Targeting aberrant neurogenesis to prevent epilepsy and associated cognitive decline

针对异常的神经发生来预防癫痫和相关的认知能力下降

• 批准号: 9247257
• 负责人: Jenny Hsieh
• 金额: $ 35.44万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247257
• 关键词: Ablation; Activities of Daily Living; Acute; Address; Adult; Adverse effects; Affect; American; Applications Grants; Brain; Cell Culture Techniques; Cell Proliferation; Cellular biology; Chronic; Clinic; Clinical; Cognitive; Cognitive deficits; Comorbidity; Data; Dendrites; Development; Disease; Electroencephalography; Epilepsy; Epileptogenesis; Exhibits; Frequencies; Generations; Genetic; Genetic Models; Goals; Hilar; Hippocampus (Brain); Histology; Hypertrophy; Impaired cognition; Individual; Knockout Mice; Knowledge; Label; Lead; Learning; Location; Long-Term Effects; Measures; Memory; Memory impairment; Mental disorders; Mission; Modeling; Molecular; Mus; Natural regeneration; Nerve Tissue; Nervous System Trauma; Neurons; Pathologic; Pharmaceutical Preparations; Pilocarpine; Play; Public Health; Publishing; Recurrence; Research Proposals; Role; Seizures; Simplexvirus; Status Epilepticus; Structure of germinal center of lymph node; Tamoxifen; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Thymidine Kinase; Transgenic Mice; Translating; Traumatic injury; United States; United States National Institutes of Health; Work; adult neurogenesis; cognitive function; conditioned fear; diphtheria toxin fragment A; granule cell; improved; innovation; insight; mossy fiber; mouse model; nerve stem cell; nervous system disorder; nestin protein; neurogenesis; newborn neuron; novel; novel therapeutics; prevent; prophylactic; public health relevance; transcription factor

 DESCRIPTION (provided by applicant): Acute seizures (or status epilepticus, SE) after a severe brain insult often leads to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Recently, we found ablation of adult neurogenesis prior to acute seizures reduced chronic seizure frequency and normalized epilepsy-associated cognitive deficits. These data helped us formulate a clear objective for this grant proposal: to determine the effect of neurogenesis ablation after acute seizures in chronic seizure generation and epilepsy-associated memory function. Our central hypothesis is adult neurogenesis plays a key role in chronic seizure development and associated memory impairment, and our preliminary results suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult. We will test this hypothesis in 3 specific aims: 1) To defie the therapeutic window of targeting adult neurogenesis to prevent epilepsy and associated cognitive deficits, 2) To evaluate the long-term effects of aberrant neurogenesis in preventing epilepsy, and 3) To identify molecules to target aberrant neurogenesis through studies on NeuroD. Aims 1 and 2 will utilize a Nestin-δ-HSV-thymidine kinase transgenic mouse to genetically ablate newborn neurons. Aim 1 will also use an Ascl1-CreERT2; inducible DT-A model to ablate neurogenesis. Aim 3 will use a NeuroD conditional knockout mouse. In all 3 Aims, we will perform continuous video-EEG recording to measure chronic seizure frequency and duration. In Aims 1 and 2, novel location, novel object, and context-dependent fear conditioning tests will be performed to measure memory function. The conceptual framework and approach is innovative because we will apply state-of-the-art genetic and knockout mouse techniques to a mouse model of temporal lobe epilepsy and dissect underlying cellular- level mechanisms of SE-dependent neurogenesis. As our long-term goal is to understand the molecular mechanisms important for how aberrant neurogenesis drives chronic epilepsy, the proposed work is disease- relevant and highly significant. It will advance and expand our basic understanding of seizure activity- dependent molecular networks regulating neural stem cell proliferation, differentiation, survival and maturation of newborn neurons, which will advance our understanding of neurogenesis in both basal and pathological states. The proposed study is relevant to NIH's mission as it will allow us to gain fundamental insight regarding the fundamental underpinnings of epilepsy and associated comorbidities as well as acquiring knowledge towards new avenues for treating neurological and psychiatric disorders.

 描述(由申请人提供)：严重脑损伤后的急性癫痫发作(或癫痫持续状态，SE)通常会导致癫痫和认知障碍。损毁后，海马神经发生异常，但成人产生的神经元在慢性癫痫发作或相关认知缺陷的发展中的作用仍有待确定。最近，我们发现，在急性癫痫发作之前消融成人神经发生可以减少慢性癫痫发作的频率，并使癫痫相关的认知障碍正常化。这些数据帮助我们为这项赠款提案制定了一个明确的目标：确定急性癫痫发作后神经发生消融对慢性癫痫发作发生和癫痫相关记忆功能的影响。我们的中心假设是成人神经发生在慢性癫痫的发展和相关的记忆障碍中起着关键作用，我们的初步结果表明，靶向异常的海马神经发生可以减少癫痫发作的反复发作，恢复癫痫前脑损伤后的认知功能。我们将在3个具体目标上验证这一假说：1)挑战以成人神经发生为靶点以预防癫痫和相关认知缺陷的治疗窗口，2)评估异常神经发生在预防癫痫中的长期效果，以及3)通过对神经D的研究来确定靶向异常神经发生的分子。AIMS 1和2将利用Nestin-δ-HSV-胸苷激酶转基因小鼠对新生神经元进行基因切割。AIM 1还将使用Ascl1-CreERT2；可诱导的DT-A模型来消融神经发生。Aim 3将使用一种神经性条件基因敲除小鼠。在所有三个目标中，我们将进行连续的视频-脑电记录，以测量慢性癫痫发作的频率和持续时间。在目标1和目标2中，将进行新的位置、新的物体和上下文相关的恐惧条件反射测试来测量记忆功能。概念框架和方法是创新的，因为我们将把最先进的遗传和基因敲除小鼠技术应用到颞叶癫痫的小鼠模型中，并剖析SE依赖神经发生的潜在细胞水平机制。由于我们的长期目标是了解异常神经发生如何驱动慢性癫痫的重要分子机制，因此拟议的工作与疾病相关，具有非常重要的意义。这将促进和扩大我们对癫痫活动依赖的分子网络调控神经干细胞增殖、分化、存活和新生神经元成熟的基本理解，这将促进我们对基础状态和病理状态下的神经发生的理解。这项拟议的研究与NIH的任务相关，因为它将使我们能够从根本上洞察癫痫及其相关共病的根本基础，并获得治疗神经和精神疾病的新途径的知识。