Parallel processing by cortical inhibition enables context-dependent behavior

Physical features of sensory stimuli are fixed, but sensory perception is context-dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones vs. performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed, while some cells became more active during behavior. Whole-cell recordings showed that excitatory inputs were only modestly affected by context, but inhibition was more sensitive, with PV, SOM+, and VIP+ interneurons balancing inhibition/disinhibition within the network. Cholinergic modulation was involved in context-switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.