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

A specific biphasic spiking response in a subpopulation of primary auditory cortex (A1) neurons is elicited by deviant, but not standard, sounds; the second peak is abolished by acute sub-anesthetic injection of ketamine, a partial non-competitive NMDA receptor antagonist. The posterior parietal cortex (PPC) responds to deviant, but not repetitive, sounds, and this response depends on intact NMDA receptor-mediated signaling. Weighted phase lag index (wPLI) analyses show functional connectivity between A1 and PPC following deviant detection, which is impaired by ketamine administration. These findings provide novel insights into NMDA receptor-dependent mechanisms underlying auditory novelty processing.

Study at a glance

Abstract

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.