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: 9127529
• 负责人: Jenny Hsieh
• 金额: $ 35.39万
• 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/9127529
• 关键词: Ablation; Activities of Daily Living; Acute; Address; Adult; Adverse effects; Affect; American; Applications Grants; Brain; Cell Culture Techniques; Cell Proliferation; 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 structure; Neurons; 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; 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; public health relevance; stem cell biology; 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。损伤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频率并使癫痫相关的认知缺陷正常化。这些数据帮助我们为这项拨款提案制定了明确的目标：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发作和相关记忆障碍中起着关键作用，我们的初步结果表明，针对异常海马神经发生可能会减少癫痫发作脑损伤后的复发性癫痫发作并恢复认知功能。我们将在 3 个具体目标中检验这一假设：1) 突破针对成人神经发生来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方面的长期影响，以及 3) 通过 NeuroD 研究确定针对异常神经发生的分子。目标 1 和 2 将利用 Nestin-δ-HSV-胸苷激酶转基因小鼠来基因消融新生神经元。目标 1 还将使用 Ascl1-CreERT2；诱导型 DT-A 模型可消除神经发生。目标 3 将使用 NeuroD 条件敲除小鼠。在所有 3 个目标中，我们将进行连续的视频脑电图记录，以测量慢性癫痫发作频率和持续时间。在目标 1 和 2 中，将进行新位置、新物体和情境相关的恐惧条件反射测试来测量记忆功能。这个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于颞叶癫痫小鼠模型，并剖析 SE 依赖性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且非常重要。它将推进和扩展我们对调节新生神经元的神经干细胞增殖、分化、存活和成熟的癫痫活动依赖性分子网络的基本理解，这将增进我们对基础和病理状态下神经发生的理解。拟议的研究与 NIH 的使命相关，因为它将使我们能够深入了解癫痫和相关合并症的基本原理，并获得治疗神经和精神疾病新途径的知识。