Effects of development and prenatal androgen exposure on GnRH neuron intrinsic properties

发育和产前雄激素暴露对 GnRH 神经元内在特性的影响

基本信息

批准号：
10721884
负责人：
Jennifer Jaime
金额：
$ 4.14万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10721884
关键词：
Action Potentials Adult Age Androgenization Androgens Automobile Driving Brain Cells Characteristics Closure by clamp Compensation Computer Models Curiosities Data Development Disease Electrophysiology (science)Estrous Cycle Etiology Exhibits Female Female infertility Fertility Fire - disasters Follicle Stimulating Hormone Frequencies Functional disorder Generations Gonadotropin Hormone Releasing Hormone Hormones Hyperactivity Hyperandrogenemia Impairment Individual Infertility Injections Kinetics Luteinizing Hormone Measures Mediating Membrane Potentials Menarche Modeling Mus Neurons Neurosecretory Systems Output Pathway interactions Patients Pattern Physiologic pulse Play Polycystic Ovary Syndrome Potassium Process Property Puberty Reporting Reproduction Role Scientist Serum Slice Stimulus Symptoms Synapses Synaptic Transmission Testing Testosterone Training Woman Work comparison control gamma-Aminobutyric Acid girls hormone deficiency insight mouse model neuroendocrine phenotype neuronal excitability neurotransmission prenatal receptor reproductive reproductive development reproductive function response subfertility transmission process voltage voltage clamp voltage gated channel

项目摘要

Project Summary Gonadotropin-releasing hormone (GnRH) neurons form the final central pathway for the control of reproductive function, releasing GnRH in a pulsatile manner. Low frequency GnRH pulses favor the secretion of follicle- stimulating hormone (FSH), whereas high frequency GnRH pulses favor the secretion of luteinizing hormone (LH). Disruptions to the secretory patterns of these hormones can result in subfertility or infertility. Polycystic ovary syndrome (PCOS), and in particular hyperandrogenemic PCOS, is a disorder in which disruptions to these hormone release patterns result in impaired fertility. Specifically, sustained high frequency LH, and presumably GnRH, pulses are a hallmark of hyperandrogenemic PCOS. To study neuroendocrine aspects that may contribute to this disorder, the proposed work uses a prenatally androgenized (PNA) mouse model. PNA mice recapitulate many neuroendocrine phenotypes reported in women with hyperandrogenemic PCOS, including disrupted reproductive cycles, elevated LH-pulse frequency and increased testosterone. Studies of GFP-identified GnRH neurons from three-week-old PNA females revealed that action potential firing activity is lower than in cells from controls. In contrast, GnRH neuron activity is increased in cells from adult PNA mice relative to controls. This was a curious observation as GABAergic transmission, which is excitatory in GnRH neurons, was increased at both of these developmental timepoints. In 3-wk old PNA females, GnRH neurons have a reduced firing response to local GABA application compared to controls, but there is no change in either reversal potential for current through the GABAA receptor or in the basal membrane potential of these cells. Together these observations suggest the postulate that changes occur in voltage-gated channels of GnRH neurons from PNA mice to compensate for increased excitatory synaptic input in young mice but that these changes are not maintained in adults, leading to hyperactivity. My early data indicate that GnRH neuron excitability and action potential characteristics can be similar among the groups, but have different underlying ionic conductance characteristics as a result of development and PNA treatment. The first aim of this project tests how voltage-gated potassium (K+) currents, which play a large role in how neurons respond to synaptic inputs and generate action potentials, are altered among these groups. Our findings we be used to generate computational models of potassium currents that will assist in this interpretation The second aim will use dynamic clamp to test if GnRH neurons from control vs PNA mice respond differently to representative trains of simulated GABA conductances from our previous work and/or current injection. We will also test how modelled potassium currents interact with the native milieu of recorded GnRH neurons to account for differences in response. Completion of this project will provide insight into the intrinsic properties of GnRH neurons, how these change during typical development and with PNA treatment, potentially providing insight into the etiology of PCOS and providing me with the training required to successfully become an independent scientist.

项目概要促性腺激素释放激素（GnRH）神经元形成控制生殖的最终中央通路功能，以脉冲方式释放 GnRH。低频 GnRH 脉冲有利于卵泡的分泌刺激激素 (FSH)，而高频 GnRH 脉冲有利于黄体生成素的分泌（左）。这些激素分泌模式的破坏可能导致生育力低下或不孕。多囊性卵巢综合征 (PCOS)，特别是高雄激素血症 PCOS，是一种卵巢功能紊乱的疾病这些激素释放模式会导致生育能力受损。具体来说，持续的高频 LH，以及据推测，GnRH 脉冲是高雄激素血症 PCOS 的一个标志。研究神经内分泌方面可能导致这种疾病，拟议的工作使用产前雄激素化（PNA）小鼠模型。 PNA 小鼠重现了高雄激素血症 PCOS 女性中报道的许多神经内分泌表型，包括生殖周期中断、LH 脉冲频率升高和睾酮升高。研究来自三周大 PNA 雌性的 GFP 鉴定的 GnRH 神经元显示，动作电位放电活动是低于对照细胞中的水平。相比之下，成年 PNA 小鼠细胞中的 GnRH 神经元活性增加相对于控件。这是一个奇怪的观察结果，因为 GABA 能传递，它在 GnRH 中是兴奋的神经元在这两个发育时间点均有所增加。在 3 周龄 PNA 雌性中，GnRH 神经元与对照组相比，对本地 GABA 应用的激发反应有所减少，但没有变化电流通过 GABAA 受体的反转电位或这些受体的基底膜电位细胞。这些观察结果表明，电压门控通道发生变化的假设来自 PNA 小鼠的 GnRH 神经元可补偿年轻小鼠兴奋性突触输入的增加，但这些变化在成年人中无法维持，从而导致多动症。我的早期数据表明 GnRH 神经元各组之间的兴奋性和动作电位特征可能相似，但具有不同的潜在特征由于显影和 PNA 处理而产生的离子电导特性。该项目的第一个目标测试电压门控钾 (K+) 电流的情况，该电流在神经元如何响应突触方面发挥着重要作用投入并产生行动潜力，在这些群体之间发生变化。我们的发现将被用来生成钾电流的计算模型将有助于这种解释第二个目标将使用动态钳测试对照小鼠和 PNA 小鼠的 GnRH 神经元对代表性序列的反应是否不同从我们之前的工作和/或电流注入模拟 GABA 电导。我们还将测试如何建模钾电流与记录的 GnRH 神经元的原生环境相互作用，以解释回复。该项目的完成将深入了解 GnRH 神经元的内在特性，这些变化在典型发育过程中和 PNA 治疗过程中发生变化，有可能提供对病因学的深入了解多囊卵巢综合症的知识，并为我提供成功成为一名独立科学家所需的培训。