Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice. [Display omitted] •A new mouse model is established to study long-term observational pain•ICR-BLAR pathway is required for the formation/consolidation of observational pain•Glutamate encodes the synaptic transmission from the ICR to BLAR•Synaptotagmin-2 and RIM3 are key signals for the regulation of observational pain Zhang et al. show that sibling but not stranger observer mice exhibit observational pain, which requires glutamate transmission from the insular cortex to the basolateral amygdala and is regulated by synaptotagmin-2 and RIM3.