Cell Rep. 2026 Jan 28;45(2):116877. doi: 10.1016/j.celrep.2025.116877. Online ahead of print.
ABSTRACT
The hypothalamus contains multiple regions, including the ventromedial hypothalamus (VMH) and arcuate (ARC), which are responsible for sex-differentiated functions such as endocrine signaling, metabolism, and reproductive behaviors. While molecular, anatomic, and sex-differentiated features of the rodent hypothalamus are well established, much less is known about these regions in humans. Here, we provide a spatially resolved single-cell atlas of sex-differentially expressed (sex-DE) genes in the human ARC and VMH. We identify neuronal populations governing hypothalamus-specific functions, define their spatial distributions, and show enrichment of sex-DE in retinoid metabolism- and retinoid receptor-regulated genes. Within the ARC and VMH, we find correlated autosomal expression differences localized to ESR1/TAC3-expressing and corticotropin-releasing hormone receptor 2 (CRHR2)-expressing neurons and extensive sex-DE genes linked to sex-biased disorders, including autism, depression, and schizophrenia. Our molecular mapping of disease associations to hypothalamic cell types with established roles in sex-divergent physiology and behavior provides insights into the mechanistic bases of sex bias in neurodevelopmental and neuropsychiatric disorders.
PMID:41615800 | DOI:10.1016/j.celrep.2025.116877
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