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

项目总结 男性和女性都患有颞叶癫痫(TLE)，这是成人最常见的部分癫痫，表现为 与普通人群相比，生殖内分泌紊乱的发生率更高。生殖内分泌 疾病严重影响生活质量，如果不治疗，可能会导致其他中枢神经系统疾病风险增加 神经系统、新陈代谢和心血管疾病，以及癌症。癫痫发作似乎是导致 生殖内分泌共病，但这种关系背后的神经机制尚未 描述。在拟议的工作中，我们将阐明将癫痫与生殖联系起来的神经机制。 内分泌功能障碍。下丘脑促性腺激素释放激素(GnRH)神经元形成最终共同 大脑控制生殖的途径，因此可能在脑部的病理生理学中起关键作用。 癫痫相关的生殖内分泌紊乱。正确的GnRH释放模式是驾驶所必需的 男性和女性的脑下垂体都会释放搏动性黄体生成素(LH)。临床研究 已经报道了癫痫患者男性和女性的促黄体生成素释放模式中断，但机制 其依据尚不清楚。因此，人们对癫痫的影响的认识存在很大差距。 促性腺激素释放激素神经元、它们的突触传入及其下游对垂体功能的影响。我们的总体目标 在拟议的研究中，旨在确定下丘脑-垂体细胞的关键功能变化和脑电活动。 TLE小鼠模型。我们最近报道，大多数癫痫女性的发情周期被打乱。 小鼠在这个模型中，表明它是适合这些研究的。我们的中心假设是癫痫发作 活动驱动促性腺激素释放激素神经元及其突触输入活动的变化，从而影响 垂体促黄体生成素的下游释放。我们将使用一种创新的膜片钳组合来验证这一假设 电生理学、脑电(EEG)、光遗传学、垂体基因表达分析以及 测定小鼠体内促黄体生成素释放模式的前沿超灵敏试验。在目标1中，我们将表演 首次直接研究与癫痫相关的GnRH神经元放电活动、内源性兴奋性、 和快速的突触输入。在目标2中，我们将确定海马癫痫发作之间的功能关系。 活动、下丘脑GnRH释放和垂体对GnRH的反应。圆满完成这些目标 将产生积极的翻译影响并通过以下方式促进NINDS癫痫研究基准的目标 提供对生殖内分泌的潜在神经和脑下垂体底物的关键机制洞察 癫痫通常会引起的疾病。

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.