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

项目摘要 颞叶癫痫（TLE）是成人中最常见的部分性癫痫， 与一般人群相比，生殖内分泌失调的发病率较高。生殖内分泌 疾病严重影响生活质量，如果不治疗，可能导致其他中枢神经系统疾病的风险升高。 神经系统、代谢和心血管疾病以及癌症。癫痫发作似乎是导致 生殖内分泌共病，但这种关系背后的神经机制还没有被发现。 介绍了在拟议的工作中，我们将阐明癫痫与生殖相关的神经机制， 内分泌失调下丘脑促性腺激素释放激素（GnRH）神经元形成最后的共同 在大脑控制生殖的途径，因此可能发挥关键作用的病理生理学 癫痫相关的生殖内分泌紊乱。适当的GnRH释放模式是必要的， 在雄性和雌性中，脉冲式促黄体生成激素（LH）从脑垂体释放。临床研究 已经报道了癫痫男性和女性LH释放模式的破坏，但机制 其依据尚待阐明。因此，关于癫痫对神经系统的影响， 促性腺激素释放激素神经元，它们的突触传入，以及对垂体功能的下游影响。我们的总体目标 在拟议的研究中，确定下丘脑-垂体细胞和回路的关键功能变化， TLE小鼠模型。我们最近报道了大多数女性癫痫患者的动情周期被打乱 小鼠在该模型中，表明它是适合这些研究。我们的核心假设是癫痫 活动驱动GnRH神经元及其突触输入活动的变化，从而影响 下游垂体LH释放。我们将测试这一假设使用一个创新的组合膜片钳 电生理学、脑电图（EEG）、光遗传学、垂体基因表达分析，以及 尖端的超灵敏测定，用于确定小鼠体内LH释放模式。在目标1中， 第一次直接研究癫痫相关的GnRH神经元放电活动，内在兴奋性， 和快速突触输入。在目标2中，我们将确定海马癫痫发作与脑梗死之间的功能关系。 活动，下丘脑GnRH释放和垂体对GnRH的反应。成功实现这些目标 将产生积极的转化影响，并进一步实现NINDS癫痫研究基准的目标， 为生殖内分泌的神经和垂体底物提供关键的机制见解 癫痫的常见症状

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.