Anesthetic and ascending arousal system modulation of cortical functional integration and BOLD functional connectivity in the rat brain

Anesthetic agents can safely, and reversibly alter the states of consciousness without significantly affecting the structural integrity of the central nervous system. Despite their widespread use, and the advances that have been made in understanding the interplay and relationship(s) between anesthetic agents with specific receptor and molecular sites, the neural mechanisms governing anesthetic induced suppression of consciousness remain poorly understood. The highly coordinated and specialized neuronal networks that give rise to emergent cortical properties (sensory perception, learning and memory, and consciousness) are believed to be disrupted by anesthetic agents via common mechanisms. In addition to their direct effects on the thalamus and cerebral cortex, anesthetic agents may encourage loss of consciousness through an interaction with the ascending arousal system (AAS).;The overall goal of this work was to use a multimodal approach to further examine mechanisms of anesthesia and the modulation of anesthetic state by manipulating components of the ascending arousal system (AAS). More specifically, I examined:;Aim 1: The concentration-dependent effects of propofol anesthesia on resting state BOLD functional connectivity. I hypothesized that brain connectivity undergoes complex changes at specific anesthetic depths and in distinct neural networks. To this end, I acquired resting state fMRI time series simultaneously with electroencephalographic (EEG) signals from rats under intravenously administered propofol at increasing doses from light sedation to deep anesthesia. Intrinsic functional connectivity was altered in a multiphasic dose-dependent, and region-specific manner during deepening anesthesia by propofol associated with diminished consciousness. Cortical connectivity was suppressed before subcortical connectivity at increasing propofol doses critical for loss of consciousness.;Aim 2: Determine whether norepinephrine infusion into the nucleus Basalis of Meynert (NBM) would elicit cortical and behavioral arousal under moderate depth of steady state anesthesia. I hypothesized that microinfusion of norepinephrine into NBM would facilitate electroencephalographic and behavioral arousal during steady-state desflurane anesthesia. Pharmacologic modulation of the NBM by norepinephrine during desflurane anesthesia produced transient behavioral arousals that, when present, were predictable by EEG desynchronization. The transient nature of the responses suggests a similarity with microarousals normally observed during natural sleep, and may imply a mechanism for transient awareness under light anesthesia.;Aim 3: The effect of electrical stimulation of the nucleus Pontis Oralis (PnO) on cortical information capacity in desflurane anesthetized rats. I hypothesized that, if cortical information processing is under the control of the AAS, and anesthesia suppresses information integration as previously proposed then a plausible question is whether exogenous reactivation of the AAS, in particular that of the nucleus Pontis Oralis (PnO), may restore cortical information integration and presumably, consciousness as well. Electrical stimulation of the PnO elicited local field potential (LFP) desynchronization, as well as alterations in the neuronal spike firing patterns of the multi-unit activity (MUA) in the parietal association and secondary visual cortex. This led to an increase in integration and interaction entropy, non-linear information-theoretic measures that are reflective of spike firing patterns, after PnO stimulation.;Aim 4: The effect of electrical stimulation of the nucleus Pontis Oralis (PnO) on cortical arousal and BOLD functional connectivity in isoflurane-anesthetized rats. I hypothesized that electrical stimulation, using the proper choice of parameters, of the PnO under an isoflurane concentration sufficient for LOC should induce cortical arousal and changes in functional connectivity (FC) in the absence of behavioral activation. Electrical stimulation of the PnO was accompanied by an increase in FC between the NBM and key regions of the limbic system that may allow affective and episodic information processing between the cortex and related subcortical networks.