ReviewAnatomy of the kisspeptin neural network in mammals
Introduction
Kisspeptin is one of a family of RFamide-related peptides (RFRP) that is now recognized as an essential endogenous regulator of the GnRH neuroendocrine system (Oakley et al., 2009a). Kisspeptin and its related peptides are ligands for the orphan G protein-coupled receptor 54 (GPR54, now called Kiss1 receptor), mutations of which produce hypogonadotropic hypogonadism and a failure to enter puberty in humans (de Roux et al., 2003, Seminara et al., 2003) and mice (Seminara et al., 2003). Kisspeptin was subsequently shown to be an extraordinarily potent stimulator of GnRH/LH secretion in a variety of species (Irwig et al., 2004, Jayasena et al., 2009, Messager et al., 2005, Shahab et al., 2005), and because of the presence of Kiss1 receptors in GnRH neurons (Han et al., 2005, Irwig et al., 2004) and the ability of GnRH antagonists to block the effects of kisspeptin (Shahab et al., 2005), early work quickly suggested that this influence was conveyed directly upon the GnRH neuroendocrine system.
Because of its key role in reproduction, there has been avid interest in identifying the location of kisspeptin neurons, and characterizing the neural circuitry by which kisspeptin acts to stimulate GnRH release and regulate reproductive neuroendocrine function (Oakley et al., 2009a). An understanding of the functional role of kisspeptin signaling in the brain depends on the anatomical framework within which kisspeptin acts, i.e., knowing the location of neuronal cell bodies that synthesize the peptide, and their afferent/efferent connections. The primary aim of this review is to update our current understanding of the anatomical organization of the kisspeptin network; in this context, we would note that there has been one previous, excellent review of the neuroanatomy of the kisspeptin system (Mikkelsen and Simonneaux, 2009). However, in light of the recent addition of information from a wider variety of mammalian species, we viewed it as timely and worthwhile to re-evaluate the range of data reported to see where consistent patterns might emerge concerning the organization of the kisspeptin neural network. In addition, we review anatomical evidence of steroid receptor colocalization in kisspeptin neurons, findings supporting the existence of direct connections between kisspeptin and GnRH neurons, and recent evidence of phenotypic heterogeneity among subsets of kisspeptin cells which may contribute to their physiological functions. Finally, we end with a consideration of current gaps in this knowledge and some suggestions of future studies to fill those gaps.
Section snippets
Distribution of kisspeptin cells and fibers in the mammalian brain
The location of kisspeptin cell bodies in the mammalian brain has been examined by two primary techniques: in situ hybridization (ISH) to detect cells expressing Kiss1 mRNA transcripts, and immunocytochemistry (ICC), using either fluorescent or histochemical detection methods, to visualize kisspeptin peptide (Table 1). Initially, the use of ICC to detect kisspeptin-positive cell populations and fibers was confounded by the use of antibodies that cross-reacted with other members of the RFRP
Steroid receptor colocalization in kisspeptin neurons
A substantial body of work has implicated kisspeptin neurons as primary mediators of gonadal steroid feedback control of GnRH release in mammals (Lehman et al., 2010, Roseweir and Millar, 2009, Smith, 2008). One of the major pieces of evidence for this role is the high degree of colocalization of kisspeptin cells with gonadal steroid receptors, specifically those for estradiol, progesterone and testosterone (Table 3). In general, studies using multiple-label ISH or ICC to evaluate
Anatomical sites of interaction between kisspeptin and GnRH neurons
Given the expression of the Kiss1 receptor (Kiss1R) within GnRH neurons (Han et al., 2005, Herbison et al., 2010, Irwig et al., 2004), as well as the demonstration of direct stimulatory effects of kisspeptin upon GnRH cell electrophysiology (Han et al., 2005, Pielecka-Fortuna et al., 2008, Roseweir et al., 2009), it has been presumed that kisspeptin neurons must synapse directly upon GnRH neurons. Nonetheless, while a number of studies have shown contacts between kisspeptin fibers and GnRH
Heterogeneity among kisspeptin cell populations
Recent evidence suggests that not all kisspeptin neurons are the same phenotypically, and, that some of these anatomical differences may underlie functional differences in the role of specific kisspeptin population in positive and negative steroid feedback controls of GnRH secretion (Dungan et al., 2006, Kauffman et al., 2007a). In particular, there is consistent evidence in the mouse, rat, sheep, goat, and human that kisspeptin cells in the ARC, but not in the POA/AVPV, colocalize two other
Summary and future directions
Key features of the kisspeptin neural network and its interactions with GnRH neurons, based on our current knowledge, are summarized in Fig. 2. Kisspeptin cell are found consistently in two major cell populations, one located in the ARC and the other in preoptic region, in either the AVPV or POA. While the ARC population is highly conserved among species, there is variation in the location and phenotype of preoptic kisspeptin neurons. In rodents, kisspeptin cells comprise a component of the
Acknowledgments
This work was supported by NIHR01 HD39916 (M.N.L. and R.L.G.) and Canadian Institutes of Health Research Operating Grant86744 (M.N.L.).
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These authors contributed equally to this work.