The breakdown of neural function under anesthesia
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Anesthetics have been used for nearly two centuries, and have proved to be one of the most important tools in surgical interventions, but their methods of action remain mysterious. Previous research has focused on high-level, low-resolution measurements (average activity of many neurons) or low-level, high-resolution measurements (single neurons). The nematode Caenorhabditis elegans provides an excellent model to bridge the gap between these two scales by measuring the activity of many neurons with single neuron resolution. C. elegans display analogous behaviors to humans under anesthesia. Employing confocal imaging of GCaMP, I measured neuronal activity at different isoflurane levels in C. elegans ganglia and in small behavior-controlling circuits. The activity in C. elegans ganglia is similar to that of human ganglia, as assessed using measures that are similar to EEG. Activity in the small behavior-controlling circuit is disrupted, but not suppressed, when dosed with moderate levels of isoflurane. Neural activity in the circuit is randomized resulting in a loss of coordination between neurons that define behavioral states of the system. As such, the onset of the behaviors of anesthesia appears to be the resultant of randomization rather than suppression of individual neuron activity. Employing light sheet microscopy and automated image analysis for neuronal tracking, I expanded the imaging techniques to measure activity of the majority of neurons in the animal’s head. Expansion of these measurements to the whole head region of the nematode confirms these findings, displaying significant decreases in neuron-to-neuron coordination, as well as randomization of individual neuron signals with the onset of anesthesia. These results reveal a new physiological mechanism of action for anesthetics, and provide an avenue forward for investigating the molecular mechanism including specific genetic mutations known to alter susceptibility to anesthetics.