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International audience; Kisspeptin (Kp), a family of peptides comprising products of the Kiss1 gene, was discovered 20 years ago; it is recognised as the major factor controlling the activity of the gonadotrophin-releasing hormone (GnRH) neurones and thus the activation of the reproductive axis in mammals. It has been widely documented that the effects of Kp on reproduction through its action on GnRH neurones are mediated by the GPR54 receptor. Kp controls the activation of the reproductive axis at puberty, maintains reproductive axis activity in adults and is involved in triggering ovulation in some species. Although there is ample evidence coming from both conditional knockout models and conditional-induced Kp neurone death implicating the Kp/GPR54 pathway in the control of reproduction, the mechanism(s) underlying this process may be more complex than a sole direct control of GnRH neuronal activity by Kp. In this review, we provide an overview of the recent advances made in elucidating the interplay between Kp- and GnRH- neuronal networks with respect to regulating the reproductive axis. We highlight the existence of a possible mutual regulation between GnRH and Kp neurones, as well as the implication of Kp-dependent volume transmission in this process. We also discuss the capacity of heterodimerisation between GPR54 and GnRH receptor (GnRH-R) and its consequences on signalling. Finally, we illustrate the role of mathematical modelling that accounts for the synergy between GnRH-R and GPR54 in explaining the role of these two receptors when defining GnRH neuronal activity and GnRH pulsatile release.

Intracellular cytoplasmic calcium ([Ca(2+) ]i ) has an important regulatory role in gamete functions. However, the biochemical components involved in Ca(2+) transport are still unknown in birds, an animal class that has lost functional sperm-specific CatSper channels. Here, we provide evidence for the presence and expression of various Ca(2+) channels in chicken sperm, including high voltage-activated channels (L and R types), the store-operated Ca(2+) channel (SOC) component Orai1, the transient receptor potential channel (TRPC1) and inositol-1,4,5-trisphosphate receptors (IP3 R1). L- and R-type channels were mainly localized in the acrosome and the midpiece, and T-type channels were not detected in chicken sperm. Orai1 was found in all compartments, but with a weak, diffuse signal in the flagellum. TRCP1 was mainly localized in the acrosome and the midpiece, but a weak diffuse signal was also observed in the nucleus and the flagellum. IP3 R1 was mainly detected in the nucleus. The L-type channel inhibitor nifedipine, the R-type channel inhibitor SNX-482 and the SOC inhibitors MRS-1845, 2-APB and YM-58483 decreased [Ca(2+) ]i sperm motility and acrosome reaction capability, with the SOC inhibitors inhibiting these functions most efficiently. Furthermore, we showed that Ca(2+) -mediated induction of AMP-activated protein kinase (AMPK) phosphorylation was blocked by SOC inhibition. Our identification of important regulators of Ca(2+) signaling in avian sperm suggests that SOCs play a predominant role in gamete function, whereas T-type channels may not be involved. In addition, Ca(2+) entry via SOCs appears to be the most likely pathway for AMPK activation and energy-requiring sperm functions such as motility and the acrosome reaction.

Kisspeptins, encoded by the Kiss1 gene, play a key role in the regulation of reproductive function, although very little is known about the ontogenesis of this system. The present study aimed to determine the period of arcuate nucleus (ARC) kisspeptin cell birth and the embryonic stage and neuroanatomical sites of onset of kisspeptin immunoreactivity. Bromodeoxyuridine (BrdU) was administered to female rats at various gestational stages and double immunohistochemistry against kisspeptin and BrdU was performed on brain sections from their offspring. The period of neurogenesis of ARC kisspeptin neurones begun between embryonic day (E) 12.5 and E13.5, reached its peak at E15.5 and was not completely over at E17.5. Kiss1 mRNA was detected in mediobasal hypothalamic punches of embryos aged E14.5, E16.5, E18.5 and E22.5 by real-time reverse transcriptase-polymerase chain reaction. Accordingly, kisspeptin-immunoreactive (-IR) cells were consistently detected in the embryonic ARC from E14.5 and their number increased until E18.5 to reach approximately half the level observed in adults. Between E18.5 and E22.5, the number of kisspeptin-IR cells and hypothalamic Kiss1 expression significantly decreased, regardless of sex, and this decrease persisted until birth. Taken together, these results demonstrate that rat ARC kisspeptin neurones are born locally during an extended embryonic period and are able to synthesise kisspeptins rapidly after their birth, consistent with the hypothesis of a role during embryonic activation of the hypothalamic-hypophyseal-gonadal axis. A sex-independent decrease of kisspeptin-IR cell numbers was observed during the perinatal period, suggestive of important regulations of kisspeptin neurones around birth.

Kisspeptins are potent secretagogues of gonadotrophin-releasing hormone, playing a key role in puberty onset. These peptides are produced by distinct neuronal populations of the hypothalamus located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC). The present immunohistochemical study aimed to determine the spatiotemporal onset of kisspeptin-immunoreactivity (-IR) in the neonatal hypothalamus of male and female rats and to evaluate changes in kisspeptin-IR around puberty. Kisspeptin-IR cells and fibres could be detected from the day of birth in the ARC of both males and females. At this stage, only females displayed some kisspeptin-IR fibres in the RP3V. From postnatal day 7 to adulthood, males displayed lower levels of kisspeptin-IR than females in both regions. During infancy, kisspeptin-IR fibre density in the female decreased in the ARC, whereas it increased in the RP3V. A sex-independent decline in RP3V kisspeptin-IR fibre density was observed in the juvenile, followed by a peripubertal increase in RP3V and ARC kisspeptin-IR. These peripubertal increases in kisspeptin-IR occurred at different timings dependent on sex and region. In females specifically, the increase in kisspeptin-IR fibre density occurred first in the ARC and later in the RP3V under constant levels of circulating oestradiol. In conclusion, the present study highlights the expression of hypothalamic kisspeptins soon after birth, as well as the neonatal establishment of a strong and persisting sex difference in ARC kisspeptin-IR in rats. Moreover, a female-specific desynchronisation of the ARC and RP3V was observed with respect to the increase in kisspeptin-IR fibre density around puberty, which was not related to peripubertal variations in circulating oestradiol.

In adult mammalian brain, two main germinative regions located in the subventricular zone of the lateral ventricle and in the subgranular cell layer of the hippocampal dentate gyrus have been considerably documented and are still under intense scrutiny. However, new neuron formation has recently been reported in various other brain areas including the hypothalamus. This central structure, responsible for the control of many major neuroendocrine functions such as reproduction, expresses high levels of PSA-NCAM and nestin, both proteins being involved in structural and morphological plasticity mechanisms. Cell proliferation and new neuron production have been demonstrated in the adult hypothalamus of numerous species, although not hitherto described in non-human primates and humans. Similarly to the subventricular zone and in the subgranular cell layer, the adult hypothalamic neurogenesis process is subject to dynamic regulation by various physiological and pharmacological signals. Several pieces of evidence support the hypothesis that a stem cell niche-like architecture exist in the hypothalamus region lining the third ventricle thereby enabling adult neural stem cells to continuously generate neurons in vivo throughout life. Furthermore, recent data indicating that new hypothalamic neurons may become functionally implicated in sensory information processing endorse the assumption that the hypothalamus might be a neurogenic region.

The neurohormone gonadotropin-releasing hormone (GnRH) is critical for all the aspects of reproductive life in vertebrates. GnRH is secreted by a small number of neurons dispersed within the preoptic-hypothalamic region. These neurons are derived from the embryonic olfactory pit. They then migrate along olfactory, vomeronasal and terminal nerves to their final destination. Classical approaches to study the regulation of GnRH secretion during the reproductive cycle have focused on the various neuronal inputs on GnRH neurons and their regulation by ovarian steroids. However, it is well known that steroids will change the microenvironment of neuronal networks and can induce plasticity and functional changes. In this review, we will focus on the intimate relationship of developing and adult GnRH neurons with the polysialylated form of neural cell adhesion molecule (PSA-NCAM), a major molecular actor in the morphogenesis and adult plasticity of the nervous system. We will first recapitulate the spatiotemporal relationship between PSA-NCAM and migrating GnRH neurons during embryogenesis of various vertebrate species and discuss its importance for GnRH neuron development as shown by various loss of function studies. In the adult, we will review the relationships between PSA-NCAM and GnRH neurons across various physiological states, and open the discussion to the use of new model systems that can help to unravel the function and mechanism of action of PSA-NCAM on GnRH neuronal network activity and GnRH release.