NGF administration is associated with increased GnRH immunoreactivity and a GnRH-associated phenotype in hypothalamic...

Age-related decline in testosterone is closely associated with hypothalamic gonadotropin-releasing hormone (GnRH) neuron dysfunction. Nerve growth factor (NGF) has emerging roles in reproductive system. However, its effect on the differentiation of hypothalamic neural stem cells (htNSCs) into GnRH-associated phenotype remains unexplored.

Male senescence-accelerated mouse P8 (SAMP8) models of age-related hypogonadism received a single intracerebroventricular injection of NGF at 6.25, 12.5, and 25 μg/kg. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone were measured 8 h, 24 h, 96 h, 7 d and 10 d post-injection. A kisspeptin agonist and antagonist were used in combination to interrogate whether NGF's endocrine effects depend on canonical kisspeptin signaling. In vivo GnRH immunoreactivity and Sox2/GnRH co-localization in the organum vasculosum of the lamina terminalis (OVLT) were evaluated by double immunofluorescence as phenotypic readouts. In parallel, a three-dimensional culture system was employed to evaluate NGF-induced differentiation of primary htNSCs into GnRH-secreting neurons. Transcriptomic profiling and quantitative PCR were used to identify key signaling pathways involved.

Central NGF administration significantly elevated serum FSH, LH, and testosterone levels in male SAMP8 mice, and these effects were not evidently mediated by canonical kisspeptin signaling. In the OVLT, NGF was associated with increased GnRH immunoreactivity and Sox2/GnRH co-localization, which may reflect phenotypic remodeling toward a GnRH-related cellular state. In vitro, NGF promoted htNSCs differentiation toward a GnRH-associated neuroendocrine phenotype, accompanied by increased Gnrh1 expression/GnRH release and enrichment of neuropeptide-related signaling pathways.

These findings suggest that central NGF administration may be associated with an increase in GnRH-immunoreactive cellular phenotypes, accompanied by enhanced the hypothalamic-pituitary-testicular axis endocrine output in male SAMP8 mice. Definitive in vivo neurogenesis will require future validation using proliferation and lineage-tracing approaches.