Poster Presentation The International Congress of Neuroendocrinology 2014

Circadian clockwork and the GnRH pulse generator (#352)

Xiaofeng LI 1 , Minghan Hu 1 , Shengyu Li 1 , Rebecca Gresham 1 , Lucilla Poston 1 , Hugh Piggins 2 , Strafford Lightman 3 , Kevin T O'Byrne 1
  1. Division of Women’s Health, School of Medicine, King's College London, London, UK
  2. Faculty of Life Sciences, University of Manchester, Manchester, UK
  3. Henry Wellcome Laboratory for Integrative Neuroscience & Endocrinology, Dorothy Hodgkin Building, University of Bristol, Bristol, UK

Circadian clocks play a fundamental role in reproduction. Less well recognised, however, are the presence of a clock mechanism intrinsic to GnRH neurones1 and that perturbation of circadian clock function in the GnRH cell line, GT1-7, markedly decreased the frequency of pulsatile GnRH secretion2. These data suggest an unexpected and important role for local clock genes in ultradian rhythmicity. Whilst we know that mice harbouring mutations in clock genes, such as Bmal1, exhibit subfertility, including delayed puberty, disturbed oestrous cycles and lack of LH surges, whether the phenotype arises from disruption to the ultradian activity of the GnRH pulse generator is unknown. We investigated whether there is any correlation between local clock gene expression and LH pulse frequency at different stages of pubertal development or during stress-induced suppression of pulsatile LH secretion in female rats. We test the hypothesis that disruption of intrinsic local circadian clock activity in the hypothalamic arcuate nucleus (ARC), the anatomical location of the GnRH pulse generator, affected pulsatile LH secretion. Expression of Bmal1 increased and Per1 mRNA decreased in micropunches of the ARC (detected by qRT-PCR) between the juvenile [postnatal days (PND) 14] and early pubertal stage (PND 32) in female rats which corresponds with increased LH pulse frequency. Immunological stress acutely decreased Bmal1 expression in the ARC within 2 hours after administration of lipopolysaccharide concomitant with LH pulse suppression in adult ovariectomized rats. Finally, we have demonstrated that inhibition of intrinsic local circadian clock activity by microinjection of Bmal1 shRNA into the ARC of ovariectomized rats caused an acute progressive slowing of LH pulse frequency. These results give rise to the novel concept that local circadian clockwork mechanisms underlie ultradian GnRH secretion and synchronisation of the GnRH neuronal network. 

  1. Hickok JR etal 2010, Neuroendocrinol 91:110.
  2. Chappell PE, 2003, J Neurosci. 23:11202.