Exciting recent studies have demonstrated autonomous circadian oscillators in many regions outside of the suprachiasmatic nucleus (SCN), the site of the mammalian master circadian pacemaker. The existence of multiple oscillators had been postulated for decades, as a basis for the desynchrony of overt circadian rhythms that occurs during shift work, jet lag and depression. These extra-SCN oscillators have been studied mainly in vitro using tissues explanted from males;thus the physiological role of these oscillators is not yet known, especially in females. We propose to investigate the regulation of circadian rhythms in clock gene expression in vivo in female neuroendocrine cells, the gonadotropin releasing hormone (GnRH) neurons, because they have an easily measured, physiologically important output, the preovulatory luteinizing hormone (LH) surge. Although the LH surge depends on the SCN, the GnRH neurons themselves express the circadian clock gene Per1. Furthermore, immortalized GnRH neurons, GT1-7 cells, exhibit circadian rhythms of clock gene expression in vitro. Disruption of these molecular circadian rhythms in GT1-7 cells alters their pattern of GnRH secretion, suggesting that molecular circadian clocks are necessary for the secretory function of GnRH neurons. This proposal aims to study the regulation and function of a circadian molecular oscillation in native GnRH neurons in female hamsters.
The specific aims are to investigate:
Aim 1) the role of circadian phase advances in control of the LH surge, Aim 2) the role of SCN GABA-A receptors in control of the LH surge, Aim 3) the role of circadian clock genes in the SCN in control of the LH surge, Aim 4) the role of vasopressin as an output signal from the SCN regulating GnRH neurons, and Aim 5) the expression of PER1 in endogenous GnRH neurons and its role in the LH surge. These studies will exploit the GnRH neurons as a model system with an essential physiological role and easily measured output, in order to elucidate the regulation and function of an extra-SCN brain oscillator in vivo. Understanding multiple oscillators is important for the amelioration of internal desynchrony of circadian rhythms that occurs during shift work and jet lag. Also, by studying females, the findings of this project may be relevant to the disruptions in circadian hormone rhythms seen in women with affective disorders.This project seeks to understand the regulation and interaction of multiple circadian oscillators that regulate circadian neuroendocrine rhythms. Understanding multiple circadian oscillators is important for amelioration of circadian rhythms desynchrony, which occurs during shift work, jet lag, aging and depression, and increases the risk of obesity, cardiovascular disease, cognitive deficits, and depression. Because this project focuses on females, the findings will also be relevant to disruptions in circadian hormone rhythms seen in women with affective disorders, such as pre-menstrual dysphoric syndrome, post-partum depression and postmenopausal depression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-D (02))
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Mitler, Merrill
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University of Kentucky
Anatomy/Cell Biology
Schools of Medicine
United States
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