Prefrontal-raphe-habenular circuit drives fear memory recall and updating

Fear memory recall is a vital defensive response, yet its underlying neuronal mechanism remains incompletely understood. Here, we identify an effective fear recall pathway. We found that hippocampal and amygdalar memory centers directly target a group of medial prefrontal cortex (mPFC) neurons, which are necessary for fear recall and directly target vesicular glutamate transporter 2 (vGluT2)-expressing neurons in the pontine median raphe region (MRR^vGluT2 neurons) in mice. We found that MRR^vGluT2 neurons are necessary for recalling contextual and cued fear memories, they exhibit scalable fear-dependent activity, bidirectionally regulate depression-like behaviors, and show prolonged activity after a fearful experience. During fear memory recall, MRR^vGluT2 neurons activate the lateral habenula (LHb), a region implicated in major depression. MRR^vGluT2 neurons are electrophysiologically and genetically diverse, and present in rodent and primate species. The identified mPFC-MRR-LHb pathway critically mediates fear memory recall, providing potential therapeutic targets for fear-related disorders.