Mechanisms of Cognitive Impairment Following Early-Life Seizures

早期癫痫发作后认知障碍的机制

• 批准号: 8217078
• 负责人: Gregory L. Holmes
• 金额: $ 34.56万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217078
• 关键词: ARHGEF5 gene; Adult; Affect; Animals; Behavior; Behavioral; Brain; Brain region; Cells; Child; Childhood; Clinical Research; Code; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Data; Delayed Memory; Development; Educational process of instructing; Electric Stimulation; Electrodes; Electroencephalography; Epilepsy; Etiology; Frequencies; Functional disorder; Goals; Hippocampus (Brain); Impact Seizures; Impaired cognition; Impairment; Intervention; Laboratories; Lead; Learning; Learning Disabilities; Life; Location; Memory; Mental Retardation; Performance; Phase; Play; Prefrontal Cortex; Property; Rattus; Relative (related person); Risk; Role; Sampling; Seizures; Source; Spatial Behavior; Structure; Techniques; Testing; Theta Rhythm; Training; adverse outcome; age related; base; brain pathway; cognitive function; density; high risk; improved; insight; novel; postnatal; public health relevance; pup; relating to nervous system; research study; restoration

DESCRIPTION (provided by applicant): Childhood epilepsy is associated with a significant risk for cognitive impairment. Understanding the mechanisms of these cognitive impairments may lead to novel therapies that minimize the adverse outcomes. We have previously shown that in rats, early-life seizures (ELS) result in substantial cognitive impairment. Preliminary data from our laboratory suggest that ELS are followed by abnormalities in neural coding and EEG oscillatory activity, both of which are believed to play a critical role in cognitive function. This project further investigates the mechanisms leading to cognitive impairments by determining the extent and relevance of brain oscillation dysfunction. We hypothesize that: i) ELS cause deficits in brain oscillatory activity; and ii) These deficits are responsible, at least in part for cognitive impairment. To reach our goal of determining the impact of ELS on oscillatory activity and its relationship to cognitive function in the developing and adult brain we will first characterize how ELS affect the developmental trajectory of oscillatory activity in hippocampus through use of multi-contact laminar electrodes in the hippocampus in non-anesthetized rat pups starting at postnatal day (P) 5. We will then analyze the relationships between oscillations and behavior in rats with and without ELS, both at the single unit and network levels. Place cell development and theta and gamma modulation of place cell firing (phase modulation, phase precession) will be studied in freely moving rats at P20 and P60 in a delayed spatial alternation task, and place cell properties will be compared between correct and incorrect trials in the same animals and between controls and ELS rats. To evaluate the effects of ELS on network properties, we will study spectral coherence on hippocampal (CA1-CA3) and hippocampal-prefrontal network function while rats are involved in a memory task. Having established the role of hippocampal oscillations in ELS-induced cognitive dysfunction in Specific Aim 1, we will then explore ways to improve cognition following ELS in Specific Aim 2. Specifically, we will evaluate the effect of artificially-induced theta and gamma oscillation on hippocampal function following ELS and whether behavioral training animals can modify hippocampal oscillations and subsequent learning. Taken together, these studies are likely to provide insights into the mechanisms and consequences behind network abnormalities of ELS and provide a strong framework for intervention. PUBLIC HEALTH RELEVANCE: During the first few years of life children with seizures are at high risk for developing cognitive disorders. In preliminary studies we have evidence that abnormalities in hippocampal rhythms may contribute to cognitive deficits following early-life seizures. In this proposal we will determine if abnormalities of hippocampal oscillations following early-life seizures are responsible for the intellectual deficits seen in children with epilepsy.

描述(由申请人提供)：儿童癫痫与认知障碍的重大风险有关。了解这些认知障碍的机制可能会导致将不良后果降至最低的新疗法。我们之前已经证明，在大鼠中，早期癫痫(ELS)会导致严重的认知障碍。我们实验室的初步数据表明，ELS伴随着神经编码和脑电振荡活动的异常，这两者被认为在认知功能中起着关键作用。该项目通过确定大脑振荡功能障碍的程度和相关性，进一步研究导致认知障碍的机制。我们假设：i)ELs导致大脑振荡活动的缺陷；ii)这些缺陷是造成认知障碍的原因，至少是部分原因。为了达到我们的目标，确定ELS对发育中和成年大脑的振荡活动的影响及其与认知功能的关系，我们将首先通过在出生后5天开始使用非麻醉大鼠海马区的多接触层流电极来表征ELS如何影响海马区振荡活动的发育轨迹。然后，我们将在单个单位和网络水平上分析ELS对有和没有ELS的大鼠的振荡和行为之间的关系。在延迟的空间交替任务中，将在P20和P60的自由活动大鼠中研究位置细胞的发育和位置细胞放电的theta和Gamma调制(相位调制，相位进动)，并将在相同动物中正确和错误的实验之间以及在对照组和ELS大鼠之间比较位置细胞的特性。为了评估ELS对网络特性的影响，我们将研究大鼠参与记忆任务时，海马区(CA1-CA3)和海马-前额叶网络功能的频谱一致性。在明确了海马区振荡在ELS诱导的认知功能障碍中的作用后，我们将探索在特定目标1中ELS后改善认知的方法。具体地说，我们将评估人工诱导的theta和Gamma振荡对ELS后海马区功能的影响，以及行为训练动物是否可以改变海马振荡和后续学习。综上所述，这些研究可能为ELS网络异常背后的机制和后果提供洞察力，并为干预提供一个强有力的框架。 与公共卫生相关：在生命的头几年，癫痫发作的儿童患认知障碍的风险很高。在初步研究中，我们有证据表明，海马体节律异常可能导致早期癫痫发作后的认知障碍。在这项建议中，我们将确定早期癫痫发作后海马体振荡的异常是否导致癫痫儿童的智力缺陷。