EphB1-NR2B receptor signaling in glutamatergic neurons of the ventroposteromedial thalamic nucleus regulates emergence from anesthesia

Understanding the brain's intrinsic mechanisms that drive the emergence of consciousness from anesthesia remains a substantial and unresolved challenge in brain research. Here, we show in mice that, when the brain is forced into a minimal responsive state by an anesthetic, a rapid activation of EphB1 receptor occurs in the ventral posteromedial nucleus (VPM) of the thalamus and contributes to promote the emergence of consciousness by activating the VPM glutamatergic neuron (VPM^Glu) → primary somatosensory cortex glutamatergic neuron pathway. The ephrinB-EphB1 receptor signaling excites VPM^Glu neurons through phosphorylation of NR2B, a subunit of N-methyl-D-aspartate receptors (NMDARs), at tyrosine-1472 (Y1472) and disinhibits VPM^Glu neurons through ubiquitin degradation of potassium-chloride co-transporter 2 (KCC2). The EphB1/NR2B Y1472 phosphorylation and EphB1/KCC2 ubiquitin degradation are two independent mechanisms in the process of emergence from anesthesia and occur independent of the molecular targets of anesthesia. The present study provides insights into understanding the molecular and neural circuit basis that allows the brain to emerge from anesthesia and regain consciousness.