In many mammalian species, including farm animals, social signals have been shown to play a pivotal role in the regulation of reproductive function. Among these signals, pheromones are probably the most widespread and efficient. Pheromones usually trigger either powerful short-term behavioral changes (“releaser” pheromones) or more long-term neuroendocrine changes (“primer” pheromone). Among the various targets that are impacted by pheromones at the level of the neuroendocrine axis, gonadotropin-releasing homone (GnRH) neurons appeared until recently as the major effectors of pheromonal stimulations on reproductive physiology. However, the recent discovery of Kisspeptin as a powerful regulator of GnRH neurons has focussed many attentions on this system. If numerous studies have for instance identified some of the functional roles of Kisspeptin neurons and their endogenous regulations, very few have adressed their modulation by environnemental cues. Among the various stimulations provided by the environment to the animal, the regulation of sexual activity by photoperiod in seasonal mammals, such as hamster or sheep, is the only one that has been so far characterised. To our knowledge, no studies showing that social signals such as pheromones can impact the Kisspeptin system and therefore modulate reproductive function have been published for instance. To test this hypothesis, we propose to use the pheromonal modulation of puberty in mice (acceleration in female puberty occurrence caused by exposure to male pheromones; also named “Vandenbergh effect”) used as a model species to explore how chemosensory cues can impact the Kisspeptin system and therefore open a new field in the neurobiology of Kisspeptin. Indeed, if the neurobiological mechanisms mediating puberty modulation by pheromonal cues are still unknown, Kisspeptin appears as an ideal candidate to mediate the effects of pheromone on puberty onset as it has been identified as a major regulator of the neuroendocrine switch for the onset of puberty. In this context, we will test whether activation of Kisspeptin neuron is needed for pheromonal modulation of puberty onset in mice. For this purpose, we will combine behavioral, neurobiological and neuroendocrine approaches to test the possibility of pheromonal puberty onset modulation when the Kisspeptin system is blocked by using genetic (Kiss1-KO mice) or pharmacological (antagonists) strategies. The effects of pheromonal stimulation on the architecture of the Kisspeptin network architecture will be then determine through immunocytochemical experiments. Finally, the pathway involved in conducting pheromonal information from sensory neurons to Kisspeptin neurons will be determined using lesional approaches (lesion of the main vs accessory olfactory system).

In birds and mammals (including humans), nutrition and energy metabolism strongly influence reproduction. In agronomy and more particularly in poultry, the intense selection of chickens for meat production promotes rapid muscle development and leads to have a negative energy balance that affects fertility. At the organism level, detectors of energy levels indicate whether energy reserves are abundant (obesity), or poor (in case of food restriction, sport training…). One of the detectors is AMPK (5 'AMP-activated protein kinase), a protein kinase activated by the ATP deficit, but also by natural substances such as polyphenols or drug (metformin used in the treatment of insulin resistance). AMPK is expressed in muscle, liver, but also at the gonadotroph axis (hypothalamus, pituitary, ovary, testis). Several studies in females suggested a role of AMPK on fertility, as used in the treatment of infertility associated with insulin resistance (polycystic ovary syndrome), but no data are available in the male until now. However, our preliminary results using a pharmacological activator of AMPK (metformin) showed a delay in development of testicular function. The goal of our project is to better understand the role of AMPK in the control of male reproduction and its interest in improving the fertility of animals of agricultural interest. This approach is based on the use of mice fed a diet supplemented with agonists of AMPK in the presence genetic background deficient or not for a1AMPK. AMPK will be inactivated either by Cre recombinase in the testis, either by expressing a dominant negative in brain (intracerebroventricular injection) in order to determine its role in the gonadal axis. Finally, a mechanistic study on cells cultured in vitro will help to define the molecular mechanisms of AMPK on testicular function. All these strategies should identify the potential role of AMPK (or its ligands) in male reproduction.