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 临时叶癫痫（TLE）的患者是成年人最常见的局灶性癫痫的形式 我们被证明以高于一般人群的速度患有生殖内分泌疾病。尤其， 临床研究还发现，在男女中，叶酸马酮（LH）释放的模式破坏了。 促性腺激素释放的马龙（GNRH）神经元构成了大脑控制中的最终共同输出 繁殖，它们在LH的垂体释放中起着关键作用。我们的实验室表明两个GNRH神经元 在汉皮门内海藻酸（IHKA）小鼠模型中，发射活性和内在激动人心会破坏 TLE。弧形核（ARC）和前腹周围的上游亲吻肽神经元种群 核（AVPV）是向GNRH神经元传播的主要来源。 ARC亲吻肽神经元发挥 在性别中LH的脉动释放中的关键作用，而AVPV亲吻​​蛋白神经元调节了卵石前的抑制作用 女性的GnRH/LH激增。但是，亲吻肽神经元功能从未在动物模型中研究 癫痫。那就是关于癫痫对下丘脑亲吻素的影响的知识差距 GnRH电路。该特定建议的总体目标是阐明与癫痫相关的变化 Kisspeptin-GNRH电路。在AIM 1中，将采用斑块夹电生理学来确定癫痫引起的 亲吻肽神经元功能的变化和与发情循环阶段和性别相关的令人兴奋的变化。组合 全细胞电流夹具和松散的录音将用于分析癫痫相关的变化 吻肽素神经元的内在激动和射击活动。在AIM 2中，将进行两光子钙成像 确定GNRH神经元轴突终末活性的癫痫相关变化和对Kisspeptin的反应。 这些目标的完成将提供必要的基本信息，以持续进展 朝着ninds癫痫研究基准控制与癫痫相关的疾病并防止 癫痫治疗的不利后果。本提案中包含的培训计划旨在促进 主要研究人员的发展，以更好地为他做好独立研究人员的职业做好准备。 该培训计划非常重视基于实验室的学习，还有少量的额外 还包括基于课堂的学习，以提供技术培训所需的概念基础。 这项研究经验也将在智力环境中进行，允许优先考虑 那些将在主要研究者的发展中起关键作用的经验。