Sunday, May 25, 2025
5/25/2025
Food and Light Cue Entrainment of the Ovulation Stimulating HPG Axis - Abstract Circadian disruptions like shift work are associated with reproductive health difficulties including infertility. When estrogen is high, the circadian system triggers the pre-ovulatory luteinizing hormone (LH) surge at lights-off in humans and rodents. These rhythms are perturbed, however, when food is eaten during the rest phase, as is common in shift work. In rodents, mistimed food reduces fertility by 30% and disrupts the normal timing of mating behavior and ovulation, but the mechanisms are not known. We will test the hypothesis that misalignment of light and food cues compromise the function of kisspeptin neurons of the anteroventral periventricular nucleus (AVPVKISS) and prevent the normal timing of the LH surge. First, in Aim 1, we will map AVPVKISS monosynaptic projections for the first time with a paired adeno associated virus and G-deleted rabies virus in Kiss1Cre mice. We have confirmed that AVPVKISS afferent neurons are located in areas that include the suprachiasmatic nucleus (site of the central circadian clock) and the arcuate nucleus (key area in feeding regulation). By mapping this circuit, it will give us insight into regions important for the induction of the LH surge and will provide our lab and the field with new mechanistic targets. In Aim 2, we will investigate whether food-sensitive arcuate AgRP and POMC neurons link mistimed food to the desynchronized LH surges. These cell groups are complementary orexigenic and anorexigenic neurons that project to the AVPV, and the AgRP cells have previously been shown to encode food timing. We will test the effect of silencing these neurons specifically during conditions of food restriction with the prediction that this will relieve the pressure of mis-timed food and rescue the normal synchronized LH surge time. Together, these experiments will establish candidate inputs to the regulation of ovulation and establish the role for food sensitive neurons in transducing food intake rhythms to rhythmic physiology and behavior. This research project provides an opportunity for learning the theory and techniques of modern systems neuroscience through the lens of reproductive neuroendocrinology. The proposed experiments will provide fundamental training in neural reproductive research and enable the study of circadian control of other neuroendocrine signaling systems in the future. Further career development training will include writing and reviewing manuscripts, didactic coursework, pedagogy and mentoring training, and opportunities to present the results and network at OHSU symposia and at national meetings. The training will take place in the Neuroscience Graduate Program's collaborative and supportive environment within the Vollum Institute at OHSU.
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