Klucznik, J. | Search bioRxiv

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↗

bioRxiv2024

Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation of Necdin and Magel2

Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 "PWS" genes and generated a novel mouse model (named "Madin") with a deletion including both genes. A subset of Madin KO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Madin KO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. Adult Madin KO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Madin KO mouse is a reliable and more genetically relevant model for the study of PWS.

systems biology↗