TY - JOUR T1 - Esr1+ hypothalamic-habenula neurons shape aversive states JF - bioRxiv DO - 10.1101/2022.11.17.516965 SP - 2022.11.17.516965 AU - Daniela Calvigioni AU - Janos Fuzik AU - Pierre Le Merre AU - Marina Slashcheva AU - Felix Jung AU - Cantin Ortiz AU - Antonio Lentini AU - Veronika Csillag AU - Marta Graziano AU - Ifigeneia Nikolakopoulou AU - Moritz Weglage AU - Iakovos Lazaridis AU - Hoseok Kim AU - Irene Lenzi AU - Hyunsoo Park AU - Björn Reinius AU - Marie Carlén AU - Konstantinos Meletis Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/11/18/2022.11.17.516965.abstract N2 - Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.Competing Interest StatementThe authors have declared no competing interest. ER -