The role of inhibitory neurons in novelty sound detection in regular and random statistical contexts

Detecting statistical regularities in sound and responding to violations of these patterns, termed novelty detection, is a core function of the auditory system. In the human brain, studies have shown that novelty responses are enhanced in regular compared to random auditory contexts, but the underlying neuronal circuit mechanisms remain unclear. Here, we examined how inhibitory neurons contribute to context-dependent novelty responses in mouse auditory cortex (AC). Using two-photon calcium imaging in AC of awake head-fixed male and female mice, we recorded neuronal activity during presentation of spectro-temporally rich ripple sounds, with novel ripples embedded in either regular or random ripple sequences. AC neurons exhibited stronger responses to novel sounds in regular contexts compared to random ones. To identify circuit mechanisms, we selectively inactivated parvalbumin (PV), somatostatin (SST), or vasoactive intestinal polypeptide (VIP) inhibitory neurons during the novel stimulus presentation. Inactivation of PV and SST neurons broadly increased novelty responses in both contexts. In contrast, VIP inactivation selectively reduced responses to novel stimuli in the regular, but not random, context, decreasing the context-dependent novelty signal enhancement. At the population level, inactivating all three neuronal subtypes increased detectability of the novel stimulus, but only for VIP inactivation, the effects were context dependent. These findings reveal a distinct role for VIP neurons in modulating novelty signals based on context regularity, suggesting that VIP circuits are critical for context-sensitive auditory processing and predictive coding.