanisms of action and its effect on circuit function at the cellular level remain a mystery. To probe the actions of isoflurane, we imaged neuron activity across the C. elegans head ganglia at cellular resolution under various levels of anesthesia. Identifying the imaged neurons within the animals completely mapped neuro-connectome, we found suppression of both neuron activity and connectivity with increasing isoflurane across a wide range of neuron and synapse types including cholinergic, glutamatergic, GABAergic, and especially gap junctions. Notably, highly connected neurons, specifically neurons with high in-degree connectivity, display the largest suppression in activity. These include hub interneurons thought to control behavioral crawling states. To measure the relevance of each neuron to systemwide dynamics and the changes under isoflurane, we performed principal component analysis (PCA), using a neuron’s magnitude in the first three PCs as a metric for its contribution to the systems coordinated activity. We found that key interneurons do indeed have the greatest drop in PCA magnitude under isoflurane. Taken as a whole, these findings suggest that volatile anesthetics generate the anesthetized state through global suppression of neuronal activity that results in the disruption of highly connected, highly active, hub loci critical to coordinating activity across neuronal circuits.