Remimazolam-induced dysfunction of thalamic reticular nucleus impairs auditory gating during postanaesthetic recovery in mice.

Abstract

Perioperative benzodiazepines increase the risk of sensory hypersensitivity and agitation during recovery, but the neural mechanisms remain unclear. Auditory gating filters redundant information to prevent network overload. We hypothesise that benzodiazepines impair auditory gating during recovery, leading to heightened auditory responsiveness. Simultaneous electroencephalography, electromyography, and behavioural analyses assessed the effects of remimazolam, a novel benzodiazepine, on arousal states. Multi-region microelectrodes and Neuropixels probes recorded cortical and subcortical local field potentials and single-unit activity. Optogenetics was applied to test the impact of remimazolam on auditory gating. Both spontaneous and paired-tone evoked neuronal activity were suppressed during anaesthesia and sedation, followed by rebound enhancement and auditory gating deficits during recovery (T2/T1 ratio in posterior parietal cortex: baseline 0.38 [0.01] vs recovery 0.82 [0.02], P<0.001; dorsal hippocampus: 0.34 [0.01] vs 1.10 [0.03], P<0.001; and mediodorsal thalamic nucleus: 0.48 [0.01] vs 1.12 [0.02], P<0.001]). Optogenetic manipulations of the prefrontal cortex and brainstem auditory nuclei revealed that both top-down and bottom-up inputs were blocked during anaesthesia. During recovery, top-down inputs normalised, whereas bottom-up inputs exceeded baseline, along with gating deficits. A subset of gamma-aminobutyric acid (GABA)ergic neurones in thalamic reticular nucleus exhibited sustained responses to paired tones. During recovery, both their proportion (63.0% vs 29.3%) and firing strength (maximum firing rate: 28.9 [3.9] vs 17.4 [3.0], P<0.001) were diminished, resulting in insufficient inhibition of bottom-up inputs and exaggerated responses to external stimuli. Our findings elucidate the dynamic changes in sensory processing and the underlying mechanisms during benzodiazepine-induced anaesthesia and recovery, providing valuable insights for optimising clinical anaesthesia management and postoperative recovery strategies.