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: 8415974
• 负责人: Gregory L. Holmes
• 金额: $ 8.76万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415974
• 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.

描述（由申请人提供）：儿童癫痫与认知障碍的重大风险相关。了解这些认知障碍的机制可能会导致新的治疗方法，最大限度地减少不良后果。我们之前已经表明，在大鼠中，早期癫痫发作（ELS）会导致严重的认知障碍。我们实验室的初步数据表明，ELS之后是神经编码和EEG振荡活动的异常，这两者都被认为在认知功能中起着关键作用。本项目通过确定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引起脑振荡活动的缺陷;和ii）这些缺陷至少部分地是认知障碍的原因。为了达到我们确定ELS对振荡活动的影响及其与发育和成年大脑中认知功能的关系的目标，我们将首先通过在出生后第5天（P）开始的非麻醉大鼠幼仔的海马中使用多接触层状电极来表征ELS如何影响海马中振荡活动的发育轨迹。然后，我们将分析振荡和行为之间的关系，在大鼠和没有ELS，无论是在单个单元和网络水平。在延迟空间交替任务中，将在P20和P60时在自由活动大鼠中研究位置细胞发育以及位置细胞放电的θ和γ调制（相位调制、相位进动），并将在相同动物的正确和不正确试验之间以及对照和ELS大鼠之间比较位置细胞特性。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（CA 1-CA 3）和海马-前额叶网络功能的光谱相干性。在特定目标1中确定了海马振荡在ELS诱导的认知功能障碍中的作用后，我们将在特定目标2中探索ELS后改善认知的方法。具体而言，我们将评估人工诱导的θ和γ振荡对ELS后海马功能的影响，以及行为训练动物是否可以修改海马振荡和随后的学习。总之，这些研究可能会提供深入了解ELS网络异常背后的机制和后果，并提供一个强有力的干预框架。