Esr1+ hypothalamic-habenula neurons shape aversive states.

Calvigioni, D.; Fuzik, J.; Le Merre, P.; Slashcheva, M.; Jung, F.; Ortiz, C.; Lentini, A.; Csillag, V.; Graziano, M.; Nikolakopoulou, I.; Weglage, M.; Lazaridis, I.; Kim, H.; Lenzi, L.; Park, H.; Reinius, B.; Carlen, M.; Meletis, K.

doi:10.1101/2022.11.17.516965

bioRxiv · 10.1101/2022.11.17.516965

Esr1+ hypothalamic-habenula neurons shape aversive states.

Calvigioni, D.·Fuzik, J.·Le Merre, P.·Slashcheva, M.·Jung, F.·Ortiz, C.·Lentini, A.·Csillag, V.·Graziano, M.·Nikolakopoulou, I.·Weglage, M.·Lazaridis, I.·Kim, H.·Lenzi, L.·Park, H.·Reinius, B.·Carlen, M.·Meletis, K.

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Abstract

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.

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Calvigioni, D., Fuzik, J., Le Merre, P., Slashcheva, M., Jung, F., Ortiz, C., Lentini, A., Csillag, V., Graziano, M., Nikolakopoulou, I., Weglage, M., Lazaridis, I., Kim, H., Lenzi, L., Park, H., Reinius, B., Carlen, M., Meletis, K.. 2022-11-18. Esr1+ hypothalamic-habenula neurons shape aversive states.. https://doi.org/10.1101/2022.11.17.516965

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