Mechanisms of Cognitive Impairment Following Early-Life Seizures

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。我们之前已经证明，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之后会出现神经编码和脑电图振荡活动的异常，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：1)ELS导致脑振荡活动缺陷；ii)这些缺陷至少在一定程度上导致了认知障碍。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认知功能的关系的目标，我们将首先通过在出生后第5天开始的非麻醉大鼠海马中使用多接触层状电极来表征ELS如何影响海马振荡活动的发育轨迹。然后，我们将在单个单元和网络水平上分析有ELS和没有ELS的大鼠的振荡和行为之间的关系。将在延迟空间交替任务中自由运动的大鼠P20和P60位置细胞发育和位置细胞放电的θ和γ调制（相位调制，相位进动）进行研究，并将在同一动物的正确和错误试验中以及在对照和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（CA1-CA3）和海马-前额叶网络功能的频谱相干性。在Specific Aim 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Specific Aim 2中探索改善ELS后认知的方法。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改变海马振荡和随后的学习。综上所述，这些研究很可能为ELS网络异常背后的机制和后果提供见解，并为干预提供强有力的框架。

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.