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 (RSG ^Glu-Cckbr ensemble) are critically implicated in the encoding and retrieval of opioid-associated memories, leading to relapse to opioid via innervating ZI GABAergic (ZI ^GABA ) rather than dopaminergic neurons. We further identify that the Cckergic neurons from anterodorsal nucleus of thalamus (AD thalamus) orchestrates RSG ^Glu-Cckbr -ZI ^GABA 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.