Brainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice

Brainstem noradrenaline (NA) neurons modulate the activity of many neural networks including those responsible for the control of fertility. Using brain slice electrophysiology, we demonstrate that the arcuate nucleus kisspeptin (ARN^KISS) neurons, recently identified to be the gonadotropin-releasing hormone (GnRH) pulse generator, are directly hyperpolarized by NA through both alpha 2- and beta-adrenergic receptors. Retrograde viral tracing shows that NA innervation of the ARN is primarily from the dorsal subdivision of the locus coeruleus (LC)-NA cell group and is substantially greater in females compared to males. Using an intersectional genetic approach allowing selective chemogenetic manipulation of NA neurons innervating the ARN alongside photometry recording of ARN^KISS neuron synchronization behavior, we find that the activation of NA inputs strongly suppresses GnRH pulse generator activity in a sexually differentiated and gonadal steroid-dependent manner. Together these studies demonstrate a direct mechanism through which heightened activity in brainstem NA neurons can pause pulsatile reproductive hormone secretion.