A non-canonical top-down pathway regulating relapse to opioid

The high relapse rates are major challenges in treating opioid addiction. However, it remains poorly understood the mechanisms underlying long-lasting vulnerability to relapse. Here, we identify the cortico-subthalamic projection from the granular retrosplenial cortex (RSG) to the zona incerta (ZI) as a key circuit for controlling relapse to opioid. We uncover that an ensemble of RSG glutamatergic neurons that locate in layer 5 and express B subtype cholecystokinin receptor (RSGGlu-Cckbr ensemble) are critically implicated in the encoding and retrieval of opioid-associated memories, leading to relapse to opioid via innervating ZI GABAergic (ZIGABA) rather than dopaminergic neurons. We further identify that the Cckergic neurons from anterodorsal nucleus of thalamus (AD thalamus) orchestrates RSGGlu-Cckbr-ZIGABA circuit function via release of cholecystokinin (Cck) in RSG. These results elucidate a previously unknown non-canonical top-down pathway regulating relapse to opioid and shed new light on the development of new therapeutic strategies to treat relapse to opioids.