Elsevier

Brain Research

Volume 1364, 10 December 2010, Pages 90-102
Brain Research

Review
Anatomy of the kisspeptin neural network in mammals

https://doi.org/10.1016/j.brainres.2010.09.020Get rights and content

Abstract

Kisspeptin has been recognized as a key regulator of GnRH secretion during puberty and adulthood, conveying the feedback influence of endogenous gonadal steroids onto the GnRH system. Understanding the functional roles of this peptide depends on knowledge of the anatomical framework in which it acts, including the location of kisspeptin-expressing cells in the brain and their connections. In this paper, we review current data on the anatomy of the kisspeptin neuronal network, including its colocalization with gonadal steroid hormone receptors, anatomical sites of interaction with the GnRH system, and recent evidence of neurochemical heterogeneity among different kisspeptin neuronal populations. Evidence to date suggests that kisspeptin cells in mammals comprise an interconnected network, with reciprocal connections both within and between separate cell populations, and with GnRH neurons. At the same time, there is more functional and anatomical heterogeneity in this system than originally thought, and many unanswered questions remain concerning anatomical relationships of kisspeptin neurons with other neuroendocrine and neural systems in the brain.

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.).

References (93)

  • S.J. Krajewski et al.

    Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat

    Neuroscience

    (2010)
  • M.N. Lehman et al.

    CSF signaling in physiology and behavior

  • A.O. Mason et al.

    Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters

    Hormones and Behavior

    (2007)
  • J.D. Mikkelsen et al.

    The neuroanatomy of the kisspeptin system in the mammalian brain

    Peptides

    (2009)
  • S. Pompolo et al.

    Evidence that projections from the bed nucleus of the stria terminalis and from the lateral and medial regions of the preoptic area provide input to gonadotropin releasing hormone (GNRH) neurons in the female sheep brain

    Neuroscience

    (2005)
  • F.G. Revel et al.

    Kisspeptin mediates the photoperiodic control of reproduction in hamsters

    Current Biology

    (2006)
  • J.T. Smith

    Kisspeptin signalling in the brain: steroid regulation in the rodent and ewe

    Brain Res. Rev.

    (2008)
  • T.M. Wintermantel et al.

    Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility

    Neuron

    (2006)
  • H. Yoon et al.

    Olfactory inputs to hypothalamic neurons controlling reproduction and fertility

    Cell

    (2005)
  • S. Adachi et al.

    Involvement of anteroventricular periventricular matastin/kisspeptin neurons in estrogen positive feedback action on leutentizing hormone release in female rats

    J. Reprod. Dev.

    (2007)
  • V.L. Adams et al.

    Morphological plasticity in the neural circuitry responsible for seasonal breeding in the ewe

    Endocrinology

    (2006)
  • L. Ansel et al.

    Differential regulation of Kiss1 expression by melatonin and gonadal hormones in male and female Syrian hamsters

    J. Biol. Rhythms

    (2010)
  • G.C. Brailoiu et al.

    KiSS-1 expression and metastin-like immunoreactivity in the rat brain

    J. Comp. Neurol.

    (2005)
  • M.C. Burke et al.

    Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus

    J. Comp. Neurol.

    (2006)
  • R.E. Campbell et al.

    Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons

    Proc. Natl. Acad. Sci.

    (2009)
  • A. Caraty et al.

    Evidence that the mediobasal hypothalamus is the primary site of action of estradiol in inducing the preovulatory gonadotropin releasing hormone surge in the ewe

    Endocrinology

    (1998)
  • G. Cheng et al.

    The Kisspeptin/Neurokinin B/Dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep

    Endocrinology

    (2010)
  • J. Clarkson et al.

    Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons

    Endocrinology

    (2006)
  • J. Clarkson et al.

    Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge

    J. Neurosci.

    (2008)
  • J. Clarkson et al.

    Distribution of kisspeptin neurones in the adult female mouse brain

    J. Neuroendocrinol.

    (2009)
  • X. d'Anglemont de Tassigny et al.

    Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals

    Endocrinology

    (2008)
  • N. de Roux et al.

    Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • Desroziers, E., Mikkelsen, J., Simonneaux, V., Keller, M., Tillet, Y., Caraty, A., Franceschini, I., 2010. Mapping of...
  • E. Ducret et al.

    Electrical and morphological characteristics of anteroventral periventricular nucleus kisspeptin and other neurons in the female mouse

    Endocrinology

    (2010)
  • H.M. Dungan Lemko et al.

    Interactions between neurotensin and GnRH neurons in the positive feedback control of GnRH/LH secretion in the mouse

    Am. J. Physiol. Endocrinol. Metab.

    (2010)
  • H.M. Dungan et al.

    Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion

    Endocrinology

    (2006)
  • K.M. Estrada et al.

    Elevated KiSS-1 expression in the arcuate nucleus prior to the cyclic preovulatory gonadotrophin-releasing hormone/lutenising hormone surge in the ewe suggests a stimulatory role for kisspeptin in oestrogen-positive feedback

    J. Neuroendocrinol.

    (2006)
  • C.D. Foradori et al.

    Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus

    Endocrinology

    (2002)
  • C.D. Foradori et al.

    Colocalisation of dynorphin A and neurokinin B immunoreactivity in the arcuate nucleus and median eminence of the sheep

    J. Neuroendocrinol.

    (2006)
  • R. Goodman et al.

    Endogenous opioid peptides control the amplitude and shape of gonadotropin-releasing hormone pulses in the ewe

    Endocrinology

    (1995)
  • R.L. Goodman et al.

    Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep

    Endocrinology

    (2004)
  • R.L. Goodman et al.

    Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B

    Endocrinology

    (2007)
  • Goodman, R.L., Nestor, C.C., Connors, J.M., Holaskova, I., Lehman, M.N., 2010. The actions of neurokinin B in the...
  • M.L. Gottsch et al.

    A role for kisspeptins in the regulation of gonadotropin secretion in the mouse

    Endocrinology

    (2004)
  • T.J. Greives et al.

    Environmental control of kisspeptin: implications for seasonal reproduction

    Endocrinology

    (2007)
  • G.B. Gu et al.

    Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat

    J. Comp. Neurol.

    (1997)
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    These authors contributed equally to this work.

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