Specialized Subpopulations of Kisspeptin Neurons Communicate With GnRH Neurons in Female Mice

Abstract

The neuropeptide kisspeptin is a potent stimulator of GnRH neurons and has been implicated as a major regulator of the hypothalamus-pituitary-gonadal axis. There are mainly two anatomically segregated populations of neurons that express kisspeptin in the female hypothalamus: one in the anteroventral periventricular nucleus (AVPV) and the other in the arcuate nucleus (ARC). Distinct roles have been proposed for AVPV and ARC kisspeptin neurons during reproductive maturation and in mediating estrogen feedback on the hypothalamus-pituitary-gonadal axis in adults. Despite their pivotal role in the regulation of reproductive physiology, little is known about kisspeptin neuron connectivity. Although previous data suggest heterogeneity within the AVPV and ARC kisspeptin neuron populations, how many and which of these potential kisspeptin neuron subpopulations are actually communicating with GnRH neurons is not known. Here we used a combinatorial genetic transsynaptic tracing strategy to start to analyze the connectivity of individual kisspeptin neurons with the GnRH neuron population in female mice with a single-cell resolution. We find that only subsets of AVPV and ARC kisspeptin neurons are synaptically connected with GnRH neurons. We demonstrate that the majority of kisspeptin neurons within the AVPV and ARC does not communicate with GnRH neurons. Furthermore, we show that all kisspeptin neurons within the AVPV connected to GnRH neurons are estrogen sensitive and that most of these express tyrosine hydroxylase. Our data demonstrate functional specialization within the two kisspeptin neuron populations.

Absence of Female-Typical Pheromone-Induced Hypothalamic Neural Responses and Kisspeptin Neuronal Activity in α-Fetoprotein Knockout Female Mice

“…Post hoc analysis revealed that exposure to male and female bedding induced a significant Fos expression in the GrA and the MiA compared with clean bedding (all P Ͻ .05) and exposure to female bedding induced a higher Fos expression compared with male bedding (P Ͻ .01). By contrast, in the MOB, twoway ANOVAs revealed a significant genotype by bedding interaction in the GrA part of the MOB, ventral part (vGrA) (F (2,46) ϭ 5.10, P Ͻ .05) and GrA layer of the MOB, dorsal part (dGrA) (F (2,45) ϭ 7.20, P Ͻ .01). Post hoc analysis showed that male odors induced significantly higher Fos-ir cells in the vGrA and dGrA of WT males compared with the other groups (all P Ͻ .05).…”

“…43). Recent studies have indicated that a subpopulation of kisspeptin neurons in the female mouse AVPV/PeN coexpresses TH (ϳ50%) (44,45) and more importantly, it has been shown that approximately 75% of kisspeptin neurons within the AVPV that project to GnRH neurons express TH (45). Others have shown in the rat that Fos-ir is augmented in TH neurons at the time of the preovulatory LH surge in the A2 cell group (46,47).…”

Effects of Selective Deletion of Tyrosine Hydroxylase from Kisspeptin Cells on Puberty and Reproduction in Male and Female Mice

“…TH is the rate-limiting enzyme in catecholamine synthesis, and AVPV/PeN TH neurons are known to be dopaminergic (Simerly et al, 1985; Scott et al, 2015). These dopaminergic AVPV neurons have both direct and indirect projections to GnRH neurons, indicating AVPV-derived dopamine may influence reproduction (Clarkson and Herbison, 2011; Kumar et al, 2015). However, there is conflicting evidence as to whether dopamine stimulates or inhibits GnRH release.…”

“…However, the function of dopamine produced in AVPV/PeN Kiss1 neurons is currently unknown. As much as 75% of AVPV/PeN kisspeptin neurons that coexpress TH send fiber projections that appose GnRH neurons (Clarkson and Herbison, 2011; Kumar et al, 2015), which suggests that dopamine signaling arising from AVPV/PeN kisspeptin neurons may directly modulate GnRH secretion, and hence, the neuroendocrine reproductive axis. The current study was designed to assess the effects of selectively deleting TH specifically from Kiss1 cells on puberty onset, hormone levels, and reproduction.…”

Impact of Proestrus on Gene Expression in the Medial Preoptic Area of Mice

“…The chemical phenotyping of the area revealed the production of a wide scale of neuropeptides and the synthesis of certain neurotransmitters. Subsets of neurons produce kisspeptin (KP; Smith et al, 2005; Clarkson and Herbison, 2006; Ducret et al, 2010; Overgaard et al, 2013; Kumar et al, 2015; Skrapits et al, 2015; Yip et al, 2015; Yeo et al, 2016), galanin (GAL; Porteous et al, 2011; Wu et al, 2014), cholecystokinin (CCK; Simerly and Swanson, 1987), substance-P (SP; Simerly and Swanson, 1987; Okamura et al, 1994), met-enkephalin (ENK; Simerly and Swanson, 1987; Porteous et al, 2011) and neurotensin (NT; Simerly and Swanson, 1987; Dungan Lemko et al, 2010) representing the peptidergic profile. Synthesis of gamma-aminobutyric acid (GABA; Cravo et al, 2011; Liu and Herbison, 2011; Liu et al, 2011; Cheong et al, 2015), glutamate (Cravo et al, 2011; Liu et al, 2011; Cheong et al, 2015) and dopamine (DA; Simerly and Swanson, 1987; Simerly et al, 1997; Clarkson and Herbison, 2011) in the area proves its capability of networking via neurotransmitter signaling.…”