Cholinergic and adrenergic modulation sculpts parallel inhibition of SST-INs in visual cortex

GABAergic interneurons are fundamental to the normal function of neuronal circuits in the neocortex. A growing literature has highlighted the role of somatostatin-expressing interneurons (SST-INs) in regulating cortical activity, and inhibition of SST-INs by other interneurons has emerged as a circuit motif leading to disinhibition of pyramidal neurons. However, the diversity and regulation of GABAergic inputs to SST-INs are only partially understood. Here, we combined widefield and 2-photon optogenetic stimulation of parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing interneurons with recordings from fluorescently identified SST-INs in layer 2/3 of primary visual cortex (V1). Our results show that both PV- and VIP-INs form inhibitory inputs onto SST-INs but with varying functional properties. PV-INs evoke strong, fast inhibition onto perisomatic regions of their target cells, while VIP-INs evoke slower inhibition onto target cell dendrites that is partially mediated by alpha subunit-containing GABA receptors. Cholinergic modulation through muscarinic receptors strongly suppresses PV-IN output while adrenergic modulation through beta receptors enhances VIP-IN output. Computational modeling suggests that these parallel inhibitory pathways can differentially regulate circuit gain and network stability across different inputs and arousal conditions. Thus, the diversity of disinhibitory GABAergic circuits in the neocortex provides a mechanism for state-dependent flexibility in circuit function.