Single-Cell Profiling Uncovers Evolutionary Divergence of Hypocretin/Orexin Neuronal Subpopulations

Dana Sagi, Muhammad Tibi, Inbal Admati, Tali Lerer-Goldshtein, Hannah Hochgerner, Amit Zeisel, Lior Appelbaum

Research output: Contribution to journalArticlepeer-review

Abstract

Brain nuclei are traditionally defined by their anatomy, activity, and expression of specific markers. The hypothalamus contains discrete neuronal populations that coordinate fundamental behavioral functions, including sleep and wakefulness, in all vertebrates. Particularly, the diverse roles of hypocretin/orexin (Hcrt)-releasing neurons suggest functional heterogeneity among Hcrt neurons. Using single-cell RNA sequencing (scRNA-seq) and high-resolution imaging of the adult male and female zebrafish hypothalamic periventricular zone, we identified 21 glutamatergic and 28 GABAergic cell types. Integration of zebrafish and mouse scRNA-seq revealed evolutionary conserved and divergent hypothalamic cell types. The expression of specific genes, including npvf, which encodes a sleep-regulating neuropeptide, was enriched in subsets of glutamatergic Hcrt neurons in both larval and adult zebrafish. The genetic profile, activity, and neurite processing of the neuronal subpopulation that coexpresses both Hcrt and Npvf (Hcrt+Npvf+) differ from other Hcrt neurons. These interspecies findings provide a unified annotation of hypothalamic cell types and suggest that the heterogeneity of Hcrt neurons enables multifunctionality, such as consolidation of both wake and sleep by the Hcrt- and Npvf-releasing neuronal subpopulation.

Original languageEnglish
Article numbere0095242024
JournalJournal of Neuroscience
Volume44
Issue number36
DOIs
StatePublished - 4 Sep 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 the authors.

Keywords

  • cross-species integration
  • hypocretin
  • hypothalamus
  • single-cell transcriptomics
  • sleep
  • zebrafish

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