Mechanisms of Cognitive Impairment Following Early-Life Seizures

项目摘要 癫痫是一种复杂的疾病，涉及的不仅仅是癫痫发作。正如国家电视台所强调的那样 科学院赞助的癫痫的公共卫生层面委员会，1癫痫可 伴随着一系列相关的共病健康状况，这些健康状况可能会有显著的健康和 对生活质量的影响。在这些合并症中，认知障碍是最常见和 癫痫的令人痛苦的方面。因为认知障碍的风险在幼儿中最大，所以 对教育、职业、社会和经济的影响是巨大的。值得注意的是，只有少数几个 实验室试图了解早期认知障碍的病理生理学基础 癫痫(ELS)。我们实验室的观点是，在预防、限制和扭转认知 合并症，了解发育认知功能障碍的神经生物学基础是至关重要的 与ELS相关联。破译复杂的认知结果问题的主要困难之一 在儿童中遵循ELS是这些缺陷所在的行为/心理领域之间的鸿沟 已证实的和潜在的生理/发育领域，都是这些缺陷的原因 以及最有可能进行治疗和干预的领域。基于强劲的初步数据显示 ELS后认知障碍的速率和时间编码异常，我们认为 神经回路动力学是认知障碍的神经生理学基础。在这项提案中，我们 希望严格研究ELS对使用多站点单小区和局域场的时间编码的影响 潜力。为了从相关实验转向因果实验，我们将首先确定认知康复 遵循ELS会反转编码异常。其次，我们将使用光遗传诱导的调制 神经元回路，以修正编码异常和纠正空间认知缺陷。基于令人信服的 初步数据，我们相信我们的发现将支持作为原因的动态神经失调的概念 ELS后认知功能障碍的因素。

Project Summary Epilepsy is a complex disorder which involves much more than seizures. As emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies,1 epilepsy may be accompanied by a range of associated co-morbid health conditions that can have significant health and quality of life implications. Of these comorbidities, cognitive impairment is one of the most common and distressing aspects of epilepsy. Because the risk of cognitive impairment is greatest in young children, the educational, vocational, social and economic implications are enormous. Remarkably, there are only a handful of laboratories attempting to understand the pathophysiological basis of cognitive disturbances in early-life seizures (ELS). It is the view of our laboratory that prior to preventing, limiting and reversing cognitive comorbidities, it is essential to understand the neurobiological basis of developmental cognitive dysfunction associated with ELS. One of the major difficulties in decoding the complex issue of cognitive outcomes following ELS in children is the gulf between the behavioral/mental spheres in which these deficits are substantiated and the underlying physiological/developmental domains that are both the cause of these deficits and the most likely domains for therapy and intervention. Based on strong preliminary data showing abnormalities in rate and temporal coding in cognitive impairment following ELS, we propose that aberrant neural circuit dynamics are the neurophysiological underpinnings of cognitive impairment. In this proposal, we wish to rigorously study the consequences of ELS on temporal coding using multi-site single cell and local field potentials. To move from correlative to causal experimentation, we will first determine if cognitive rehabilitation following ELS reverses coding abnormalities. Secondly, we will use optogenetic-induced modulation of neuronal circuits to modify coding abnormalities and correct spatial cognitive deficits. Based on compelling preliminary data, we believe our findings will support the concept of dynamic neural discoordination as a causal factor of cognitive dysfunction following ELS.