Brain-wide mapping of efferent projections of glutamatergic (Onecut3+) neurons in the lateral mouse hypothalamus

Zupančič, Maja and Tretiakov, Evgenii and Máté, Zoltán and Erdélyi, Ferenc and Szabó, Gábor and Clotman, Frédéric and Hökfelt, Tomas and Harkany, Tibor and Keimpema, Erik (2023) Brain-wide mapping of efferent projections of glutamatergic (Onecut3+) neurons in the lateral mouse hypothalamus. ACTA PHYSIOLOGICA. ISSN 1748-1708

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Abstract

Aim: This study mapped the spatiotemporal positions and connectivity of Onecut3+ neuronal populations in the developing and adult mouse brain. Methods: We generated fluorescent reporter mice to chart Onecut3+ neurons for brain- wide analysis. Moreover, we crossed Onecut3- iCre and Mapt- mGFP (Tau- mGFP) mice to visualize axonal projections. A dual Cre/Flp- dependent AAV construct in Onecut3- iCre cross- bred with Slc17a6-FLPo mice was used in an intersectional strategy to map the connectivity of glutamatergic lateral hypo- thalamic neurons in the adult mouse. Results: We first found that Onecut3 marks a hitherto undescribed Slc17a6+/Vglut2+ neuronal cohort in the lateral hypothalamus, with the majority expressing thyrotropin-releasing hormone. In the adult, Onecut3+/Vglut2+ neu- rons of the lateral hypothalamus had both intra- and extrahypothalamic effer- ents, particularly to the septal complex and habenula, where they targeted other cohorts of Onecut3+ neurons and additionally to the neocortex and hippocam- pus. This arrangement suggests that intrinsic reinforcement loops could exist for Onecut3+ neurons to coordinate their activity along the brain's midline axis. Conclusion: We present both a toolbox to manipulate novel subtypes of hypo- thalamic neurons and an anatomical arrangement by which extrahypothalamic targets can be simultaneously entrained.

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