Complex biological, technological, and sociological networks can be of very different sizes and connectivities, making it difficult to compare their structures. Here we present an approach to systematically study similarity in the local structure of networks, based on the significance profile (SP) of small subgraphs in the network compared to randomized networks. We find several superfamilies of previously unrelated networks with very similar SPs. One superfamily, including transcription networks of microorganisms, represents "rate-limited" information-processing networks strongly constrained by the response time of their components. A distinct superfamily includes protein signaling, developmental genetic networks, and neuronal wiring. Additional superfamilies include power grids, protein-structure networks and geometric networks, World Wide Web links and social networks, and word-adjacency networks from different languages.

The cortical microcircuit is built with recurrent excitatory connections, and it has long been suggested that the purpose of this design is to enable intrinsically driven reverberating activity. To understand the dynamics of neocortical intrinsic activity better, we performed two-photon calcium imaging of populations of neurons from the primary visual cortex of awake mice during visual stimulation and spontaneous activity. In both conditions, cortical activity is dominated by coactive groups of neurons, forming ensembles whose activation cannot be explained by the independent firing properties of their contributing neurons, considered in isolation. Moreover, individual neurons flexibly join multiple ensembles, vastly expanding the encoding potential of the circuit. Intriguingly, the same coactive ensembles can repeat spontaneously and in response to visual stimuli, indicating that stimulus-evoked responses arise from activating these intrinsic building blocks. Although the spatial properties of stimulus-driven and spontaneous ensembles are similar, spontaneous ensembles are active at random intervals, whereas visually evoked ensembles are time-locked to stimuli. We conclude that neuronal ensembles, built by the coactivation of flexible groups of neurons, are emergent functional units of cortical activity and propose that visual stimuli recruit intrinsically generated ensembles to represent visual attributes.

Summary Simultaneous co-activation of neocortical neurons is likely critical for brain computations ranging from perception and motor control to memory and cognition. While co-activation of excitatory principal cells (PCs) during ongoing activity has been extensively studied, that of inhibitory interneurons (INs) has received little attention. Here we show in vivo and in vitro that members of two non-overlapping neocortical IN populations, expressing somatostatin (SOM) or vasoactive intestinal peptide (VIP), are active as populations rather than individually. We demonstrate a variety of synergistic mechanisms, involving population-specific local excitation, GABAergic disinhibition and excitation through electrical coupling, which likely underlie IN population co-activity. Firing of a few SOM or VIP INs recruits additional members within the cell type via GABAergic and cholinergic mechanisms, thereby amplifying the output of the population as a whole. Our data suggest that IN populations work as cooperative units, thus generating an amplifying nonlinearity in their circuit output.

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".

Highlights d Side-by-side comparison of genetically encoded voltage indicators (GEVIs) d Side-by-side evaluation of 8 GEVIs in cultured neurons with 1-photon imaging d Side-by-side evaluation of 4 GEVIs in vivo with 1-photon and 2-photon imaging d Detection of optical field potential (OFP) with GEVIs in vivo