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

Abstract 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.