General anesthetics may suppress consciousness through two complementary neural pathways: a bottom-up mechanism that alters arousal by acting on brainstem and diencephalon sleep-wake nuclei, and a top-down mechanism that disrupts cortical and thalamocortical circuits responsible for integrating information. This article synthesizes these approaches by mapping them to two interrelated dimensions of consciousness—level and content. The framework explains why different anesthetic drugs produce diverse effects on subjective experience. The authors argue that level and content interact to generate consciousness, and understanding this interaction is key to explaining how anesthetics induce unconsciousness.
Injecting the NMDAR antagonist MK-801 into mice produced a 10-fold higher density of c-Fos—a marker of neuronal activity—in the medial entorhinal cortex (MEC) compared to other forebrain regions. c-Fos was concentrated in layer 3 of the dorsal MEC. Parvalbumin (PV)-positive inhibitory neurons showed a spatial correlation with c-Fos: high and medium PV neurons correlated positively with c-Fos density, while low PV neurons correlated negatively. During postnatal development, PV expression appeared on day 12, two days before c-Fos emerged on day 16. The findings suggest that specific subtypes of inhibitory and excitatory neurons in local circuits are critical for sustained neuronal responses to NMDAR antagonists, and that dense PV input may be necessary for inducing c-Fos in MEC principal neurons.
General anesthetics may suppress either the level of consciousness (arousal) or its contents (specific percepts, thoughts, feelings). This distinction is important for understanding both anesthesia and the neural bases of consciousness. Evidence indicates that both level and content depend on apical input to neocortical pyramidal cells, which selectively amplifies relevant signals. What these cells transmit information about can be separated from arousal levels controlled by sub-cortical nuclei and from prioritization set by thalamocortical interactions. The authors hypothesize that when conscious, we have particular directly experienced mental states, and that anesthetics disrupt the subcellular processes that selectively amplify contextually relevant activities.