Marie-Emilie Sébert

Dopaminergic inhibition of reproduction in teleost fishes: ecophysiological and evolutionary implications.

Abstract: In many teleosts, dopamine (DA) exerts direct inhibitory control on gonadotropes, counteracting the stimulatory effect of gonadotropin‐releasing hormone (GnRH) on gonadotropin release. This dual control by GnRH and DA has been demonstrated in various adult teleosts and has major implications for aquaculture. Because of its unique life cycle, the European eel has provided a powerful model for demonstrating the key role of DA in the control of puberty. Data from tetrapods suggest that the inhibitory role of DA on reproduction is not restricted to the teleosts. Thus, DA inhibitory control could represent an ancient evolutionary component in the neuroendocrine regulation of reproduction that may have been differentially maintained throughout vertebrate evolution. The intensity of DA inhibition, its main site of action, and its involvement in the control of puberty, seasonal reproduction, ovulation, spermiation, or even sex change may differ among classes of vertebrates, as well as within smaller phylogenetic units such as teleosts or mammals. An inhibitory role for DA has been reported also in some invertebrates, indicating that neuronal DA pathways may have been recruited in various groups of metazoa to participate in the control of reproduction. In addition to the incontestable GnRH neurons, the recruitment of DA neurons for the neuroendocrine control of reproduction provides an additional brain pathway for the integration of various species‐specific, internal, and environmental cues. In teleosts, the plasticity of the DA neuroendocrine role may have contributed to their large diversity of biological cycles and to their successful adaptation to various environments.

Stimulatory Effect of RFRP-3 on the Gonadotrophic Axis in the Male Syrian Hamster: The Exception Proves the Rule

In seasonal mammals, a distinct photoneuroendocrine circuit that involves the pineal hormone melatonin tightly synchronizes reproduction with seasons. In the Syrian hamster, a seasonal model in which sexual activity is inhibited by short days, we have previously shown that the potent GnRH stimulator, kisspeptin, is crucial to convey melatonins message; however, the precise mechanisms through which melatonin affects kisspeptin remain unclear. Interestingly, rfrp gene expression in the neurons of the dorsomedial hypothalamic nucleus, a brain region in which melatonin receptors are present in the Syrian hamster, is strongly down-regulated by melatonin in short days. Because a large body of evidence now indicates that RFamide-related peptide (RFRP)-3, the product of the rfrp gene, is an inhibitor of gonadotropin secretion in various mammalian species, we sought to investigate its effect on the gonadotrophic axis in the Syrian hamster. We show that acute central injection of RFRP-3 induces c-Fos expression in GnRH neurons and increases LH, FSH, and testosterone secretion. Moreover, chronic central administration of RFRP-3 restores testicular activity and Kiss1 levels in the arcuate nucleus of hamsters despite persisting photoinhibitory conditions. By contrast RFRP-3 does not have a hypophysiotrophic effect. Overall, these findings demonstrate that, in the male Syrian hamster, RFRP-3 exerts a stimulatory effect on the reproductive axis, most likely via hypothalamic targets. This places RFRP-3 in a decisive position between the melatonergic message and Kiss1 seasonal regulation. Additionally, our data suggest for the first time that the function of this peptide depends on the species and the physiological status of the animal model.

Neuroendocrine control by dopamine of teleost reproduction

While gonadotropin-releasing hormone (GnRH) is considered as the major hypothalamic factor controlling pituitary gonadotrophins in mammals and most other vertebrates, its stimulatory actions may be opposed by the potent inhibitory actions of dopamine (DA) in teleosts. This dual neuroendocrine control of reproduction by GnRH and DA has been demonstrated in various, but not all, adult teleosts, where DA participates in an inhibitory role in the neuroendocrine regulation of the last steps of gametogenesis (final oocyte maturation and ovulation in females and spermiation in males). This has major implications for inducing spawning in aquaculture. In addition, DA may also play an inhibitory role during the early steps of gametogenesis in some teleost species, and thus interact with GnRH in the control of puberty. Various neuroanatomical investigations have shown that DA neurones responsible for the inhibitory control of reproduction originate in a specific nucleus of the preoptic area (NPOav) and project directly to the region of the pituitary where gonadotrophic cells are located. Pharmacological studies showed that the inhibitory effects of DA on pituitary gonadotrophin production are mediated by DA-D2 type receptors. DA-D2 receptors have now been sequenced in several teleosts, and the coexistence of several DA-D2 subtypes has been demonstrated in a few species. Hypophysiotropic DA activity varies with development and reproductive cycle and probably is controlled by environmental cues as well as endogenous signals. Sex steroids have been shown to regulate dopaminergic systems in several teleost species, affecting both DA synthesis and DA-D2 receptor expression. This demonstrates that sex steroid feedbacks target DA hypophysiotropic system, as well as the other components of the brain-pituitary gonadotrophic axis, GnRH and gonadotrophins. Recent studies have revealed that melatonin modulates the activity of DA systems in some teleosts, making the melatonin-DA pathway a prominent relay between environmental cues and control of reproduction. The recruitment of DA neurons for the neuroendocrine control of reproduction provides an additional brain pathway for the integration of various internal and environmental cues. The plasticity of the DA neuroendocrine role observed in teleosts may have contributed to their large diversity of reproductive cycles.

TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin

In mammals, melatonin is the pivotal messenger synchronizing biological functions, notably reproductive activity, with annual daylength changes. Recently, two major findings clarified melatonins mode of action. First, melatonin controls the production of thyroid stimulating hormone (TSH) by the pars tuberalis of the adenohypophysis. This TSH regulates local thyroid hormone availability in the mediobasal hypothalamus. Second, the RF‐amides kisspeptin and RFRP‐3, recently discovered regulators of the gonadotropic axis, are involved in the melatonin control of reproduction. This study aims to establish a mechanistic link between the melatonin‐driven TSH and the RF‐amide control of reproduction. We treated short‐day‐adapted male Djungarian and Syrian hamsters with a chronic central infusion of TSH. In both hamster species, the central administration of 5 mIU/d TSH for 4 to 6 wk restored the summer phenotype of both testicular activity and kisspeptin and RFRP expression. Vehicle treated hamsters remain sexually inactive. Furthermore, the TSH treatment increased the body weight of lean short‐day‐adapted Djungarian hamsters and reduced hypothalamic somatostatin expression to the summer phenotype. In summary, our study demonstrates the pivotal role of melatonin‐driven TSH for the seasonal regulation of reproduction and body weight, and uncovers the neuropeptides relaying this signal within the hypothalamus.—Klosen, P., Sébert, M.‐E., Rasri, K., Laran‐Chich, M.‐P., Simonneaux, V. TSH restores a summer phenotype in photoinhibited mammals via the RF‐amides RFRP3 and kisspeptin. FASEB J. 27, 2677–2686 (2013). www.fasebj.org

Melatonin Activates Brain Dopaminergic Systems in the Eel with an Inhibitory Impact on Reproductive Function

In the eel, a deficit in gonadotrophin‐releasing hormone (GnRH) and a strong dopaminergic (DA) inhibition are responsible for the blockade of gonad development if silver eels are prevented from their reproductive migration. Environmental factors that eels encounter during their oceanic reproductive migration are thought to play an important role in the stimulation of eel pubertal development. We investigated the potential role of melatonin, a known mediator of the effects of external factors on reproductive function in vertebrates. We demonstrated that a long‐term melatonin treatment increased brain tyrosine hydroxylase (TH, the rate limiting enzyme of DA synthesis) mRNA expression in a region‐dependent way. Melatonin stimulated the dopaminergic system of the preoptic area, which is involved in the inhibitory control of gonadotrophin [luteinising hormone (LH) and follicle‐stimulating hormone (FSH)] synthesis and release. Moreover, we showed that the increased TH expression appeared to be consistent with melatonin binding site distribution as shown by 2[125I]‐melatonin labelling studies. On the other hand, melatonin had no effects on the two eel native forms of GnRH (mGnRH and cGnRH‐II) mRNA expression. Concerning the pituitary–gonad axis, we showed that melatonin treatment decreased both gonadotrophin β‐subunit (LHβ, FSHβ) mRNA expression and reduced sexual steroid (11‐ketotestosterone, oestradiol) plasma levels. This indicates that melatonin treatment had a negative effect on eel reproductive function. To our knowledge, the results of the present study provide the first evidence that melatonin enhances TH expression in specific brain regions in a non‐mammalian species. By this mechanism melatonin could represent one pathway by which environmental factors could modulate reproductive function in the eel.

Dopamine Inhibition of Eel Reproduction

The silvering process includes various physiological and morphological changes that prepare the future genitors (silver eels) for the oceanic reproductive migration (e.g. Lokman et al. 1998). Silvering also marks the beginning of puberty (Aroua et al. 2005, and Chapter 11). However, silver eels are still sexually immature when they leave the continental habitats, and they remain blocked at this prepubertal stage if prevented from their reproductive migration. Because no maturing or spawning eels have ever been observed in the wild, the silver prepubertal stage is the last known stage of the eel biological cycle (for review, see Dufour et al. 2003). Accordingly, the regulatory mechanisms of puberty, sexual development, migration, and finally spawning are still not well understood. Puberty can be defined as the transformation from a sexually immature juvenile into a mature adult by providing the brain-pituitary-gonad (BPG) axis with its full hormonal and gametogenetic capacity (Norris 1997; Schulz et al. 2000). Puberty is marked by the onset of gametogenesis, and the age of puberty and sexual maturation is determined by genetic factors as well as controlled by the nutritional status and/or body growth rate. Both in teleosts and mammals it seems that activation of the brain neuroendocrine system(s) is the key event to initiate puberty. What leads to this activation is, however, not understood. The BPG axis consists of three physiologically connected constituents: brain, pituitary and gonads (Fig. 12.1). Stimulatory and inhibitory inputs merge in the