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Role of RFRP neurons in driving daily and seasonal reproductive rhythms in female rodents

Research unit

UPR 3212 - Institut des Neurosciences Cellulaires et Intégratives (INCI)
5, rue Blaise Pascal, 67084 STRASBOURG

Group

Name: Mélatonine et rythmes saisonniers

Group leader: SIMONNEAUX Valérie - simonneaux@inci-cnrs.unistra.fr

Group leader's phone: 0388456671

Website: Visit website

Group organization:
- Chercheurs: 4
- ITA: 3
- Doctorants: 7
- Post-Docs: 2
- Autres: 1

Publications of the team linked to the topic (3 last years):
1) Henningsen JB, Poirel VJ, Mikkelsen JD, Tsutsui K, Simonneaux V and Gauer F (2015)
Sex differences in the photoperiodic regulation of RF-amide related peptide (RFRP)and its receptor GPR147 in the Syrian hamster. J. Comp Neurol, 31 oct 2015 in press
2) Chassard D, Bur I, Poirel VJ, Mendoza J and Simonneaux V (2015)
Evidence for a Putative Circadian Kiss-Clock in the Hypothalamic AVPV in Female Mice. Endocrinology, 156: 2999-3011
3) Sáenz de Miera C, Monecke S, Bartzen-Sprauer J, Laran-Chich MP, Pévet P, Hazlerigg D, Simonneaux V (2014). A circannual clock drives expression of genes central for seasonal reproduction. Current Biology, 24(13):1500-1506

About PhD

PhD Director: GAUER François - gauer@inci-cnrs.unistra.fr

Phone: 038845668

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Role of RFRP neurons in driving daily and seasonal reproductive rhythms in female rodents

Project: In mammalian females, the control of the reproductive axis is quite complex as it is submitted to both sexual steroid hormone feedback and daily and annual changes of their living environment. The main goal of our research team is dedicated to the study of the neuroendocrine systems implicated in the integration of both daily rhythms (generated within the main biological circadian clock located into the suprachiasmatic nuclei) and seasonal rhythms (vehicled through the photoperiodic variations of the melatonin peak duration). Recently, we showed that the two peptides kisspeptin and RF‐related peptide‐3 (RFRP3), produced in the arcuate nuclei and the mediobasal hypothalamus respectively, are critical for the regulation of reproductive activity by a specific action upstream of the GnRH neurons. When Kp is always a strong activator of the gonadal axis, the effects of RFRP3 on the reproductive system however vary with sex and species.
Recently, we have analyzed the precise function of RFRP3 neurons on the reproductive system of a seasonal model: the Syrian hamster (Repramide ANR program). We found that the neuroanatomical distribution of RFRP-immunoreactive fibers and GPR147 mRNA are mainly expressed in cerebral structures involved in the control of the reproductive axis (preoptic area, anteroventral-periventricular nucleus (AVPV), arcuate nucleus) but also in structures involved in the control of biological rhythms and metabolism. Strikingly, the whole RFRP system is particularly developed in females, and in females, the RFRP neuronal activity exhibits both daily and seasonal variations, in contrast with what was observed in males. We also demonstrated that the RFRP3 effects on the gonadal activity varies with the daily and the seasonal timings of the treatment. All these results clearly suggest that RFRP3 is a critical component of the regulatory mechanisms implicated in the seasonal control of the reproductive axis, and our main hypothesis is that RFRP is certainly acting upstream of Kp, the major activator of the GnRH neurons.
The goal of present PhD program is to extend our current researches and especially to characterize the mechanisms implicated in the RFRP3 sex-dependent effects on the reproduction rhythms with complementary physiological, pharmacological and molecular approaches.
1)       The physiological approach will consist in RFRP3 ICV administration protocols to precisely characterize the RFRP3 effects on the gonadal axis according to the injection locations, sex and photoperiod background of the treated animals. In order to determine the pharmacological profile of the RFRP-3 binding sites, different agonist and antagonists of the GPR 147 will be tested both in vitro and in vivo. This part will be achieved in collaboration with Dr F Simonin (ANR Repramide, ESBS, University of Strasbourg).
2)       RFRP is known to undergo melatonin driven seasonal variations, but the mechanisms implicated in its daily variations remains unclear so far. Putative effect of several neuropeptides secreted by SCN neurons, such as vasopressine or VIP, on the RFRP neuron daily activity will be investigated.
3)       An optogenetic activation protocol of the RFRP neurons will be set up and will allow us to clarify the differential sex dependent effects of RFRP3 on the central control of the reproductive axis. Transgenic RFRP-Cre mices generated in the laboratory of Dr Greg Anderson (Otago University, New Zealand) will be injected with CRE-dependent recombinant adenoviruses expressing the channel rhodopsin 2 (ChR2). The reproductive status of the mices whose RFRP neurons will be locally and specifically light activated by optical fibers under different experimental conditions, will be fully analyzed. Finally, crossbreeding RFR-Cre mices with GPR147 knocked out mices will be carried out to validate our hypothesis on the role of RFRP3 on the reproductive axis control.

Wished skills: A very good background in neurosciences but also in neuroendocrinology will be requested.
A practical experience with the classical protocols in molecular and cellular biology will also be asked. The candidate will be asked to be able to work in a thorough and independent manner in a research collaborating network.

Expertises which will be acquired during the training: Cerebral surgery, in situ hybridization, immunochemistry, RNA extraction, plasmidic constructions, cloning, cell cultures, cell transfection, ligand receptor binding studies. Trasngenic mices, optogenetic activation.