Supraspinal facilitation of nociception by glutamatergic innervation from the retrosplenial cortex to anterior cingulate cortex

Abstract Anterior cingulate cortex (ACC) is critical for pain perception; while the retrosplenial cortex (RSC) plays an important role in navigation and memory. It is known that RSC projects to ACC, less is known about the function of this projection. Here we used integrative approaches to show that there is direct excitatory glutamatergic projections from the RSC to the ACC, and postsynaptic excitatory responses are mediated by AMPA receptors. Activation of RSC-ACC by optogenetics significantly facilitated behavioral responses to nociceptive stimuli (mechanical and thermal) in freely moving mice. By contrast, spinal nociceptive tail-flick and anxiety-like activities were not affected. Our results suggest that RSC to ACC projection preferentially affects nociceptive process in supraspinal cortical region. Our results have identified a new facilitatory cortico-cortical circuit for sensory nociceptive process, and this pathway serves to link memory ‘engram’ to pain perception in humans and animals.