PROJECT 3 - Steroid-Metabolic Interactions In the Control of GnRH Neurons

促性腺激素释放激素(GnRH)神经元是大脑控制的最终共同途径 生育能力。在常见的生殖障碍多囊卵巢综合征(PCOS)中，GnRH神经元 过度活跃，导致脑下垂体释放黄体生成素(LH)的频率增加 提高睾丸激素的分泌水平。雄激素具有中枢刺激作用，形成积极的 反馈环，以增加GnRH神经元的活性。雄激素也干扰正常的负反馈。 黄体酮的作用，这通常会降低这一系统的活动。除了不孕不育，多囊卵巢综合征 使女性易患许多代谢紊乱，包括胰岛素抵抗、中心性肥胖症和 血脂异常。升高的胰岛素也可以增加睾丸素的产生，进一步刺激上述 正反馈环路。在这项提案中，我们将研究潜在的神经生物学机制。 雄激素、孕酮和代谢信号在调节GnRH神经元中的作用，以及这些因素是如何 使用最先进的电生理方法与仔细结合在一起在中央层面进行互动 动物模型开发。这一主要推力将由电生理和有限的 具有多囊卵巢综合征妇女许多表型特征的小鼠模型的代谢研究。 在目标1中，类固醇和代谢信号对促性腺激素释放激素神经元内在特性的影响将是 研究，包括这些因素如何相互作用来改变离子通道功能。Aim 2将研究以下变化 激素和代谢引起的GABA能快速突触传递给GnRH神经元 暗示。在目标3中，我们将继续描述产前雄激素化的小鼠作为临床前模型的特征 多囊卵巢综合征。产前服用双氢睾丸酮的小鼠表现出动情周期中断，并升高 睾酮和黄体生成素水平与多囊卵巢综合征患者相似。初步数据显示这些老鼠 糖耐量低减，不受肥胖改变的影响。我们将进一步鉴定代谢表型。 并检查这种疾病的生殖和代谢方面之间的因果关系。同舟共济 这些研究将为促性腺激素释放激素神经元的基础生物学和病理学提供新的信息。 将导致新疗法的临床前和临床试验的多囊卵巢综合征的状况

Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway by which the brain controls fertility. In the common reproductive disorder polycystic ovary syndrome (PCOS), GnRH neurons are hyperactive, leading to increased frequency of luteinizing hormone (LH) release from the pituitary, driving increased levels of testosterone production. Androgens have a stimulatory role centrally, forming a positive feedback loop to increase GnRH neuron activity. Androgens also interfer with the normal negative feedback actions of progesterone, which typically reduce activity of this system. In addition to infertility, PCOS predisposes women to many metabolic disorders, including insulin resistance, central adiposity and dyslipidemia. Elevated insulin can also act to increase testosterone production, further stimulating the above positive feedback loop. In this proposal, we will examine neurobiological mechanisms underlying the effects of androgens, progesterone and metabolic cues in regulating GnRH neurons, as well as how these factors interact at the central level using state-of-the-art electrophysiological approaches combined with careful animal model development. This main thrust will be complemented by electrophysiological and limited metabolic studies of a mouse model that has many of the phenotypic characteristics of women with PCOS. In Aim 1, the effects of steroids and metabolic cues on the intrinsic properties of GnRH neurons will be studied, including how these factors interact to alter ion channel function. Aim 2 will examine the changes in GABAergic fast synaptic transmission to GnRH neurons that are brought about by steroids and metabolic cues. In Aim 3, we will continue characterization of prenatally androgenized mice as a preclinical model for PCOS. Mice treated prenatally with dihydrotestosterone exhibit disrupted estrous cycles, and elevated levels of testosterone and LH similar to women with PCOS. Preliminary data indicate these mice are glucose intolerant independent of altered adiposity. We will further characterize the metabolic phenotype and examine the causal relationships between reproductive and metabolic aspects of this disorder. Together these studies will provide novel information about the basic biology of GnRH neurons and the pathological state of PCOS that will lead to preclinical and clinical trials of new therapies