The Role of the Prefrontal Cortex in Regulating Level of Consciousness

Abstract

Consciousness is determined by content (i.e., experience) and level (e.g., degree of wakefulness). There is ongoing debate over the roles of prefrontal versus posterior cortical areas in regulating consciousness. Lesioning, stimulation, and psychomotor studies have shown that a temporo-parietal-occipital cortical zone is an anatomical candidate for content of consciousness and that prefrontal cortex is involved in task-oriented waking interactions. Prefrontal cortex (PFC), unlike parietal areas, shares reciprocal connections with several subcortical brain areas that have casual roles in arousal, a fundamental and objective measure of level of consciousness. We therefore tested the hypothesis that the PFC plays a prominent role in regulating level of consciousness and is a key node in an arousal-promoting network. We first assessed the effects of pharmacologic stimulation of PFC and two parietal cortical areas on arousal in sevoflurane-anesthetized Sprague Dawley rats. We showed that cholinergic, but not noradrenergic, stimulation of PFC via local carbachol infusion during anesthesia led to wake-like behaviors and a 6-fold increase in prefrontal levels of the wake-associated neurotransmitter acetylcholine (ACh). By contrast, there was no effect on behavioral arousal after cholinergic stimulation of posterior parietal or medial parietal cortices, or following noradrenergic stimulation of posterior parietal cortex. These results demonstrate that the cholinergic system in PFC regulates level of consciousness. Despite differential behavioral profiles, all cohorts exhibited wake-like cortical electroencephalogram (EEG) patterns following stimulation. We next processed these cortical EEG signals collected from rats before, during, and after sevoflurane anesthesia and carbachol/noradrenaline infusion into prefrontal and posterior parietal cortices to test whether wakefulness can be further dissociated from established computational markers of consciousness. We analyzed frontal-parietal functional connectivity and spatiotemporal complexity, as several studies across multiple species suggest disruption in these measures correlates with unconsciousness. Sevoflurane-induced unconsciousness was as expected characterized by a bidirectional suppression of frontal-parietal gamma (85 – 155 Hz) connectivity and reduction in frontal and parietal complexity. Surprisingly, connectivity remained depressed in all stimulation conditions/cohorts, despite the appearance of wake-like behaviors following cholinergic stimulation of PFC. The changes in complexity correlated with EEG activation observed across all cohorts rather than with level of consciousness. We conclude that PFC does not regulate level of consciousness through large-scale corticocortical connectivity. Basal forebrain (BF), a subcortical structure, is the major source of cortical ACh and BF cholinergic neurons promote wakefulness. Given the direct cholinergic projections from BF to PFC and the increase in prefrontal ACh in association with wakefulness induced by carbachol infusion into PFC, we tested whether activation of the BF cholinergic system is sufficient for restoration of wakefulness. We conducted bilateral chemogenetic stimulation of BF cholinergic neurons in transgenic ChAT-Cre rats, which was sufficient to induce wakefulness during continuous exposure to clinically relevant levels of sevoflurane anesthesia. To test whether the PFC (in addition to its potential role in activating BF) was a cortical effector site or “gate” for BF-induced arousal, we conducted bilateral electrical stimulation of BF in sevoflurane-anesthetized Sprague Dawley rats without or with concurrent inactivation of PFC via local bilateral infusion of tetrodotoxin. Electrical stimulation alone was sufficient to induce wakefulness, but concurrent inactivation of PFC during electrical stimulation of BF attenuated these arousal promoting effects. These studies demonstrate that the PFC plays a causal role in regulation of level of consciousness, likely both as an activator and a critical cortical effector arm of cholinergic BF.