A kiss for daily and seasonal reproduction.

Reproduction is a fundamental biological function ensuring individual descendant survival and species perpetuity. It is an energy-consuming process, and therefore, all underlying mechanisms have to work in synchrony to ensure reproductive success. Synchronization of reproductive activity with the best time of the day or the year is part of such adaptive processes. Recently, a neuropeptide named kisspeptin, synthesized in two discrete hypothalamic nuclei, the anteroventral periventricular nucleus and the arcuate nucleus, has been demonstrated to be a potent stimulator operating upstream of the gonadotropic axis. In this review, we show how kisspeptinergic neurons integrate daily and seasonal time cues to synchronize reproductive activity with the cycling environment.

Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory.

Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

Maturation of kisspeptinergic neurons coincides with puberty onset in male rats.

Kisspeptins, derived from the Kiss1 gene play a central role in activation of the hypothalamo-pituitary gonadal (HPG) axis via stimulation of GnRH neurons. Both Kiss1 and Kiss1R (receptor) mRNA levels are found to be low in pre-pubertal rats, but whether an increase in kisspeptin and/or its receptor is the primary component in the initiation of puberty and where in the hypothalamus regulation of the kisspeptin/Kiss1R system occurs is unresolved. Using immunohistochemistry and in situ hybridization, we analyzed the level of Kiss1 mRNA and kisspeptin-immunoreactivity in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus of male rats along pubertal development. Neurons expressing Kiss1 mRNA were first detected at PND15, but increased significantly around puberty, and declined again in the adult rat. While virtually no immunoreactive cell bodies were detectable in the AVPV at any age, numerous kisspeptin-positive neurons in the arcuate nucleus were detected in the adult rat. Increasing doses of kisspeptin-54 given peripherally to male rats at PND15, 30, 45, and 60 evoked roughly similar effects, as revealed by the induction of c-Fos in the pituitary and secretion of LH and testosterone. These results show that both Kiss1 mRNA and the peptide increase in arcuate nucleus along pubertal maturation. Since kisspeptin signaling is potentially functional, even for peripheral activation, and well before the kisspeptin neuronal system is fully matured, our data support that the regulation of kisspeptin synthesis and release are key events in puberty onset in the male rat.

Comparison of the effects of peripherally administered kisspeptins.

Kisspeptins are structurally closely related peptides derived from the Kiss1 gene that have been demonstrated to stimulate the hypothalamo-pituitary gonadal axis. The natural peptide products derived from post-translational processing of the kisspeptin precursor have not been elucidated. We examined the acute effect on serum levels of free testosterone in the adult male mouse after systemic administration of kisspeptins with different lengths of both human and mouse origin. Mouse kisspeptin-10 and -52 dose-dependently increased serum testosterone, and both peptides showed similar potency and efficacy. Human kisspeptin-10 and kisspeptin-54 evoked robust increase in serum testosterone, with the same potency as for mouse kisspeptins. Other members of the RFRP family of peptides, i.e. RFRP-1 and -3 were inactive. Time-course experiments revealed that the longer forms had a slower onset of action, and the long human form also a more prolonged effect. The effect of the peripherally administered mouse kisspeptin-10 could be totally blocked by the GnRH antagonist acyline. Finally, peripherally administered mouse kisspeptin-10 had no effect on Fos induction in GnRH cells. These data show that all peptides tested are active and supports the concept that their effect is mediated by a target upstream of the pituitary, such as the median eminence.

Kisspeptin and the seasonal control of reproduction in hamsters.

Reproduction is a complex and energy demanding function. When internal and external conditions might impair reproductive success (negative energy balance, stress, harsh season) reproductive activity has to be repressed. Recent evidence suggests that these inhibitory mechanisms operate on Kiss1-expressing neurons, which were recently shown to be implicated in the regulation of GnRH release. Hamsters are seasonal rodents which are sexually active in long photoperiod and quiescent in short photoperiod. The photoperiodic information is transmitted to the reproductive system by melatonin, a pineal hormone whose secretion is adjusted to night length. The photoperiodic variation in circulating melatonin has been shown to synchronize reproductive activity with seasons, but the mechanisms involved in this effect of melatonin were so far unknown. Recently we have observed that Kiss1 mRNA level in the arcuate nucleus of the Syrian hamster is lower in short photoperiod, when animals are sexually quiescent. Notably, intracerebroventricular infusion of Kiss1 gene product, kisspeptin, in hamsters kept in short photoperiod is able to override the inhibitory photoperiod and to reactivate sexual activity. The inhibition of Kiss1 expression in short photoperiod is driven by melatonin because pinealectomy prevents decrease in Kiss1 mRNA level in short photoperiod and melatonin injection in long photoperiod down regulates Kiss1 expression. Whether melatonin acts directly on arcuate Kiss1 expressing neurons or mediates its action via interneurons is the subject of the current investigations.

Kisspeptin: a key link to seasonal breeding.

In seasonal species, photoperiod (i.e. daylength) tightly regulates reproduction to ensure that birth occurs at the most favorable time of year. In mammals, a distinct photoneuroendocrine circuit controls this process via the pineal hormone melatonin. This hormone is responsible for the seasonal regulation of reproduction, but the anatomical substrate and the cellular mechanism through which melatonin modulates sexual activity is far from understood. The Syrian hamster is widely used to explore the photoneuroendocrine system, because it is a seasonal model in which sexual activity is promoted by long summer days (LD) and inhibited by short winter days (SD). Recent evidences indicate that the products of the KiSS-1 gene, kisspeptins, and their specific receptor GPR54, represent potent stimulators of the sexual axis. We have shown that melatonin impacts on KiSS-1 expression to control reproduction in the Syrian hamster. In this species, KiSS-1 is expressed in the antero-ventral-periventricular and arcuate nuclei of the hypothalamus at significantly higher levels in hamsters kept in LD as compared to SD. In the arcuate nucleus, the downregulation of KiSS-1 expression in SD appears to be mediated by melatonin and not by secondary changes in gonadal hormones. Remarkably, a chronic administration of kisspeptin restores testicular activity in SD hamsters, despite persisting photoinhibitory conditions. Overall, these findings are consistent with a role of KiSS-1/GPR54 in the seasonal control of reproduction. We propose that the photoperiod, via melatonin, modulates KiSS-1 neurons to drive the reproductive axis.