Voltage-sensitive dye imaging reveals inhibitory modulation of ongoing cortical activity

Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. In particular, it is unclear how VSDI signals relate to population firing rates. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5. We proceed by exploring experimentally inaccessible circuit properties to show that during periods of spontaneous activity, membrane potential fluctuations are anticorrelated with population firing rates. Furthermore, we manipulate network connections to show that this effect depends on recurrent connectivity and is modulated by external input. We conclude that VSDI primarily reflects inhibitory responses to ongoing excitatory dynamics.