title: Kisspeptin signaling in the amygdala modulates reproductive hormone secretion.
abstract: Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a 'master regulator' of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.
authors.affiliation: Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Comninos
authors.affiliation: Metabolic and Molecular Imaging Group, MRC Clinical Science Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Anastasovska
authors.affiliation: Metabolic and Molecular Imaging Group, MRC Clinical Science Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Meliz
authors.initials: M
authors.lastname: Sahuri-Arisoylu
authors.affiliation: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Shengyun
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Minghan
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Channa N
authors.initials: CN
authors.lastname: Jayasena
authors.affiliation: Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.affiliation: Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.affiliation: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: O'Byrne
authors.affiliation: Metabolic and Molecular Imaging Group, MRC Clinical Science Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Bell
authors.affiliation: Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. w.dhillo@imperial.ac.uk.
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D003287:Contrast Media; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D059648:Kisspeptins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008345:Manganese; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction
chemical_list: D003287:Contrast Media; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D008345:Manganese; D007986:Luteinizing Hormone
keywords: Amygdala; Gonadotropin-releasing hormone neuron; Hypothalamus; Kisspeptin; Manganese-enhanced MRI; Reproductive axis