Innervation of Gonadotropin-Releasing Hormone Neurons by Peptidergic Neurons Conveying Circadian or Energy Balance Information in the Mouse

BACKGROUND: Secretion of gonadotropin-releasing hormone (GnRH) produced in neurons in the basal forebrain is the primary regulator of reproductive maturation and function in mammals. Peptidergic signals relating to circadian timing and energy balance are an important influence on the reproductive axis. The aim of this study was to investigate the innervation of GnRH neurons by peptidergic neurons. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry and confocal microscopy were used to detect appositions of peptidergic fibers (NPY, β-endorphin, MCH) associated with energy balance and metabolic status in transgenic mice expressing a green fluorescent protein reporter construct in GnRH neurons. The frequency of these appositions was compared to those of vasoactive intestinal peptide (VIP), a hypothalamic neuropeptide likely to convey circadian timing information to the GnRH secretory system. The majority of GnRH neurons (73–87%) were closely apposed by fibers expressing NPY, β-endorphin, or MCH, and a significant proportion of GnRH neurons (28%) also had close contacts with VIP-ir fibers. CONCLUSIONS/SIGNIFICANCE: It is concluded that GnRH neurons in the mouse receive a high frequency of direct modulatory inputs from multiple hypothalamic peptide systems known to be important in conveying circadian information and signalling energy balance.