Inhibitory interneurons in the neocortex often connect in a promiscuous and extensive fashion, extending a “blanket of inhibition” on the circuit. This raises the problem of how can excitatory activity propagate in the midst of this widespread inhibition. One solution to this problem could be the vasoactive intestinal peptide (VIP) interneurons, which disinhibit other interneurons. To explore how VIP interneurons affect the local circuits, we use two-photon optogenetics to activate them individually in mouse visual cortex in vivo while measuring their output with two-photon calcium imaging. We find that VIP interneurons have narrow axons and inhibit nearby somatostatin interneurons, which themselves inhibit pyramidal cells. Moreover, via this lateral disinhibition, VIP cells in vivo make local and transient “holes” in the inhibitory blanket extended by SOM cells. VIP interneurons, themselves regulated by neuromodulators, may therefore enable selective patterns of activity to propagate through the cortex, by generating a “spotlight of attention”.

SIGNIFICANCE STATEMENT Most inhibitory interneurons have axons restricted to a nearby area and target excitatory neighbors indiscriminately, raising the issue of how neuronal activity can propagate through cortical circuits. Vasoactive intestinal peptide-expressing interneurons (VIPs) disinhibit cortical pyramidal cells through inhibition of other inhibitory interneurons, and they have very focused, “narrow” axons. By optogenetically activating single VIPs in live mice while recording the activity of nearby neurons, we find that VIPs break open a hole in blanket inhibition with an effective range of ∼120 μm in lateral cortical space where excitatory activity can propagate.

Local inhibition through GABAergic inhibitory interneurons (INs) is a crucial element of neocortical information processing. Lateral inhibition is a fundamental principle in neuronal networks (Harris and Mrsic-Flogel, 2013; Karnani et al., 2014) first characterized 60 years ago (Hartline et al., 1956). In the rodent neocortex disynaptic lateral inhibition between nearby pyramidal cells (PCs) is thought to work through somatostatin-expressing INs (SOMs; Kapfer et al., 2007; Silberberg and Markram, 2007; Adesnik et al., 2012). SOMs constitute a major division of neocortical INs along with parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing INs. Members of the SOM, PV, and chandelier cell populationsmediate a broad blanket-like inhibition of most if not all PCs within their axonal arbors (Fino and Yuste, 2011; Packer and Yuste, 2011; Karnani et al., 2014; Inan et al., 2013).

This widespread inhibition, in principle, should suppress the propagation of excitatory activityin neocortex. In fact, because PV and SOM are activated specifically with fast and slow inputs, and relay fast and slow inhibition, it seems as if the interneuron population was selectively designed to block both fast and slow excitatory activity. How can cortical neurons become activated if they are under the control of theseinhibitory blankets? One solutionis by disinhibition, i.e., the selective removal of this blanket inhibition. Indeed, inhibitory connectivity among SOM, VIP, and PV populations has recently been shown to form specific disinhibitory motifs, most importantly through the inhibitory connection from VIPs to SOMs (Lee et al., 2013; Pfeffer et al., 2013; Pi et al., 2013; Fu et al., 2014; Zhang et al., 2014). However, little is known about the fine structure of PC disinhibition through the VIP¡SOM¡PC circuit, although recent evidence suggests a spatially restricted mode of action for this circuit that may be related to “the spotlight of attention” (Zhang et al., 2014). This facilitation of visual responses is enhanced during locomotion (Fu et al., 2014).

Reconstructions of VIPs show many double bouquet-like axons (Kawaguchi and Kubota, 1996; Bayraktar et al., 2000;Tahvildari et al., 2012;Lee et al., 2013), consistentwith horizontally local output. However, individual neuron activation experiments necessary to directly measure the spatial extent of disinhibition mediated by a VIP cell have not been performed. In this study, we show with intracellular recordings and optogenetics in neocortical layer 2/3 that VIP activation can override lateral disynaptic inhibition between PCs in slices. In vivo, pairwise correlations between layer 2/3 VIP and PC activity were more local than those among PCs and two-photon activation of single VIPs created disinhibitory “holes” of increased visual responses during stimulusevoked activity. Our data indicate that VIPs can make 240 m diameter holes in the blanket of inhibition mediated by SOMs (Fino and Yuste, 2011; Karnani et al., 2014).

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Opening Holes in the Blanket of Inhibition: Localized Lateral Disinhibition by VIP Interneurons

Mahesh M. Karnani, J et al, The Journal of Neuroscience, March 23, 2016 • 36(12):3471–3480 • 3471