Repetitive nociceptive stimulation increases spontaneous neural activation similar to nociception-induced activity in mouse insular cortex

Recent noninvasive neuroimaging technology has revealed that spatiotemporal patterns of cortical spontaneous activity observed in chronic pain patients are different from those in healthy subjects, suggesting that the spontaneous cortical activity plays a key role in the induction and/or maintenance of chronic pain. However, the mechanisms of the spontaneously emerging activities supposed to be induced by nociceptive inputs remain to be established. In the present study, we investigated spontaneous cortical activities in sessions before and after electrical stimulation of the periodontal ligament (PDL) by applying wide-field and two-photon calcium imaging to anesthetized GCaMP6s transgenic mice. First, we identified the sequential cortical activation patterns from the primary somatosensory and secondary somatosensory cortices to the insular cortex (IC) by PDL stimulation. We, then found that spontaneous IC activities that exhibited a similar spatiotemporal cortical pattern to evoked activities by PDL stimulation increased in the session after repetitive PDL stimulation. At the single-cell level, repetitive PDL stimulation augmented the synchronous neuronal activity. These results suggest that cortical plasticity induced by the repetitive stimulation leads to the frequent PDL stimulation-evoked-like spontaneous IC activation. This nociception-induced spontaneous activity in IC may be a part of mechanisms that induces chronic pain.