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INRA
24, chemin de Borde Rouge –Auzeville – CS52627
31326 Castanet Tolosan CEDEX - France

Dernière mise à jour : Mai 2018

Menu Logo Principal Tours university CNRS IFCE NMR

Neuroendocrinologie Moleculaire de la Reproduction

Themes

Team leader Hugues Dardente

 NMR
© Bertrand Godfroy

Reasearch topic: Our team performs basic research into the neuroendocrine mechanisms of reproduction in mammals. We also have an interest in using such knowledge to devise novel tools aimed at a better control of reproduction in small ruminants such as sheep and goats.

Rationale

Sheep and goats are seasonal breeders. This leads to a marked seasonal fluctuation in the production of milk and meat. Current methods to control breeding have two main objectives: (i) synchronize ovulations in the flock during the breeding season, (ii) trigger breeding out of season. These methods mostly rest upon the use of hormonal treatments, which are efficient but have well-known side effects for the treated animal, the environment (endocrine disruptors) and ultimately human health. The development of alternative methods is therefore an important goal.

Research aims

Photoperiod is the main synchronizer of seasonal breeding. However, cues such as food availability, social interaction and stress may modulate its impact. At the organism level, all these cues are integrated to yield a coherent behavioral output. At the central level, within the hypothalamus, the control of breeding depends on the action of the neurohormone GnRH on the production of pituitary gonadotropins (LH and FSH). GnRH neurons are themselves slaves to neurons expressing the neuropeptide Kisspeptin (Kiss). Kiss neurons are not only responsive to steroid feed-back but also appear to be involved in the integration of multiple hormonal signals, which are collectively involved in fine-tuning reproduction. Other peptides and hormones such as RFRP3 and thyroid hormone T3 also appear implicated in transducing environmental cues. Our work focuses on the integrated neuroendocrine network which underlies the impact of those cues on various cell types of the mediobasal hypothalamus, such as those producing Kiss, RFRP3 and T3. We study local effects of these peptides and hormones in the adult, during ontogenesis and in the course of aging. We also develop synthetic analogues of Kiss for a better control of breeding in farms.

Neuroendocrine mechanisms of photoperiodic read-out

The metabolism of thyroid hormones (TH) within the medio-basal hypothalamus is a critical component of the photoperiodic control of multiple seasonal functions, including reproduction. However, targets of HT remain quite elusive. We use various approaches (e.g. RNAseq) to identify the transcriptional landscape of HT within the ovine hypothalamus. Target genes are validated through classical molecular biology approaches. Our aim is to characterize the targets and mechanisms of action of HT within the hypothalamus, with special reference to Kiss and RFRP3 neurons, which are known to be impacted by photoperiod

Photoperiodic transduction cascade within the mediobasal hypothalamus (MBH)

Figure 1 - Photoperiodic transduction cascade within the mediobasal hypothalamus (MBH). Melatonin acts within the pars tuberalis (PT) to trigger seasonal changes in T3 levels in the MBH. Targets of T3 are ill-characterized (black box) but Kiss1 and Rfrp are likely amongst these (Dardente et al 2014).

Control of Kiss and RFRP3 neurons by metabolic cues and stress

Metabolic cues and stress are well-known modulators of the impact of photoperiod upon breeding. All these cues appear to have an indirect impact on GnRH neurons, most likely through Kiss and RFRP3 neurons. Our aim is to identify cell populations that relay these informations and characterize how these cues impact onneuroanatomical relationships and cellular mechanisms that influence Kiss and RFRP3 neurons. We also study how metabolic cues and stress impinge on TH signaling triggered by photoperiodic changes..

Figure-2

Figure 2 – Photomicrograph at the level of the arcuate nucleus showing a Kiss neuron (green) apposed by its cell body to a neuron expressing somatostatin (red). Cell nucleus is stained with DAPI (blue). Dufourny and Lomet, GCE, 2017

Ontogeny of Kiss and RFRP systems and impact of environmental cues

The gonadotropic axis is sensitive to environmental cues not only in aldult, but also during childhood (puberty) as well as in the course of the development in utero (foetal programming). Our goal is to identify the time-windows and humoral factors that are key to the setting up of Kiss and RFRP3 networks in vivo, and to understand how these early events impact functioning and plasticity of the system in adults and throughout aging. We also develop specific in vitro models (e.g. neurosphere assays and stable cell lines) to evaluate the impact of TH and sex steroids on Kiss neurons.

Figure 3

Figure 3 – A: Ontogeny of Kiss neurons ;  double immunofluorescence for Kiss (green) and BrdU (red) in the arcuate nucleus of the adult rat follwoing in utero injection of BrdU (Desroziers et al 2012, J.Neuroendo.). B: Mapping of Kiss cells in the foetal hypothalamus of Kiss1-GFP mice (Alfaïa et Franceschini, unpublished). C: Neurosphere assay reveals the presence of stem cells in the subventricular zone in ault pig (Liard and Moyse 2013)

Synthetic analogues of Kiss for breeding control

This project combines basic and applied research and aims at developing synthetic analogues of Kiss. The use of such molecules appears an interesting and promising alternative to current hormonal treatments and their undesirable drawbacks

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Chemical structure of the endogenous Kiss10 neuropeptide

Figure 4 – A: Chemical structure of the endogenous Kiss10 neuropeptide. B: Rational design yielded novel molecules with potencies similar to that of Kiss, but improved resistance to degradation; the molecule shown here is one such example. C: Injection of a very low dose of the molecule shown in panel B to anestrus ewes induces a sustained increase in plasma LH concentration (Beltramo et al 2015).

Figure 4 – A: Chemical structure of the endogenous Kiss10 neuropeptide. B: Rational design yielded novel molecules with potencies similar to that of Kiss, but improved resistance to degradation; the molecule shown here is one such example. C: Injection of a very low dose of the molecule shown in panel B to anestrus ewes induces a sustained increase in plasma LH concentration (Beltramo et al 2015).

See also