Kisspeptin signaling in the amygdala modulates reproductive hormone secretion

Abstract

Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a ‘master regulator’ of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.

Amygdala Kisspeptin Neurons: Putative Mediators of Olfactory Control of the Gonadotropic Axis

“…In addition to the neuroanatomical data presented here, recent functional studies have shown that kisspeptin signalling in the amygdala regulates gonadotropin secretion [44] . Together, these data provide evidence of a role for the amygdala kisspeptin neurons in the control of the gonadotropic axis, thus integrating limbic circuits and reproductive hormone secretion.…”

“…We demonstrate here that many kisspeptin neurons are located in the caudal areas of the MePD. The function of kisspeptin neurons in the amygdala is unknown, but the amygdala has been implicated in numerous physiological and behavioural processes, including those related to reward, social behaviours, and reproduction [13][14][15]44] .…”

Medial Amygdala <b><i>Kiss1</i></b> Neurons Mediate Female Pheromone Stimulation of Luteinizing Hormone in Male Mice

“…Therefore, future studies will be required to identify the exact cellular substrate in the POA responsive to modulation by MeA Kiss neurons. A decrease in neuronal activity in the POA in association with an increase in LH secretion has been previously reported in response to peripheral administration of kisspeptin [48]. It was proposed that kisspeptin suppresses GABA neurons in the POA to reduce inhibition of GnRH neurons, which leads to increased LH secretion.…”

Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing

“…Direct intra-amygdala injection of kisspeptin results in increased LH secretion, while conversely blocking endogenous amygdala kisspeptin signalling with a kisspeptin antagonist decreases both LH secretion and LH pulsatility [25], clearly demonstrating the influence of kisspeptin signalling outside the hypothalamus on the HPG axis.…”