Neural and pituitary mechanisms linking epilepsy to co-morbid reproductive endocrine dysfunction

将癫痫与共病生殖内分泌功能障碍联系起来的神经和垂体机制

• 批准号: 9815934
• 负责人: Catherine A Christian-Hinman
• 金额: $ 6.08万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815934
• 关键词: Action Potentials; Acute; Adult; Amenorrhea; Animal Model; Benchmarking; Biological Assay; Brain; CNS Metabolic Disorders; Cardiovascular Diseases; Cells; Clinical; Clinical Research; Collaborations; Comorbidity; Convulsants; Data; Electroencephalography; Electrophysiology (science); Endocrine; Endocrine System Diseases; Epilepsy; Estrous Cycle; Estrus; Exhibits; Female; Functional disorder; GNRH1 gene; Gene Expression; Gene Expression Profiling; General Population; Genes; Genetic; Glutamates; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Health; Hippocampus (Brain); Hypothalamic structure; Impairment; Injections; Investigation; Kainic Acid; Knowledge; Link; Luteinizing Hormone; Malignant Neoplasms; Measurement; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Partial Epilepsies; Pathway interactions; Patients; Pattern; Periodicity; Pituitary Gland; Pituitary Gonadotropins; Play; Polycystic Ovary Syndrome; Premature Menopause; Property; Publishing; Quality of life; Receptor Activation; Reporting; Reproduction; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Role; Saline; Seizures; Seminal fluid; Slice; Steroid biosynthesis; Synapses; Synaptic Transmission; Temporal Lobe Epilepsy; Testing; Testosterone; Therapeutic; Time; Woman; Work; experimental study; gamma-Aminobutyric Acid; improved; in vivo; innovation; insight; male; men; mind control; mouse model; neuromechanism; novel; optogenetics; patch clamp; relating to nervous system; reproductive; reproductive function; response; sex; translational impact; transmission process

PROJECT SUMMARY Both men and women with temporal lobe epilepsy (TLE), the most common partial epilepsy in adults, exhibit higher rates of reproductive endocrine disorders compared to the general population. Reproductive endocrine disorders significantly impact quality of life and, if untreated, can result in elevated risks for other central nervous system, metabolic, and cardiovascular disorders, and cancer. Seizures appear to be major drivers of reproductive endocrine co-morbidities, but the neural mechanisms underlying this relationship have not been described. In the proposed work, we will elucidate neural mechanisms that link epilepsy to reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons form the final common pathway in the brain's control of reproduction and thus likely play critical roles in the pathophysiology of epilepsy-associated reproductive endocrine disorders. Proper GnRH release patterns are necessary to drive pulsatile luteinizing hormone (LH) release from the pituitary gland in both males and females. Clinical studies have reported disrupted patterns of LH release in men and women with epilepsy, but the mechanistic underpinnings have yet to be elucidated. A major gap in knowledge thus exists about the effects of epilepsy on GnRH neurons, their synaptic afferents, and downstream impacts on pituitary function. Our overall objectives in the proposed studies are to determine key functional changes in hypothalamic-pituitary cells and circuits in a mouse model of TLE. We recently reported that female estrous cyclicity is disrupted in most epileptic female mice in this model, indicating that it is appropriate for these studies. Our central hypothesis is that seizure activity drives changes in the activity of GnRH neurons and their synaptic inputs, thereby impacting downstream pituitary LH release. We will test this hypothesis using an innovative combination of patch clamp electrophysiology, electroencephalography (EEG), optogenetics, pituitary gene expression analysis, and a cutting-edge ultrasensitive assay for determining mouse LH release patterns in vivo. In Aim 1 we will perform the first direct investigations of epilepsy-associated changes in GnRH neuron firing activity, intrinsic excitability, and fast synaptic inputs. In Aim 2 we will determine the functional relationships between hippocampal seizure activity, hypothalamic GnRH release, and pituitary response to GnRH. Successful completion of these Aims will have positive translational impact and further the goals of the NINDS Epilepsy Research Benchmarks by providing key mechanistic insights into the underlying neural and pituitary substrates of reproductive endocrine disorders that commonly arise with epilepsy.

项目摘要 颞叶癫痫（TLE）的男性和女性，成人最常见的部分癫痫 与普通人群相比，生殖内分泌疾病的率更高。生殖内分泌 疾病会显着影响生活质量，如果未经治疗，可能会导致其他中央的风险升高 神经系统，代谢和心血管疾病以及癌症。癫痫发作似乎是 生殖内分泌合并症，但这种关系的神经机制尚未 描述。在拟议的工作中，我们将阐明将癫痫连接到生殖的神经机制 内分泌功能障碍。下丘脑促性腺激素释放激素（GNRH）神经元构成最终常见 大脑控制繁殖的途径，因此可能在病理生理中起关键作用 癫痫相关的生殖内分泌疾病。适当的GNRH释放模式是必要的 男性和雌性的垂体腺素（LH）从垂体中释放出来。临床研究 报告了患有癫痫的男性和女性的LH释放模式中断，但机械 基础尚未阐明。因此，知识的主要差距存在有关癫痫对的影响 GNRH神经元，其突触传入和下游对垂体功能的影响。我们的整体目标 在拟议的研究中，是确定下丘脑 - 垂体细胞和电路中的关键功能变化 TLE的鼠标模型。我们最近报道说，大多数癫痫女性的女性发情环境受到破坏 该模型中的小鼠，表明它适合这些研究。我们的中心假设是癫痫发作 活动驱动GNRH神经元及其突触输入的活动的变化，从而影响 下游垂体LH释放。我们将使用斑块夹的创新组合检验该假设 电生理学，脑电图（EEG），光遗传学，垂体基因表达分析和A 尖端的超敏化测定法，用于确定体内小鼠LH释放模式。在AIM 1中，我们将表演 首次直接研究GNRH神经元发射活性的癫痫相关变化，内在的兴奋性， 和快速的突触输入。在AIM 2中，我们将确定海马癫痫发作之间的功能关系 活性，下丘脑GNRH释放以及对GNRH的垂体反应。这些目标成功完成 将产生积极的翻译影响，并进一步进一步 提供对生殖内分泌的基本神经和垂体底物的关键机理见解 癫痫通常引起的疾病。