Epilepsy-Associated Dysfunction in the Kisspeptin-GnRH Neural Circuit

Kisspeptin-GnRH 神经回路中癫痫相关的功能障碍

• 批准号: 10579170
• 负责人: Robbie Ingram
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579170
• 关键词: Acute; Adult; Amenorrhea; Animal Model; Beds; Benchmarking; Brain; Bypass; Calcium; Cell Nucleus; Cells; Clinical Research; Closure by clamp; Data; Development; Diagnosis; Diestrus; Electric Stimulation; Electrophysiology (science); Endocrine; Endocrine System Diseases; Environment; Epilepsy; Estrous Cycle; Estrus; Exhibits; Female; Foundations; Functional disorder; GNRH1 gene; General Population; Goals; Gonadotropin Hormone Releasing Hormone; Hippocampus; Hypothalamic structure; Image; In Vitro; KISS1 gene; Kainic Acid; Knowledge; Laboratories; Laboratory Research; Learning; Link; Luteinizing Hormone; Mediator; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Output; Partial Epilepsies; Patients; Pattern; Periodicity; Pituitary Gland; Play; Polycystic Ovary Syndrome; Population; Presynaptic Terminals; Reproduction; Research; Research Personnel; Seizures; Seminal fluid; Slice; Source; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; Temporal Lobe Epilepsy; Testing; Testosterone; Therapeutic; Training; Ventricular; Woman; adverse outcome; career; comorbidity; experience; extracellular; gamma-Aminobutyric Acid; insight; male; median eminence; men; mind control; mouse model; neural circuit; neuromechanism; neuronal circuitry; neuronal excitability; novel therapeutic intervention; patch clamp; postsynaptic; prevent; reproductive; reproductive function; reproductive system disorder; response; sex; sex cycle; translational impact; transmission process; two-photon

PROJECT SUMMARY Patients with temporal lobe epilepsy (TLE), the most commonly diagnosed form of focal epilepsy in adults, have been shown to experience reproductive endocrine disorders at a rate higher than the general population. Notably, clinical studies have also found disrupted patterns of luteinizing hormone (LH) release in both sexes. Gonadotropin-releasing hormone (GnRH) neurons form the final common output in the brain’s control of reproduction, and they play a key role in the pituitary release of LH. Our lab has shown that both GnRH neuron firing activity and intrinsic excitability are disrupted in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Upstream kisspeptin neuron populations in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are major sources of synaptic transmission to GnRH neurons. ARC kisspeptin neurons play a key role in the pulsatile release of LH in both sexes, and AVPV kisspeptin neurons regulate the preovulatory GnRH/LH surge in females. However, kisspeptin neuron function has never been studied in an animal model of epilepsy. Thus, there is a gap in knowledge regarding the effects of epilepsy on the hypothalamic kisspeptin- GnRH circuit. The overall objective of this specific proposal is to elucidate epilepsy-associated changes in the kisspeptin-GnRH circuit. In Aim 1, patch clamp electrophysiology will be employed to determine epilepsy-induced changes in kisspeptin neuron function and excitability in relation to estrous cycle stage and sex. A combination of whole-cell current clamp and loose-patch recordings will be used to analyze epilepsy-associated changes in kisspeptin neuron intrinsic excitability and firing activity. In Aim 2, two-photon calcium imaging will be conducted to identify epilepsy-associated changes in GnRH neuron axon terminal activity and response to kisspeptin. Completion of these aims will provide the foundational information necessary to make continued progress towards the NINDS Epilepsy Research Benchmarks of controlling epilepsy-related conditions and preventing the adverse consequences of seizure treatment. The training plan contained within this proposal seeks to facilitate the development of the primary investigator to better prepare him for a career as an independent researcher. This training plan places heavy emphasis on laboratory-based learning, with small amounts of additional classroom-based learning also included to provide the conceptual foundation needed for the technical training. This research experience will also take place in an intellectual environment that allows for the prioritization of those experiences that will play key roles in the development of the primary investigator.

项目摘要 颞叶癫痫（TLE）是成人中最常见的局灶性癫痫， 生殖内分泌失调的发病率高于一般人群。值得注意的是， 临床研究还发现两性的促黄体激素（LH）释放模式被破坏。 促性腺激素释放激素（GnRH）神经元形成大脑控制的最终共同输出， 生殖，并在垂体释放LH中发挥关键作用。我们的实验室已经证明， 在海马内红藻氨酸（IHKA）小鼠模型中， TLE。弓状核和前腹侧脑室周围的上游kisspeptin神经元群 AVPV是GnRH神经元突触传递的主要来源。ARC kisspeptin神经元发挥作用， AVPV kisspeptin神经元在两性LH的脉冲式释放中起关键作用，AVPV kisspeptin神经元调节排卵前 雌性GnRH/LH激增。然而，Kisspeptin神经元功能从未在动物模型中进行过研究。 癫痫因此，关于癫痫对下丘脑kisspeptin的影响的知识存在空白- GnRH回路。这一具体建议的总体目标是阐明癫痫相关的变化， kisspeptin-GnRH回路在目的1中，将采用膜片钳电生理学来确定癫痫诱导的 Kisspeptin神经元功能和兴奋性的变化与动情周期阶段和性别的关系。的组合 将使用全细胞电流钳和松斑记录来分析癫痫相关的变化， kisspeptin神经元内在兴奋性和放电活性。在目标2中，将进行双光子钙成像 确定癫痫相关的GnRH神经元轴突终末活性变化和对kisspeptin的反应。 这些目标的完成将为继续取得进展提供必要的基础信息 NINDS癫痫研究基准控制癫痫相关疾病和预防 癫痫治疗的不良后果。本提案所载的培训计划旨在促进 主要研究者的发展，以更好地为他作为一个独立的研究人员的职业生涯做好准备。 该培训计划非常强调以实验室为基础的学习，并有少量的额外培训。 还包括课堂学习，为技术培训提供必要的概念基础。 这种研究经验也将发生在一个知识环境，允许优先考虑 这些经验将在主要研究者的发展中发挥关键作用。