Optogenetic stimulation of kisspeptin neurones within the posterodorsal medial amygdala increases luteinising hormone pulse frequency in female mice

Abstract

Kisspeptin within the arcuate nucleus of the hypothalamus is a critical neuropeptide in the regulation of reproduction. Together with neurokinin B and dynorphin A, arcuate kisspeptin provides the oscillatory activity that drives the pulsatile secretion of gonadotrophin‐releasing hormone (GnRH), and therefore luteinising hormone (LH) pulses, and is considered to be a central component of the GnRH pulse generator. It is well established that the amygdala also exerts an influence over gonadotrophic hormone secretion and reproductive physiology. The discovery of kisspeptin and its receptor within the posterodorsal medial amygdala (MePD) and our recent finding showing that intra‐MePD administration of kisspeptin or a kisspeptin receptor antagonist results in increased LH secretion and decreased LH pulse frequency, respectively, suggests an important role for amygdala kisspeptin signalling in the regulation of the GnRH pulse generator. To further investigate the function of amygdala kisspeptin, the present study used an optogenetic approach to selectively stimulate MePD kisspeptin neurones and examine the effect on pulsatile LH secretion. MePD kisspeptin neurones in conscious Kiss1‐Cre mice were virally infected to express the channelrhodopsin 2 protein and selectively stimulated by light via a chronically implanted fibre optic cannula. Continuous stimulation using 5 Hz resulted in an increased LH pulse frequency, which was not observed at the lower stimulation frequencies of 0.5 and 2 Hz. In wild‐type animals, continuous stimulation at 5 Hz did not affect LH pulse frequency. These results demonstrate that selective activation of MePD Kiss1 neurones can modulate hypothalamic GnRH pulse generator frequency.

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

“…Moreover, stress decreases inhibitory GABAergic control within the amygdala leading to enhanced inhibitory efferent output from the amygdala (42,43). Kisspeptin signalling in the MePD regulates GnRH pulse generator frequency (44) and recently we have shown selective optogenetic stimulation of MePD kiss1 neurons increases LH pulse frequency (19). Direct neural projections, of unknown phenotype, extend from the MePD to kiss1 neurons in the ARC (17,18).…”

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is modulation of the reproductive axis by the MePD may involve a disinhibitory system whereby kiss1 neuron activity in the MePD stimulates inhibitory GABAergic interneurons which in turn inhibit GABAergic efferents from the MePD to the ARC, thus allowing for the observed increase in GnRH pulse generator frequency in response to activation of MePD kiss1 neurons (19). Conversly, reduced kisspeptin signalling in the MePD, as with kisspeptin antagonism, decreases GnRH pulse generator frequency (44).…”

“…This amygdaloid nucleus is also known to project to the KNDy neural population in the ARC (17,18). Extrahypothalamic kiss1 neuronal populations exist in the MePD and we have recently shown that optogenetic stimulation of these neurons increases LH pulse frequency in mice (19).…”

Novel insights into the metabolic action of Kiss1 neurons

“…Moreover, Kiss1 ARC neurons are predominantly glutamatergic (9,10) and have the potential to release the fast-acting transmitter glutamate onto (1) neighboring neurons in the ARC to potentially regulate metabolism (discussed in later sections), and (2) Kiss1 AVPV/PeN neurons to regulate fertility (10,11). An additional population of Kiss1 neurons has been recently identified in the posterodorsal part of the medial amygdala (Kiss1 MePD (12)), and a number of chemogenetic (13) and optogenetic (14) studies by our lab and others suggest an important role of Kiss1 MePD signaling in the regulation of the GnRH pulse generator, besides a potential role in driving emotional and sexual behavior, pubertal timing and ovulation -at least in mice (15,16).…”

Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice

“…This amygdaloid nucleus is also known to project to the KNDy neural population in the ARC ( 17 , 18 ). Extrahypothalamic kiss1 neuronal populations exist in the MePD, and we have recently shown that optogenetic stimulation of these neurons increases LH pulse frequency in mice ( 19 ).…”