The overall goal of our research is to better understand the mechanism of general anesthesia at an integrative level with special reference to the toss and return of conscious sensory functions. The general hypothesis is that a neural correlate of volatile anesthetic-induced loss of consciousness (LOC) is the disruption of gamma-frequency synchronization of neuronal activity among primary sensory and association cortices. This work focuses onthe anesthetic modulation of visual cortical function in the rat and applies a combination of intracortical field potential (FP) and multichannel unit activity (UA) recordings and functional magnetic resonance imaging (fMRI) to determine the respective effects of halothane and isoflurane. The loss of righting reflex (LORR) will be used as a behavioral index of LOC assessed simultaneously with the electrophysiological recordings in freely moving rats. Four specific hypotheses that we will test are: (1) synchronization of visual stimulus-induced FP gamma oscillations among specific visual and fronto-parietal association cortical regions is diminished by both agents at concentrations corresponding to LORR; (2) UA of neuronal populations will follow the FP gamma oscillations such that the visual stimulus-related neuronal firing synchrony among cortical regions will be diminished with increasing anesthetic concentration in correlation with the LORR; (3) anesthetic depression of poststimulus cortico-cortical gamma synchronization and the righting reflex will both be restored by cortical arousal achieved by electrical or pharmacological (glutamate, norepinephrine, neurotensin) stimulation of the basal forebrain (n. basalis of Meynert) or the parabrachial region (n. cuneiformis); (4) cortical blood oxygen level dependent (BOLD) fMRI response to visual stimulation will correlate with the gamma FP response and J will be reduced in parallel with cortico-cortical functional connectivity at increasing depth of anesthesia. Analysis of functional connectivity will involve the determination of synchrony and mutual information of FP and UA recorded with chronically implanted bipolar electrodes and high density microelectrode arraysl sampling simultaneously more than 100 neurons. This research should advance our understanding of the neurobiological basis of consciousness and the mechanism of sedative/hypnotic effect of general anesthetic agents and may lead to the development of more specific agents and of monitors of anesthetic depth monitors.
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