Sub‐Anesthetic Ketamine Administration Decreases Deviance Detection Responses at the Cellular, Population‐ and Mesoscale Levels

In the neocortex, neuronal processing of sensory events is significantly influenced by their predictability. A common example is the suppression of responses to repetitive stimuli in sensory cortices, a phenomenon known as habituation. Within a sensory information stream, whenever a novel stimulus deviates from expectations, enhanced brain responses are observed. Mismatch negativity (MMN), the electroencephalographic waveform reflecting rule violations, is a well-established biomarker for auditory deviant detection. MMN has been shown to depend on intact NMDA receptor signaling across species; nevertheless, the underlying mechanisms at the neuronal and mesoscale levels are still not fully understood. Using multi-electrode array recordings in awake mice, we identified a specific biphasic spiking response in a subpopulation of primary auditory cortex (A1) neurons elicited by deviant, but not standard, sounds, wherein the second peak is abolished by acute sub-anesthetic injection of ketamine, a partial non-competitive NMDA receptor antagonist. We further showed that the posterior parietal cortex (PPC), a critical hub for multisensory integration and sensorimotor coordination, responds to deviant, but not repetitive, sounds, and this response is dependent upon intact NMDA receptor-mediated signaling. Finally, to explore the effects of ketamine on inter-cortical communication following deviance detection, we performed weighted phase lag index (wPLI) analyses during the presentation of deviant and standard sounds. This analysis showed a functional connectivity between A1 and PPC following deviant detection, which is impaired by ketamine administration. Altogether, our findings provide novel insights into the NMDA receptor-dependent mechanisms underlying the processing of novelty in auditory stimuli.