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Circadian Regulation of Hypothalamic Kiss1 in Neonatal Development, Adulthood and Pregnancy in the Mouse

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Circadian Regulation of Hypothalamic Kiss1 in Neonatal Development, Adulthood and Pregnancy in the Mouse Circadian Regulation of Hypothalamic Kiss1 in Neonatal Development, Adulthood and Pregnancy in the Mouse by Cassandra Ching-Lin Yap M.Sc. This thesis is presented for the degree of DOCTOR OF PHILOSOPHY of The University of Western Australia School of Anatomy, Physiology and Human Biology Submitted: June 2016 ii Preface The experimental work presented in this thesis was undertaken in the School of Anatomy, Physiology and Human Biology, The University of Western Australia, under the supervision of Dr. Jeremy T. Smith, Dr. Peter J. Mark and Prof. Brendan J. Waddell, with the financial assistance of an Australian Postgraduate Award, a UWA Safety-Net Top- Up Scholarship and a UWA PhD Completion Scholarship. The experimental work was supported, in part, by an Australian Research Council Discovery Project Grant (Discovery Project 120100521) and the Western Australian Department of Health (Grant number 1062158 2014). The work described is original and was carried out by myself except where the specific contributions of other persons are acknowledged. Cassandra Ching-Lin Yap June 2016 iii iv Abstract Kisspeptin is the product of the Kiss1 gene; it drives the hypothalamic-pituitary-gonadal (HPG) axis and is crucial for reproduction and pubertal maturation. It is expressed in two discrete populations of hypothalamic neurons, located in the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC kisspeptin neurons are negatively regulated by estrogen, suggestive of its role here in negative feedback regulation of the pulsatile secretion of gonadotropin-releasing hormone (GnRH), while AVPV kisspeptin neurons are positively regulated by estrogen, indicating its involvement in the generation of the preovulatory GnRH/luteinizing hormone (LH) surge that occurs in females. The LH surge in female rodents is under tight circadian control and its timing is governed by the central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. Kisspeptin neurons in the AVPV receive circadian input through arginine vasopressin (AVP) neurons from the SCN, integrating circadian and estrogen signals, and consequently triggering the LH surge. The overall objective of the studies described herein was to investigate the circadian expression of hypothalamic Kiss1 during neonatal development (pre-pubertal), adulthood (post-pubertal) and pregnancy. Four separate studies were carried out for this thesis. As AVPV kisspeptin neurons are heavily involved in generating the LH surge, the circadian patterns of kisspeptin neuronal activation and mRNA expression are synchronous with LH levels at proestrus. However, it is not known if this kisspeptin rhythm persists during pregnancy and was therefore investigated in Chapter 5 using real- time PCR. In non-pregnant mice, Kiss1 expression in the AVPV peaked in the evening of proestrus, preceded by an increase Avpr1a mRNA levels at noon and followed by an LH surge. In addition, the circadian variation in Avpr1a and Kiss1 expression seen at proestrus was not observed at any stage of pregnancy despite high E2 concentrations, indicating a disruption of the normal kisspeptin circadian rhythm during pregnancy. As E2 levels were high during pregnancy and clock gene circadian rhythms remained intact, suppression of the kisspeptin circadian rhythm was potentially due to a disruption of circadian input to the AVPV. Since progesterone (P4) and prolactin (PRL) greatly increase during pregnancy and have direct effects on kisspeptin, Chapter 6 investigated whether either of these hormones is able to affect the evening increase in Kiss1 in E2- v treated ovariectomised (OVX) mice. Kiss1 and Kiss1r mRNA expression increased in the evening, compared to the morning, in OVX mice that were treated with E2 only. Moreover, time-of-day variation in Bmal1 expression was observed across all treatment groups, suggestive of persistent clock gene rhythmicity in the pregnant state. The study indicates that P4 and PRL may play a role in disrupting circadian input to the AVPV during pregnancy, resulting in a suppression of the circadian kisspeptin rhythm. Chapter 7 utilised RNA sequencing to examine genes in the anterior hypothalamus that were differentially expressed between proestrus and pregnancy, to elucidate potential mechanisms underlying the suppression of the kisspeptin circadian rhythm during pregnancy. While there was a trend for increased Kiss1 expression in the evening of proestrus similar to Chapter 5, this failed to reach statistical significance, possibly due to the low number of replicates. Several genes involved in haemoglobin production and the suppression of cytokine signalling were elevated during pregnancy compared to proestrus. In addition, although a number of genes were found to exhibit oscillatory expression at proestrus but not during pregnancy, similar to the pattern of Kiss1 expression observed in Chapter 5, their lack of specific association with kisspeptin signalling suggests that they may not be involved in the suppression of the kisspeptin circadian rhythm during pregnancy. Finally, Chapter 8 in this thesis shifted the focus to Kiss1 expression during the neonatal period and whether the circadian kisspeptin rhythm observed in adult proestrus females is present before puberty. Hypothalamic Kiss1 mRNA expression in neonatal mice at postnatal days (P) 5, 15 and 25 showed no circadian variation. Furthermore, expression of the clock genes Bmal1 and Rev-erbα was not fully rhythmic at P25; Bmal1 demonstrated rhythmicity only in P25 females, while Rev-erbα was rhythmic in P25 males. The results indicate that immature SCN rhythmicity, in combination with low E2 levels, precludes the development of the circadian kisspeptin rhythm before puberty. Overall, the studies presented in this thesis investigated the circadian patterns of Kiss1 expression in the mouse hypothalamus. In doing so, this thesis provides new insights into kisspeptin and its role in reproduction during the pre-pubertal period, adulthood and in pregnancy. vi Acknowledgements I would first and foremost like to thank my supervisor Jeremy Smith for his guidance, encouragement, patience and understanding throughout this journey. It has been an honour being your first PhD student. I am very grateful to my co-supervisors Peter Mark and Brendan Waddell; the advice and wisdom they have imparted to me have been invaluable. A big thank you goes to the ladies of Room 2.36, past and present. You made all of this bearable and I truly appreciate the friendship each and every one of you has extended me, especially Michaela Wharfe, Rachael Crew and Lauren Butchart. To my parents, I wish to express my heartfelt gratitude for their unwavering support in my doctoral pursuit. I could not have made it this far without their unconditional love and support. vii viii Table of Contents Preface ........................................................................................................ iii Abstract ........................................................................................................ v Acknowledgements ................................................................................... vii Table of Contents ....................................................................................... ix List of figures ........................................................................................... xiii List of tables............................................................................................... xv Thesis Format .......................................................................................... xvii Abbreviations ........................................................................................... xix Publications arising from this and related work ................................ xxiii Presentations ......................................................................................... xxiii Chapter 1: Introduction ............................................................................ 1 Chapter 2: Literature Review .................................................................. 3 2.1 Reproductive Biology of the Laboratory Mouse .......................................... 3 2.1.1 Puberty ..................................................................................................................... 3 2.1.2 Estrous cycle ............................................................................................................ 3 2.1.3 Ovulation .................................................................................................................. 4 2.1.4 Pregnancy ................................................................................................................. 4 2.1.5 Hormone levels during the estrous cycle and pregnancy ......................................... 5 2.2 The Hypothalamus .......................................................................................... 8 2.2.1 Suprachiasmatic nucleus .......................................................................................... 8 2.2.2 Anteroventral periventricular nucleus ...................................................................... 9 2.2.3 Arcuate nucleus ........................................................................................................ 9 2.3 The hypothalamic-pituitary-gonadal (HPG) axis ...................................... 10 2.4 Kisspeptin ...................................................................................................... 11 2.4.1
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