Boldizsár Zsolt Balog, Albert M Barth, Krisztián Zichó, Abel Major, Zsuzsanna Bardóczi, János Brunner, Charlotte Seng, Márta Jelitai, Katalin E Sos, Réka Z Sebestény, András Szőnyi, Nikolas Karalis, Áron Orosz, Eszter Sipos, Erik Misák, György Cserey, Andreas Lüthi, Viktor Varga, Csaba Földy, János Szabadics, Gábor Nyiri
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 (MRRvGluT2 neurons) in mice. We found that MRRvGluT2 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, MRRvGluT2 neurons activate the lateral habenula (LHb), a region implicated in major depression. MRRvGluT2 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.