"THE BREAKDOWN OF NEURAL CIRCUIT FUNCTION UNDER VOLATILE ANESTHESIA: IN VIVO, MULTINEURONAL IMAGING IN C. ELEGANS"
Volatile anesthetics produce all stages of general anesthesia, including unconsciousness, amnesia, analgesia, and muscle relaxation. In this state, the experience, memory, and physical response to pain are all lost, yet patients can be returned to consciousness, making it an essential tool in modern medicine. However the mechanism by which neuronal systems are disrupted to cause such effects remains a mystery. Medical methods of interrogation are limited by their resolution, with fMRI and EEG measurements reporting the mean activity of millions of neurons. Previous research has developed the nematode worm C. elegans as an effective model for volatile anesthetics demonstrating that they display the same behavioral response to increasing levels of anesthesia as humans and identifying numerous genetic mutants that alter anesthetic susceptibility. Taking advantage of C. elegans simple neuro-anatomy and its comprehensive capabilities in multi-neuron imaging, we are defining the mechanism of anesthesia on a circuit level with single neuron resolution. Employing calcium based neuronal reporters (GCaMP), we can measure activity of neurons within the well-defined command interneuron circuit that controls the animal's forward and backward crawling with and without anesthetic. We find that under moderate anesthesia, at which point C. elegans have become unresponsive to external stimuli, activity of individual neurons is not abolished. Rather activity becomes randomized as measured through a loss in coordination between neurons and an increase in random high frequency dynamics. Under higher levels of anesthesia, dysynchrony in the system is retained, while individual neuronal activity is reduced mimicking the reduced activity observed in EEG measurements from humans at a similar level of anesthesia. Our results indicate that the state of anesthesia stems from randomization of individual neuron activity and dysynchrony between neurons thus disrupting circuit signaling and function.