Intrinsic Clocks

Author : Xue Wei Lin
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (973 download)

DOWNLOAD NOW!

Download or read book Role of Circadian Clocks Intrinsic to SCN and GnRH Neurons in Regulating Luteinizing Hormone Surge and Other Reproductive Functions written by Xue Wei Lin and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The circadian clock represents a self-sustaining, entrainable oscillator driving rhythms of ~24 hours. The mammalian circadian system is organized in a hierarchical manner in which the suprachiasmatic nucleus (SCN) acts as the master pacemaker, coordinating the oscillations of peripheral clocks. Desynchrony of these oscillators due to shift work and intercontinental travel may contribute to reproductive dysfunction, warranting the study of the role that circadian clocks play in reproduction. Ovariectomized (OVX) rodents supplemented with surge-permissive estradiol exhibit a daily luteinizing hormone (LH) surge even in constant darkness, arguing that the surge is circadian regulated. While our lab has previously shown that mice deficient of clock function in all tissues (Bmal1-/-) completely lacked a LH surge, the contribution of individual clocks in specific hypothalamic-pituitary-gonadal (HPG) axis elements to the surge is still largely unclear. Our lab has already studied mice carrying a gonadotrope-specific disruption of the essential clock component Bmal1 (GBmal1KO) by means of Cre-LoxP technology and found evidence that the clock intrinsic to gonadotropes has no major role in the generation of the preovulatory LH surge. This suggests that circadian clocks elsewhere must be required for surge production. Therefore, my aim was to explore the specific contributions of the intrinsic clocks in the GnRH-expressing neurons in the preoptic area (POA) of the hypothalamus and of the SCN to the regulation of the LH surge. To this end, we created mice that lack clock function selectively in either GnRH-expressing neurons or in the SCN by disrupting Bmal1 employing, again, Cre-LoxP technology. We were able to achieve Bmal1 ablation efficacies of approximately 76% and 94% in the hypothalamic GnRH neurons of our GnBmal1KO line and the SCN cells of our SCN-Bmal1KO line, respectively. Examinations of puberty onset, body weight, estrus cyclicity as well as serum gonadotropin levels in GnBmal1KO females, however, indicate that these animals were reproductively normal under laboratory conditions. SCN-Bmal1KO females, on the contrary, displayed prolonged estrus cycles likely due to extended time spent in estrus. Moreover, these females also displayed blunted LH surge levels as well as a dysregulation of LH surge timing. FSH levels were highly dysregulated as well. As Bmal1-/- females completely lacked a LH surge, this suggests that either the residual BMAL1+ cells in the SCN of the SCN-Bmal1KOs were sufficient to produce the observed LH surge or that surge production depends on clocks at different levels of the HPG axis, possibly by a concerted action. Studying clocks in kisspeptin neurons, which are thought to serve a central role in reproduction, as well as clocks in the ovarian cells may, therefore, represent the crucial next step in the quest for the mechanism underlying the timed production of the LH surge. " --