A “Timed” Kiss Is Essential for Reproduction: Lessons from Mammalian Studies

Abstract

Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to “time” reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion.

GnIH Control of Feeding and Reproductive Behaviors

“…Accordingly, downregulation of GnIH expression by estrogen may be the mechanism of estrogen positive feedback to GnRH/LH release at least in female rodents [see Ref. (114, 115) for reviews].…”

Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization

“…Kisspeptin neurons in the ARN, located on both sides of the third ventricle, develop at embryonic day 16.5 and become synaptically connected to GnRH neurons [5], unlike another kisspeptin population in the anteroventral periventricular nucleus (AVPV) detected at later developmental stages [6]. Kisspeptin neurons are thought to "time" reproduction by coordinating inputs for maturation and regulation of the GnRH pulse generator [7]. Loss-of-function mutations in Kiss1R cause the absence of sexual maturation [8].…”

Eel Kisspeptins: Identification, Functional Activity, and Inhibition on both Pituitary LH and GnRH Receptor Expression

“…Since these discoveries, the kisspeptin system has been considered as a major puberty gatekeeper and reproductive regulator, upstream of GnRH [for reviews see Ref. ( 15 – 17 )]. Nevertheless, Tang and collaborators ( 18 ) recently showed that gametogenesis and reproductive capability are not impaired in zebrafish mutant lines for Kiss, as well as for kisspeptin receptors (KissR), suggesting that the Kiss/KissR systems may be dispensable for the reproduction of some non-mammalian vertebrates.…”