Modeling Synaptic Effects of Anesthesia and its Cortical Cholinergic Reversal

Abstract

General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common inhalation anesthetics induces decreases in synaptic excitation while promoting synaptic inhibition. Animal studies have shown that, during anesthesia, exogenously induced increases in acetylcholine-mediated effects in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. Less investigated, however, is the question of whether the brains electrophysiological activity is also restored to pre-anesthetic levels and quality by such interventions. Here we apply a computational model of a network composed of excitatory and inhibitory neurons to simulate the network effects of changes in synaptic inhibition and excitation due to anesthesia and its reversal by muscarinic receptor-mediated cholinergic effects. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts reversal of the neurons spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model results predict a possible neuronal mechanism for the induced reversal of the effects of anesthesia on post synaptic potentials, consistent with experimental behavioral observations. Author SummaryHere, we apply a computational model of a network composed of excitatory and inhibitory neurons to simulate the network effects of changes in synaptic inhibition and excitation due to anesthesia and we investigate the possibility of its reversal by muscarinic receptor-mediated cholinergic effects. Specifically, we use a differential evolution algorithm to fit model parameters to match dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that changes of the fitted synaptic parameters in response to the increasing desflurane concentration matched those established by neurophysiology. Further, our results demonstrate that the cellular effects induced by anesthesia can be mitigated by the changes in cellular excitability due to acetylcholine.