Defining the neurophysiologic mechanisms engaged by estradiol feedback in regulating reproductive neuroendocrine function

定义雌二醇反馈调节生殖神经内分泌功能的神经生理机制

• 批准号: 10004137
• 负责人: Joseph Rudolph Starrett
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004137
• 关键词: Action Potentials; Affect; American; Animal Model; Anovulation; Anterior Pituitary Gland; Anxiety; Automobile Driving; Biosensor; Brain; Calcium; Cell Nucleus; Cells; Country; Couples; Data; Development; Diestrus; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrous Cycle; Family; Feedback; Female infertility; Fiber; Follicle Stimulating Hormone; Frequencies; Goals; Gonadotropin Hormone Releasing Hormone; Growth; Hormone secretion; Hormones; Human; Infertility; Ion Channel; KISS1 gene; Knowledge; Lead; Location; Luteinizing Hormone; Macaca mulatta; Mammals; Measures; Mediating; Membrane Potentials; Modeling; Mus; Neurons; Neurosecretory Systems; Output; Ovarian; Ovulation; Pattern; Physiological; Pituitary Gland; Play; Potassium; Primates; Process; Proestrus; Property; Reproduction; Reproductive Health; Rodent; Role; Signal Transduction; Site; Slice; Sodium; Source; Stress; Synapses; Synaptic Transmission; System; Testing; Woman; gamma-Aminobutyric Acid; improved; infertility treatment; insight; neuromechanism; neurophysiology; neuroprotection; novel; postsynaptic; presynaptic; proliferative phase Menstrual cycle; reproductive; reproductive function; response; steroid hormone; transmission process; voltage

Project Summary 15-20% of American couples struggle with infertility problems. The most common cause of infertility in women is anovulation, thus understanding how ovulation is controlled is critical for assisting the formation and growth of families, improving the reproductive health of our country, and increasing our fundamental knowledge of reproduction. Ovulation is stimulated by a switch in the pattern of luteinizing hormone (LH) secretion from episodic to continuous release (LH surge). At low physiological concentrations, estradiol regulates episodic secretion (negative feedback). Sustained elevation of estradiol at the end of the follicular phase (proestrus in rodents) stimulates the onset of the LH surge (positive feedback). In most mammals, the LH surge is triggered by an estradiol-induced surge in gonadotropin-releasing hormone (GnRH) secretion and an accompanying increase in pituitary response to this hormone. Although a shift in the pattern of GnRH input is not needed to induce an LH surge in humans, both pre-ovulatory and estradiol-induced surges have been observed in rhesus macaques, suggesting a GnRH surge likely plays a role in typical reproductive function in primates as well. The goals of this proposal are to increase our knowledge of the central neuronal mechanisms driving the transition from negative to positive feedback during the cycle, and to determine if these mechanisms are estradiol- sensitive. GnRH neurons themselves do not express detectable levels of estrogen receptor α (ERα), thus estradiol-sensitive afferents are needed in this process The anteroventral-periventricular nucleus (AVPV) is postulated to be a critical site for estradiol positive feedback as it contains neurons that co-express both kisspeptin, a potent activator of GnRH secretion, and ERα, AVPV kisspeptin neurons express more kisspeptin and are more active in an estradiol-dependent manner during positive feedback, suggesting increased signaling from these cells helps drive positive feedback. There are still gaps in our understanding of how estradiol activates AVPV kisspeptin neurons and modulates their transmission of kisspeptin and fast synaptic signals to GnRH neurons. We hypothesize estradiol modulates potassium currents and synaptic properties of AVPV neurons during positive feedback to increase their activity and subsequent transmission of excitatory signals to GnRH neurons. In two Aims, we will measure potassium currents, functional synaptic connectivity and plasticity, and kisspeptin release by AVPV kisspeptin neurons to determine if these parameters are modified by the transition from negative to positive feedback during the cycle by comparing diestrous and proestrous mice. To examine which mechanisms are specifically regulated by estradiol, we will utilize a murine estradiol-induced LH surge model. These studies will help provide mechanistic insights that will help build on our understanding of the neurophysiological mechanisms by which estradiol regulates reproductive neuroendocrine output. This knowledge can inform new fertility treatments as well as treatments targeted at other estradiol-modulated central processes, such as anxiety, neuroprotection, and response to stress.

项目总结