Prefrontal engrams of long-term fear memory perpetuate pain perception

Abstract A painful episode can lead to life-long increase in an individual’s experience of pain; however, mechanisms for such long-lasting modulation are not well understood. Fearful anticipation of imminent pain has been suggested to play a role1, 2, but the neurobiological underpinnings are unclear, since fear can paradoxically both suppress and enhance pain2,3. Here, we show in mice that in contrast to acute or innate fear, chronic fear memory encoded and stored in neuronal engrams in the prefrontal cortex is both necessary and sufficient to define whether a painful episode profoundly shapes the experience of ongoing pain at a later point in life. Furthermore, in conditions of inflammatory and neuropathic pain, prefrontal engrams for fear memory expand to encompass neurons representing nociception and tactile sensation, leading to pronounced changes in prefrontal connectivity to key brain areas. In contrast, silencing prefrontal fear memory engrams reverses chronically established hyperalgesia and allodynia. These results reveal that a discrete subset of prefrontal cortical neurons can account for the debilitating comorbidity of long-term fear and chronic pain and show that attenuating the fear memory of pain can alleviate chronic pain itself.