Inhibitory and disinhibitory VIP IN-mediated circuits in neocortex

Cortical GABAergic interneurons (INs) are comprised of distinct types that provide tailored inhibition to pyramidal cells (PCs) and other INs, thereby enabling precise control of cortical circuit activity. INs expressing the neuropeptide vasoactive-intestinal peptide (VIP) have attracted attention recently following the discovery that they predominantly function by inhibiting dendritic-targeting somatostatin (SST) expressing INs, thereby disinhibiting PCs. This VIP-SST disinhibitory circuit motif is observed throughout the neocortex from mice to humans, and serves as a key mechanism for top-down (feedback) and context-dependent information processing. Thus, VIP IN-mediated disinhibition has been found to play an important role in sensory processing, control of executive functions, attention, sensorimotor integration and other cortico-cortical and thalamocortical feedback interactions. Furthermore, VIP INs have been implicated in mediating the effects of reinforcement signals, both reward and aversive, via their responsiveness to neuromodulators such as acetylcholine (ACh), and in facilitating synaptic plasticity and learning. While it is evident from transcriptomic analyses that VIP INs are a molecularly heterogeneous group, the physiological significance of this diversity is unclear at present. Here, we have characterized the functional diversity of VIP INs in the primary somatosensory cortex by leveraging intersectional genetic approaches to study distinct VIP IN subtypes. We found that VIP INs can be divided into four different populations: a group that expresses the Ca ²⁺ -binding protein calretinin (CR), two distinct groups that express the neuropeptide cholecystokinin (CCK), and a group that does not express either CR or CCK (non-CCK non-CR; or nCCK nCR). VIP neurons in each group exhibit different laminar distributions, axonal and dendritic arbors, intrinsic electrophysiological properties, and efferent connectivity, VIP/CR INs target almost exclusively SST INs, VIP/nCCK nCR INs also mainly target SST INs but also have connections to parvalbumin (PV) expressing INs. These two groups have essentially no connectivity to pyramidal cells (PCs). On the other hand, the two types of VIP/CCK INs target PCs, but differ in the degree to which synaptic release from each type is modulated by endocannabinoids. We also found that long-range inputs differentially recruit distinct VIP IN groups. Intriguingly, we find that distinct VIP IN populations target distinct SST INs subtypes in turn, indicating the presence of specialized VIP-SST disinhibitory subcircuits. Activation of distinct VIP IN subpopulations in vivo results in differential effects on the cortical network, thus providing evidence for modularity in VIP IN-mediated actions during cortical information processing.