Scientific project


Infertility is a devastating condition that affects several million couples worldwide. Experts predict that infertility will double in Europe over the next decade. There is thus an urgent need to elucidate the molecular and cellular pathways underlying reproduction and, in particular, the neuroendocrine mechanisms that confer reproductive capacity. The neuroendocrine control of sexual maturation at puberty and its underlying molecular mechanisms, for example, remain among the greatest mysteries of human biology 1. The secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus represents the first known step in the reproductive cascade that leads to the pulsatile release of gonadotropins, the gonadal secretion of sex steroids, pubertal development and gametogenesis. Although the central role of GnRH in the reproductive hierarchy of all mammals is undisputed, little is understood of the genetic and/or molecular factors that modulate its secretion. The identification of such factors is critical to advance our understanding of normal reproduction and to provide new insights into disorders of the pubertal process and adult fertility. Seminal studies from our laboratory have revealed that mutations in genes coding for chemotrophic factors that guide GnRH neuronal migration during embryogenesis alter fertility both in mice and humans 2-4 and that glial cells play a critical role in the homeostatic regulation of GnRH neuronal excitability and secretion during postnatal development 5-7. In addition, our studies using advanced imaging techniques suggest that the morphological changes seen within the hypothalamus during the estrous cycle in rodents 8 may also occur in the human brain 9.

 

Metabolic disorders such as obesity and type-2 diabetes have become major causes of morbidity and mortality in Western countries. In France, in less than 3 years, 650 000 new cases of obesity were diagnosed: 50% of the adults (30 million) are overweight, and among them, 12.4% (7 million) are obese. This increase in obesity and type-2 diabetes mellitus, previously observed primarily in adult populations and associated with a sedentary lifestyle, has now become a medical problem in children as well 10,11 . During the past 30 years, we have witnessed a 7-fold increase in the incidence of childhood obesity. Over time, the stress of obesity on a genetically susceptible background causes insulin resistance and glucose intolerance 12. Studies from our laboratory have led to several breakthroughs in the understanding of the neurodevelopmental substrates responsible for obesity and diabetes 13-15. In parallel, we have identified a new physiological concept in the regulation of energy homeostasis by showing that the nutritional status of an individual modulates the permeability of discrete blood-hypothalamus barriers to circulating signals of adiposity, controlling their direct access the metabolic brain 16, a phenomenon that could be altered in obesity.

The alarming data described above concerning two major public health issues indicates that it is of primordial interest to identify the mechanisms underlying the regulation of energy balance and fertility by the brain throughout the life cycle of the individual, thus paving the way for innovative therapeutic strategies. Our laboratory uses a combination of cellular, molecular, neuroanatomical, electrophysiological, physiological and genomic approaches:

1. To study how developmental changes in hormone levels in the brain and body shape the individual’s neuronal circuit formation and function at different life stages, with childhood and adolescence being increasingly recognized as critical periods of vulnerability.

2. To determine how genes and the environment interact to modify these unfolding developmental processes and evaluate the risks for the onset of metabolic and reproductive disorders later in life.

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Abbreviations: ARH/me[r1] : arcuate nucleus of the hypothalamus/médian eminence; GnRH: gonadotropin releasing hormone; POA: preoptic region; PVH: Periventricular nucleus of the hypothalamus; DMH: dorsomedial nucleus of the hypothalamus; LHA: lateral hypothalamic area; AMH: anti-Mullerian hormone.

References

1 Kennedy, D. & Norman, C. Science 309, 75 (2005).

2 Hanchate, N. K. et al. PLoS Genet 8, e1002896 (2012).

3 Messina, A. et al. Hum Mol Genet 20, 4759-4774 (2011).

4 Parkash, J. et al. J Neurosci 32, 16992-17002 (2012).

5 Prevot, V. et al. J.Neurosci. 23, 230-239 (2003).

6 Clasadonte, J. et al. Proc Natl Acad Sci U S A 108, 16104-16109 (2011).

7 de Seranno, S. et al. Endocrinology 151, 1760-1772 (2010).

8 Prevot, V. et al. Neuroscience 94, 809-819 (1999).

9 Baroncini, M. et al. Neuroimage 50, 428-433 (2010).

10 Ebbeling, C. B., Pawlak, D. B. & Ludwig, D. S. Lancet 360, 473-482 (2002).

11 Rocchini, A. P. N Engl J Med 346, 854-855 (2002).

12 Groop, L. & Orho-Melander, M. J Intern Med 250, 105-120 (2001).

13 Bouret, S. G., Draper, S. J. & Simerly, R. B. Science 304, 108-110 (2004).

14 Bouret, S. G. et al. Cell Metab 7, 179-185 (2008).

15 Coupe, B. et al. Cell Metab 15, 247-255 (2012).

16 Langlet, F. et al. Cell Metab 17, 607-617 (2013).




[r1]Why is me not in capitals? Also, “hormones” in the figure is missing an “m”