Transcriptional conservation and evolutionary divergence of cell types across mammalian hypothalamus development

The hypothalamus, an “ancient” subcortical brain structure, maintains physiological homeostasis and controls native behaviors. The evolution of homeostatic regulation and behavioral control in mammals may rely on adaptable neuronal identity establishment but conserved neural patterning mechanisms during neurodevelopment. Here, we combined single-cell, single-nucleus, and spatial transcriptomic datasets to map the spatial patterning of diverse progenitor domains and reconstruct their neurogenic lineages in the developing human and mouse hypothalamus. While the regional organizers orchestrating neural patterning are conserved between primates and rodents, we identified a human-enriched neuronal subtype and found a substantial increase in neuromodulatory gene expression among human neurons. Furthermore, cross-species comparison demonstrated a potential redistribution of two neuroendocrine neuronal subtypes and a shift in inter-transmitter and transmitter-peptide coupling within hypothalamic dopamine neurons. Together, our study lays a critical foundation for understanding cellular development and evolution of the mammalian hypothalamus.