Nerve injury induces long-term changes in neuronal activity in the primary somatosensory cortex (S1), which has often been implicated as the origin of sensory dysfunction. However, the cellular mechanisms underlying this phenomenon remain unclear. C-fos is an immediate early gene, which has been shown to play an instrumental role in plasticity. By developing a new platform to image real-time changes in gene expression in vivo, we investigated whether injury modulates the levels of c-fos in layer V of S1, since previous studies have suggested that these neurons are particularly susceptible to injury. The yellow fluorescent protein, ZsYellow1, under the regulation of the c-fos promoter, was expressed throughout the rat brain. A fiber-based confocal microscope that enabled deep brain imaging was utilized, and local field potentials were collected simultaneously. In the weeks following limb denervation in adult rats (n=10), sensory stimulation of the intact limb induced significant increases in c-fos gene expression in cells located in S1, both contralateral (affected, 27.6±3 cells) and ipsilateral (8.6±3 cells) to the injury, compared to controls (n=10, 13.4±3 and 1.0±1, respectively, p value<0.05). Thus, we demonstrated that injury activates cellular mechanisms that are involved in reshaping neuronal connections, and this may translate to neurorehabilitative potential.