Neonatal Seizures and Hippocampal Neuronal Activity

新生儿癫痫发作和海马神经元活动

• 批准号: 6794729
• 负责人: Gregory L. Holmes
• 金额: $ 37.53万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794729
• 关键词: AMPA receptors; GABA receptor; NMDA receptors; behavior test; brain electrical activity; brain injury; brain morphology; central nervous system stimulants; cognition disorders; developmental neurobiology; electroencephalography; epilepsy; hippocampus; histology; laboratory rat; memory; neural inhibition; neurogenesis; newborn animals; pyramidal cells; relapse /recurrence

DESCRIPTION (provided by applicant): Newborns are at high risk for seizures and seizure-associated brain injury. Between 20-40 percent of term infants who have seizures are subsequently handicapped and this increases to almost 90 percent in pre-term babies. Despite the clinical importance of this problem, little is known about the pathophysiological basis of seizure-induced brain damage in newborns. The goals of this proposal are to delineate the neurobiological consequences of neonatal seizures. We have demonstrated that neonatal seizures, while not causing cell loss, result in changes in synaptic organization with sprouting of mossy fibers in the CA3 and supragranular regions, reductions in neurogenesis, and impairment in spatial memory. We hypothesize that neonatal seizures perturb the development of the hippocampal network by disrupting normal excitatory and inhibitory synapse development resulting in permanent alterations in hippocampal neuronal circuits and hippocampal network patterned activities. Furthermore, these alterations in hippocampal network properties result in functional impairment. To assess this hypothesis, we will employ ex vivo and in vivo electrophysiological techniques and behavioral studies in three specific aims. In the first aim we hypothesize that seizures in the neonatal period result in alterations in neuronal circuitry with subsequent decreases of place firing field precision and stability and abnormal hippocampal rhythms and patterns. Further, we hypothesize that these abnormalities will be associated with abnormalities in visual-spatial memory. We will assess place cell firing patterns and hippocampal network activity in animals with and without a history of neonatal seizures and compare these findings to performance in the water maze. We also hypothesize that neonatal seizures result in alterations in hippocampal patterned activity. Our second aim complements the first aim by determining the persistence of changes in network activity after neonatal seizures by monitoring hippocampal rhythms and patterns throughout development. Our third specific aim is to determine the effects of neonatal seizures on developmental changes in synaptic connections that can underlie the alterations in ontogenesis of hippocampal network activity described in aim 2 and the long-term effects of neonatal seizures on cognition and place cell physiology described in aim 1. These integrated aims will provide insight into the mechanisms of seizure-induced injury in newborns and form the basis for subsequent therapeutic interventions.

描述（由申请人提供）：新生儿有癫痫发作和癫痫发作相关的脑损伤的高风险。随后有癫痫发作的患者中，有20-40％的癫痫发作的婴儿被残障，这在前孕前的婴儿将近90％。 尽管该问题的临床重要性，但对新生儿癫痫引起的脑损伤的病理生理基础知之甚少。该提议的目标是描述新生儿癫痫发作的神经生物学后果。 我们已经证明，新生儿癫痫发作虽然不会导致细胞损失，但会导致突触组织的变化，随着CA3和上部区域的苔藓纤维发芽，神经发生的减少以及空间记忆的损害。我们假设新生儿癫痫发作通过破坏正常的兴奋性和抑制性突触的发展，从而扰乱了海马网络的发展，从而导致海马神经元回路和海马网络图案活动的永久改变。此外，海马网络特性中的这些改变会导致功能障碍。为了评估这一假设，我们将在三个特定目标中采用离体和体内电生理技术和行为研究。在第一个目的中，我们假设在新生儿期间癫痫发作会导致神经元电路发生变化，随后降低位置射击场精度和稳定性以及海马节律异常的降低。此外，我们假设这些异常将与视觉空间记忆中的异常有关。我们将评估有和没有新生儿癫痫病史的动物中的动物中的细胞发射模式和海马网络活性，并将这些发现与水迷宫的性能进行比较。我们还假设新生儿癫痫发作会导致海马图案活动的改变。我们的第二个目标通过确定新生儿癫痫发作后网络活动变化的持久性，通过监测整个开发过程中的海马节奏和模式来补充第一个目标。我们的第三个具体目的是确定新生儿癫痫发作对突触连接的发展变化的影响，这可以是AIM 2中描述的海马网络活性的个体发生变化的基础，以及新生儿癫痫发作的长期影响，新生儿癫痫发作对AIM 1中所描述的认知和将细胞生理学的影响置于AIM 1中。干预措施。