VIP interneuron contributions to state-dependent sensory processing

Several populations of GABAergic interneurons (INs) are strongly regulated by neuromodulatory input during distinct behavioral states, and thus may be key contributors to flexible cortical function. One prominent model suggests vasoactive intestinal peptide-expressing INs (VIP-INs) activate upon arousal, suppress the activity of downstream INs (SST-INs), and consequently disinhibit pyramidal neurons (PNs). This VIP-SST-PN disinhibitory circuit is hypothesized to be a general cortical circuit motif allowing behavioral state signals to modulate sensory processing. Cortical VIP-INs, however, have complex patterns of connectivity, including synaptic connections to excitatory PNs, and reciprocal inhibitory (I) connections with other INs. Current models largely fail to account for these complex context-dependent I-I interactions, leaving the role of distinct IN populations within the active cortical network largely unexplored. Furthermore, in inhibitory stabilized networks, hyperpolarization of INs may lead to a paradoxical increase in inhibitory activity, suggesting that I-I interactions are unlikely to be as straightforward as initially hypothesized. We used both chronic and acute manipulations to examine the state- and context-dependent role of I-I interactions. We expressed the calcium indicator GCaMP6 in VIP-INs and, using intersectional genetic tools, in SST-INs or PNs. We used two-photon imaging and high-throughput analyses to assess how VIP-INs influence SST-IN or PN activity in the primary visual cortex of awake mice across arousal states. To determine the behavioral impact of VIP-INs, we assessed mouse perceptual performance on a contrast detection task while optogenetically inhibiting VIP-INs. Our data reveals that VIP-INs contribute significantly to the encoding of low contrast stimuli and have an unanticipated non-linear contribution to the stimulus size tuning properties of SST-INs and PNs. In a contrast detection task, perceptual thresholds for stimulus detection were significantly higher when VIP-IN were inhibited, an effect that was amplified for small stimuli, indicating that VIP-INs cells play a powerful functional non-linear role in visual perception.