The overall goal of our research is to understand the mechanism of general anesthesia at an integrative level with respect to the loss of consciousness (LOC). The general hypothesis is that LOC is due to the disruption of functional connectivity (FC) of neuronal activity among primary sensory and fronto-parietal association cortices which are involved in the integration of sensory information. In this work, two clinically used volatile anesthetics, isoflurane and desflurane and one clinically used intravenous anesthetic, propofol will be used to seek the common, agent-invariant effects on FC in chronically instrumented, freely moving rats. FC will be characterized by the statistical parameter mutual information as estimated from measurements of intracortical local field potentials and unit activities at gamma frequency (20-80 Hz) using chronically implanted high- density microelectrode arrays. The loss of righting reflex will be used as the primary behavioral index of LOC assessed simultaneously with the electrophysiological recordings. Three specific hypotheses that we will test are: (1) anesthetics will preferentially suppress neuronal feedback FC from frontal to visual cortex at anesthetic concentrations that produces unconsciousness, (2) inactivation of the frontal cortex by local cooling will suppress neuronal feedback FC as revealed by the suppression of long-latency flash-evoked potentials in visual cortex, (3) generalized cortical activation by electrical or neurochemical (glutamate, norepinephrine and neurotensin) stimulation of specific forebrain and brainstem nuclei (n. Basalis of Meynert and n. Cuneiformis) will reverse the suppressive effects of anesthetics on FC and consciousness. Public Health: This research should advance our understanding of the neurobiological basis of consciousness and of the mechanism of hypnotic effect of general anesthetic agents. It should help develop novel methods for monitoring the state of consciousness based on established neurobiological mechanisms and of new anesthetic agents with more specific hypnotic effects.
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