Differential Role of Prefrontal and Parietal Cortices in Controlling Level of Consciousness

Abstract

Consciousness is determined both by level (e.g., being awake versus being anesthetized) and content (i.e., the qualitative aspects of experience). Subcortical areas are known to play a causal role in regulating the level of consciousness [1-9], but the role of the cortex is less well understood. Clinical and correlative data have been used both to support and refute a role for prefrontal and posterior cortices in the level of consciousness [10-22]. The prefrontal cortex has extensive reciprocal connections to wake-promoting centers in the brainstem and diencephalon [23, 24], and hence is in a unique position to modulate level of consciousness. Furthermore, a recent study suggested that the prefrontal cortex might be important in regulating level of consciousness [25] but causal evidence, and a comparison with more posterior cortical sites, is lacking. Therefore, to test the hypothesis that prefrontal cortex plays a role in regulating level of consciousness, we attempted to reverse sevoflurane anesthesia by cholinergic or noradrenergic stimulation of the prefrontal prelimbic cortex and two areas of parietal cortex in rat. General anesthesia was defined by loss of the righting reflex, a widely used surrogate measure in rodents. We demonstrate that cholinergic stimulation of prefrontal cortex, but not parietal cortex, restored wake-like behavior, despite continuous exposure to clinically relevant concentrations of sevoflurane anesthesia. Noradrenergic stimulation of the prefrontal and parietal areas resulted in electroencephalographic activation but failed to produce any signs of wake-like behavior. We conclude that cholinergic mechanisms in prefrontal cortex can regulate the level of consciousness.

Keywords: acetylcholine; carbachol; consciousness; electroencephalogram; microdialysis; noradrenaline; parietal cortex; prefrontal cortex; rat; sevoflurane anesthesia.

Figure 1. Cholinergic stimulation of prefrontal prelimbic cortex in anesthetized rat is sufficient to restore level of consciousness and wake-like behavior

Panels in (A) and (B) show behavior after dialysis delivery of 5 mM carbachol (CARB) or 20 mM noradrenaline (NA) into prefrontal prelimbic cortex (PFC) of rats receiving continuous sevoflurane anesthesia (1.9–2.4%); numbers on the top right corner show the time elapsed (min:s) after CARB/NA reached the target site. C) and (D) demonstrate CARB- and NA-induced electroencephalographic activation, respectively. E) and (G) show representative spectrograms across the experimental timeline for CARB and NA groups, respectively; vertical color bar is the log scale for power spectral density. Black arrows indicate the approximate time of CARB- and NA-induced electroencephalographic activation quantified as theta/delta ratio in (F) and (H), respectively. I) and (J) show the effect of CARB on respiration and heart rate, respectively. K) and (L) show the effect of NA on respiration and heart rate, respectively. M) and (N) show changes in acetylcholine levels for each rat during sevoflurane anesthesia (Sevo), CARB/NA delivery into PFC during Sevo, and post-Sevo recovery wake (Rec wake) epochs as percent change from pre-anesthesia wake state (Wake). Significance symbols (p<0.05) show group level comparisons using Student’s two-tailed paired t-test: *compared to Wake, #compared to Sevo, §compared to CARB/NA. Multiple comparisons were Bonferroni corrected. Actual p values are reported in the results section. Frtl - frontal, δ - delta, Prtl - parietal, SD - standard deviation, θ - theta. See also Figure S1, Tables S1–S3, and Video S1.

Figure 2. Cholinergic stimulation of posterior parietal cortex in anesthetized rat does not affect the level of consciousness

Panels in (A) and (B) show behavior after dialysis delivery of 5 mM carbachol (CARB) or 20 mM noradrenaline (NA) into posterior parietal cortex (PPC) of rats receiving continuous sevoflurane anesthesia (1.9–2.4%); numbers on the top right corner show the time elapsed (min:s) after CARB/NA reached the target site. C) and (D) demonstrate CARB- and NA-induced electroencephalographic activation, respectively. E) and (G) show representative spectrograms across the experimental timeline for CARB and NA groups, respectively; vertical color bar is the log scale for power spectral density. Black arrows indicate the approximate time of CARB- and NA-induced electroencephalographic activation quantified as theta/delta ratio in (F) and (H), respectively. I) and (J) show the effect of CARB on respiration and heart rate, respectively. K) and (L) show the effect of NA on respiration and heart rate, respectively. M) and (N) show changes in acetylcholine levels for each rat during sevoflurane anesthesia (Sevo), CARB/NA delivery into PFC during Sevo, and post-Sevo recovery wake (Rec wake) epochs as percent change from pre-anesthesia wake state (Wake). Significance symbols (p<0.05) show group level comparisons using Student’s two-tailed paired t-test: *compared to Wake, #compared to Sevo, §compared to CARB/NA. Multiple comparisons were Bonferroni corrected. Actual p values are reported in the results section. Frtl - frontal, δ - delta, Prtl - parietal, SD - standard deviation, θ - theta. See also Figure S1, Tables S1–S3, and Video S2.

Figure 3. Cholinergic stimulation of medial parietal association cortex in anesthetized rat does not affect the level of consciousness

A) shows effect on behavior after dialysis delivery of 5 mM carbachol (CARB) into medial parietal association cortex (MPtA) of rats receiving continuous sevoflurane anesthesia (1.9–2.4%). B) demonstrates CARB-induced electroencephalographic activation. C) representative spectrograms across the experimental timeline; vertical color bar is the log scale for power spectral density. Black arrows indicate the approximate time of CARB-induced electroencephalographic activation quantified as theta/delta ratio in (D). E) and (F) show the effect of CARB delivery on respiration and heart rate, respectively. G) show changes in acetylcholine levels for each rat during sevoflurane anesthesia (Sevo), CARB/NA delivery into PFC during Sevo, and post-Sevo recovery wake (Rec wake) epochs as percent change from pre-anesthesia wake state (Wake). Significance symbols (p<0.05) show group level comparisons using Student’s two-tailed paired t-test: *compared to Wake, #compared to Sevo, §compared to CARB/NA. Multiple comparisons were Bonferroni corrected. Actual p values are reported in the results section. Frtl - frontal, δ – delta, Prtl - parietal, SD - standard deviation, θ - theta. See also Figure S1 and Tables S1 and S2.