TY - JOUR T1 - Assessing the role of inhibition in stabilizing neocortical networks requires large-scale perturbation of the inhibitory population JF - bioRxiv DO - 10.1101/123950 SP - 123950 AU - Sadra Sadeh AU - R. Angus Silver AU - Thomas Mrsic-Flogel AU - Dylan Richard Muir Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/12/123950.abstract N2 - Neurons within cortical microcircuits are interconnected with recurrent excitatory synaptic connections that are thought to amplify signals (Douglas and Martin, 2007), form selective subnetworks (Ko et al., 2011) and aid feature discrimination. Strong inhibition (Haider et al., 2013) counterbalances excitation, enabling sensory features to be sharpened and represented by sparse codes (Willmore et al., 2011). This “balance” between excitation and inhibition makes it difficult to assess the strength, or gain, of recurrent excitatory connections within cortical networks, which is key to understanding their operational regime and the computations they perform. Networks of neurons combining an unstable high-gain excitatory population with stabilizing inhibitory feedback are known as inhibition-stabilized networks (ISNs; Tsodyks et al. 1997). Theoretical studies using reduced network models predict that ISNs produce paradoxical responses to perturbation, but experimental perturbations failed to find evidence for ISNs in cortex (Atallah et al., 2012). We re-examined this question by investigating how cortical network models consisting of many neurons behave following perturbations, and found that results obtained from reduced network models fail to predict responses to perturbations in more realistic networks. Our models predict that a large proportion of the inhibitory network must be perturbed in order to robustly detect an ISN regime in cortex. We propose that wide-field optogenetic suppression of inhibition under a promoter targeting all inhibitory neurons may provide a perturbation of sufficient strength to reveal the operating regime of cortex. Our results suggest that detailed computational models of optogenetic perturbations are necessary to interpret the results of experimental paradigms.Significance statement Many useful computational mechanisms proposed for cortex require local excitatory recurrence to be very strong, such that local inhibitory feedback is necessary to avoid epileptiform runaway activity (an “inhibition-stabilized network” or “ISN” regime). However, recent experimental results suggest this regime may not exist in cortex. We simulated activity perturbations in cortical networks of increasing realism, and found that in order to detect ISN-like properties in cortex, large proportions of the inhibitory population must be perturbed. Current experimental methods for inhibitory perturbation are unlikely to satisfy this requirement, implying that existing experimental observations are inconclusive about the computational regime of cortex. Our results suggest that new experimental designs, targetting a majority of inhibitory neurons, may be able to resolve this question. ER -