Spatially resolved molecular sex differences at single-cell resolution in the adult human ventromedial and arcuate hypothalamus

Le résumé fourni par la source

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.

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