Genetic Identification of GnRH Receptor Neurons: A New Model for Studying Neural Circuits Underlying Reproductive Physiology in the Mouse Brain

• Published in: Endocrinology (Philadelphia) 2011-04, Vol.152 (4), p.1515-1526
• Main Authors: Wen, Shuping, Götze, Iris N, Mai, Oliver, Schauer, Christian, Leinders-Zufall, Trese, Boehm, Ulrich
• Format: Article
• Language: English
• Subjects: Animal reproduction; Animals; Biological and medical sciences; Brain; Brain - metabolism; Brain slice preparation; Calcium (extracellular); Calcium imaging; Calcium ions; Calcium signalling; Central nervous system; Chemoreception; Female; Fluorescence; Fluorescent Antibody Technique; Functionals; Fundamental and applied biological sciences. Psychology; Gonadotropin-releasing hormone; Hypothalamic-pituitary-gonadal axis; Hypothalamus; Hypothalamus - cytology; Hypothalamus - metabolism; In Vitro Techniques; Luteinizing hormone; Male; Mice; Neural Conduction - genetics; Neural Conduction - physiology; Neural networks; Neuroimaging; Neurons; Neurons - metabolism; Odorants; Olfactory pathways; Olfactory stimuli; Pheromones - metabolism; Physiology; Pituitary; Pituitary-gonadal axis; Proteins - genetics; Proteins - metabolism; Receptors; Receptors, LHRH - genetics; Receptors, LHRH - metabolism; Reproduction; Reproductive behavior; RNA, Untranslated; Sexual behavior; Sexual Behavior, Animal - physiology; Signal Transduction - genetics; Signal Transduction - physiology; Thalamus - cytology; Thalamus - metabolism; Vertebrates; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1208

This study uses a binary genetic strategy to identify GnRH receptor neurons in the mouse brain and starts to characterize these cells anatomically and physiologically. GnRH signaling regulates reproductive physiology in vertebrates via the hypothalamic-pituitary-gonadal axis. In addition, GnRH signaling has been postulated to act on the brain. However, elucidating its functional role in the central nervous system has been hampered because of the difficulty in identifying direct GnRH signaling targets in live brain tissue. Here we used a binary genetic strategy to visualize GnRH receptor (GnRHR) neurons in the mouse brain and started to characterize these cells. First, we expressed different fluorescent proteins in GnRHR neurons and mapped their precise distribution throughout the brain. Remarkably, neuronal GnRHR expression was only initiated after postnatal day 16, suggesting peri- and postpubertal functions of GnRH signaling in this organ. GnRHR neurons were found in different brain areas. Many GnRHR neurons were identified in areas influencing sexual behaviors. Furthermore, GnRHR neurons were detected in brain areas that process olfactory and pheromonal cues, revealing one efferent pathway by which the neuroendocrine hypothalamus may influence the sensitivity towards chemosensory cues. Using confocal Ca2+ imaging in brain slices, we show that GnRHR neurons respond reproducibly to extracellular application of GnRH or its analog [D-TRP6]-LH-RH, indicating that these neurons express functional GnRHR. Interestingly, the duration and shape of the Ca2+ responses were similar within and different between brain areas, suggesting that GnRH signaling may differentially influence brain functions to affect reproductive success. Our new mouse model sets the stage to analyze the next level of GnRH signaling in reproductive physiology and behavior.