Function and Control of Hypothalamic Oscillators

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DESCRIPTION (provided by applicant): Fertility depends upon the appropriate timing of functions controlled by specialized neurons of the hypothalamus and preoptic area. The control of ovulation by the suprachiasmatic nucleus (SCN) is one of the best-established physiological functions of the circadian clock. The central question of this proposal is whether circadian oscillators in the SCN are not only necessary, but also sufficient, to explain the timing of the LH surge. Circadian rhythms arise from the operation of well-defined transcriptional-translational feedback loops in which the oscillating expression of core clock genes is critical. These loops underlie circadian rhythms that take place not only in the SCN, but also in other brain regions and the periphery. Neither the extent nor the physiological importance of clock gene expression in specific cell types is well understood. Crosses between mice in which clock genes are floxed and lines bearing appropriate Cre drivers has led to exciting progress in studies of the peripheral organs and the retina, but application of this strategy to understanding the role of circadian rhythms in specific brain functions has not yet been accomplished. Circadian clocks appear to run not only in both GnRH cells which directly regulate the preovulatory LH surge and kisspeptinergic neurons from which they receive input. We will use Cre-Lox technology to determine not only the role of circadian function in each of these cell types, but also the importance for normal function of the coordination of phase and period of master and subordinate oscillators. First, we will selectively eliminate clock function by targeting Bmal1 in neurons that express GnRH or kisspeptin in order to determine whether the appropriate timing of the preovulatory LH surge depends upon local circadian oscillations. Second, we will selectively manipulate the period of master and subordinate oscillators to determine the consequences for the LH surge. Establishment of this approach will open new tools for understanding the mechanisms by which circadian systems coordinate behavior and physiology more generally. Given the pivotal role of neurons that contain such oscillators in a variety of homeostatic and reproductive processes, this research will reveal mechanisms that underlie metabolic diseases and infertility and lead to development of new therapies.