Abstract
Studies aimed at investigating brain regions involved in arousal state control have been traditionally limited to subcortical structures. In the current study, we tested the hypothesis that inactivation of prefrontal cortex, but not two subregions within parietal cortex—somatosensory barrel field and medial/lateral parietal association cortex—would suppress arousal, as measured by an increase in anesthetic sensitivity. Male and female Sprague Dawley rats were surgically prepared for recording electroencephalogram and bilateral infusion into prefrontal cortex (N = 13), somatosensory barrel field (N = 10), or medial/lateral parietal association cortex (N = 9). After at least 10 days of post-surgical recovery, 156 μM tetrodotoxin or saline was microinjected into one of the cortical sites. Ninety minutes after injection, rats were anesthetized with 2.5% sevoflurane and the time to loss of righting reflex, a surrogate for loss of consciousness, was measured. Sevoflurane was stopped after 45 min and the time to return of righting reflex, a surrogate for return of consciousness, was measured. Tetrodotoxin-mediated inactivation of all three cortical sites decreased (p < 0.05) the time to loss of righting reflex. By contrast, only inactivation of prefrontal cortex, but not somatosensory barrel field or medial/lateral parietal association cortex, increased (p < 0.001) the time to return of righting reflex. Burst suppression ratio was not altered following inactivation of any of the cortical sites, suggesting that there was no global effect due to pharmacologic lesion. These findings demonstrate that prefrontal cortex plays a causal role in emergence from anesthesia and behavioral arousal.
Highlights
Studies over the past century have demonstrated an unequivocal role for subcortical nuclei in behavioral arousal
While inactivation of all three cortical sites reduced the time to loss of righting reflex after sevoflurane anesthesia, only prefrontal cortex inactivation increased the time to return of righting reflex, i.e., delayed the emergence time from sevoflurane anesthesia
Similar to the effect of TTX-mediated inactivation of prefrontal cortex and S1BF, TTX infusion into medial/lateral parietal association cortex (M/LPtA) decreased the time to loss of righting reflex (LORR), as compared to that observed after saline injection [mean ± standard deviation (SD): 157.6 s ± 37.8 for TTX vs. 191.9 s ± 45.4 for saline, t(8) = −2.43, p = 0.02, 95% confidence interval (CI) (−63.40, −5.15), β = −34.28] (Figure 3C)
Summary
Studies over the past century have demonstrated an unequivocal role for subcortical nuclei in behavioral arousal. Lesions in brainstem and the adjoining basal forebrain have been shown to disrupt consciousness and produce a coma-like state or behavioral unresponsiveness (Lindsley et al, 1950; Parvizi and Damasio, 2003; Fuller et al, 2011; Hindman et al, 2018), whereas stimulation of structures within these areas was shown to produce behavioral arousal (Moruzzi and Magoun, 1949; Solt et al, 2014; Vazey and Aston-Jones, 2014; Muindi et al, 2016; Taylor et al, 2016; Luo et al, 2018; Gao et al, 2019; Wang et al, 2019) Of note, these subcortical regions send projections to cortex (Briand et al, 2007; Hoover and Vertes, 2007). We demonstrated that infusion of carbachol into prefrontal cortex during slow-wave sleep reduced the latency to the onset of wakefulness and increased the time spent in wakefulness (Parkar et al, 2020) These studies suggest a causal role for prefrontal cortex in behavioral arousal. While inactivation of all three cortical sites reduced the time to loss of righting reflex after sevoflurane anesthesia, only prefrontal cortex inactivation increased the time to return of righting reflex, i.e., delayed the emergence time from sevoflurane anesthesia
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