Ciofi, P. | bioRxiv Science

bioRxiv2026

An Ultra-High-Resolution 17.2 T MRI Atlas (HypoAtlas) and Multimodal Pipeline to Study the Mouse Hypothalamus: Sexual Dimorphism and Lateralization Insights

Structural and functional insights into the mouse hypothalamus are hampered by its small size and deep location. Here, we leverage ultra-high-field magnetic resonance imaging (UHF-MRI) at 17.2 Tesla to achieve unprecedented spatial resolution in structural, functional and neurochemical imaging of the mouse hypothalamus, including sexual dimorphism in certain nuclei. High-resolution ex vivo anatomical MRI enabled precise hypothalamic parcellation, improving on existing atlases and revealing nuclei previously unresolved by MRI. Diffusion MRI and tractography mapped intra- and extra-hypothalamic pathways, facilitating circuit-level exploration without a priori assumptions. Resting-state fMRI combined with independent component analysis identified novel hypothalamic networks, demonstrating the enhanced capacity of UHF MRI to detect deep-brain activity. {superscript 1}H-magnetic resonance spectroscopy quantified neurochemical profiles, revealing sexually dimorphic heterogeneity within the hypothalamus. Our comprehensive multimodal approach uncovers sex differences in hypothalamic anatomy, microstructure, and neurochemistry, emphasizing the importance of sex as a biological variable. This integrated pipeline offers a valuable resource for dissecting hypothalamic circuits and functions, advancing our understanding of neuroendocrine regulation, behavior, and disease mechanisms, with direct translational relevance.

neuroscience↗

bioRxiv2025

Vesicle-mediated oxytocin release drives melanocortin circuit maturation during a neonatal critical period

The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.

neuroscience↗