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: 8606664
• 负责人: Gregory L. Holmes
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC 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/8606664
• 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; 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有关。了解这些认知障碍的机制可能会导致新的疗法，从而最大程度地减少不良结果。我们先前已经表明，在大鼠中，早期癫痫发作（ELS）会导致重大认知障碍。我们实验室的初步数据表明，EL之后是神经编码和脑电图振荡活性的异常，这两者都被认为在认知功能中起着至关重要的作用。该项目通过确定脑振荡功能障碍的程度和相关性，进一步研究了导致认知障碍的机制。我们假设：i）Els导致脑振荡活性的缺陷； ii）这些缺陷至少部分是由于认知障碍。 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具有和没有EL的大鼠的行为，无论是单位和网络级别。将在延迟的空间交替任务中自由移动的大鼠在P20和p60的自由移动大鼠中研究位置细胞的位置开发以及theta和伽马调制（相位调节，相位序列），并将在同一动物以及对照组和ELS大鼠之间进行正确和错误试验之间的位置细胞性能。为了评估ELS对网络属性的影响，我们将研究海马（CA1-CA3）和海马 - 前额外网络功能的光谱相干性，而大鼠参与记忆任务。 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.综上所述，这些研究可能会提供有关ELS网络异常背后的机制和后果的见解，并为干预提供了强大的框架。