Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH

癫痫，特别是儿童癫痫，与认知、行为和精神疾病的发病率非常高有关。 精神合并症通常比癫痫发作本身对整体生活质量的损害更大。 积极治疗癫痫发作一直是黄金标准，相信这也将使 认知和精神并存。然而，很少有人关注这些疾病的治疗。 合并症的直接和临床数据表明，仅专注于癫痫治疗并不有效 治疗认知障碍。我们最近发现，ACTH，下丘脑的内源性部分- 对于患有严重癫痫的儿童，经常外源性使用的垂体-肾上腺轴可以改善 在不改变癫痫参数的情况下，大鼠的认知结果。虽然之前人们认为初选 ACTH的作用机制是通过释放皮质类固醇，新的研究表明 神经元和神经胶质细胞中黑素皮质素4受体(MC4R)的激活具有神经保护作用，可以 改善其他疾病模型的结果。 我们推测，中枢神经系统MC4R激动型ACTH是其重要的作用机制。 可以改善早期生活癫痫(ELS)后的认知结果。我们进一步假设早些时候 使用ACTH治疗将标准化神经网络内部和之间的功能组织 前额叶皮质和海马体，这一改进将提供系统水平 支撑其行动机制的机制。了解促肾上腺皮质激素如何阻止认知 在不改变癫痫参数的情况下治疗这些缺陷对于找到治疗这些缺陷的新方法至关重要。 因此，本研究的科学目的是：1)(阶段I)确定MC4R信号在大脑中的作用 在对照动物和(第二阶段)ELS动物的后续认知上，2)(第一阶段)决定了 早期应用ACTH对ELS后PFC神经元网络突触可塑性的影响 (II期)确定ACTH早期治疗对体内和执行中成人神经元网络的影响 与ELS相关的功能障碍。 为了实现这些目标，我需要额外的培训，这两种培训都是通过“计算方法”来完成的 海洋生物实验室的神经科学课程，与我的合作导师马奥尼博士在 以开发探索系统级所需的神经计算建模工具 ELS后认知损害的机制及ACTH的预防作用这个 建议的研究旨在了解ACTH和MC4Rs在认知方面的发育作用 ELS中的网络。这个项目的成功完成有可能改变我们思考的方式 儿童癫痫的治疗，并可能对其他神经发育的治疗有影响 疾病也是如此。

Epilepsy, particularly pediatric epilepsy, is associated with a very high incidence of cognitive, behavioral and psychiatric comorbidities that are often more detrimental to overall quality of life than the seizures themselves. Aggressive treatment of seizures has been the gold standard, with the belief that this will also minimize cognitive and psychiatric comorbidities. However, very little focus has been placed on treatment of these comorbidities directly and clinical data suggest that focusing on seizure treatment alone does not effectively treat cognitive impairment. We have recently found that ACTH, an endogenous part of the hypothalamic- pituitary-adrenal axis that is often exogenously administered to children with severe epilepsies, can improve cognitive outcome in rats without altering seizure parameters. While it was previously thought that the primary mechanism of action for ACTH was through the release of corticosteroids, new research suggests that melanocortin 4 receptor (MC4R) activation in neuronal and glial populations is neuroprotective and can improve outcomes in other disease models. We hypothesize that MC4R agonism in the CNS with ACTH is a key mechanism of action by which it can improve cognitive outcomes after early life seizures (ELS). We further hypothesize that early treatment with ACTH will normalized functional organization of neural networks within and between the prefrontal cortex and the hippocampus, and that this improvement will provide a systems-level mechanism underpinning its mechanism of action. Understanding how ACTH can prevent cognitive deficits without altering seizure parameters is crucial for finding novel treatment approaches for these deficits. Therefore, the scientific aims of this study are to: 1) (Phase I) determine the role of MC4R signaling in the brain on subsequent cognition in control animals and (Phase II) ELS animals, 2) (Phase I) determine the effect of early treatment with ACTH on synaptic plasticity in adult neuronal networks in the PFC after ELS and finally 3) (Phase II) determine the effect of early treatment with ACTH on adult neuronal networks in vivo and executive dysfunction associated with ELS. To achieve these goals, I require additional training, both formal through a “Methods in Computational Neuroscience” course at the Marine Biological Laboratory and informal with my co-mentor, Dr. Mahoney, in order to develop the neurocomputational modeling tools necessary for exploring the systems-level mechanisms of cognitive impairment after ELS and the prevention of such impairments with ACTH. The studies proposed are designed to understand the developmental role of ACTH and MC4Rs on cognitive networks in ELS. Successful completion of this project has the potential to change the way we think about treatment of pediatric epilepsy, and may have implications for the treatment of other neurodevelopmental disorders as well.