Accelerated depletion of hippocampal neural stem cells in neurological disease

神经系统疾病中海马神经干细胞的加速消耗

• 批准号: 8672951
• 负责人: JEANNIE CHIN
• 金额: $ 41.61万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672951
• 关键词: Accounting; Acute; Adult; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Antiepileptic Agents; Anxiety; Appearance; Astrocytes; Behavioral; Brain; Cell model; Characteristics; Chronic; Cognition; Cognitive; Cognitive deficits; Coupled; Data; Disease; Epilepsy; Exhibits; Functional disorder; Goals; Hippocampus (Brain); Human; Impact Seizures; Impaired cognition; Impairment; Incidence; Kainic Acid; Learning; Levetiracetam; Light; Memory; Mental Depression; Modeling; Moods; Mus; Neurons; Patients; Performance; Pharmaceutical Preparations; Play; Population; Process; Recurrence; Regulation; Relative (related person); Rodent; Role; Seizures; Series; Staging; Stem cells; Symptoms; Testing; Therapeutic; Time; Transgenic Mice; Wild Type Mouse; adult neurogenesis; age related; cognitive function; dentate gyrus; forging; improved; kainate; mouse model; nerve stem cell; nervous system disorder; neurogenesis; newborn neuron; novel; premature; prevent; public health relevance; research study; self-renewal; stem cell division; therapy design

DESCRIPTION (provided by applicant): Adult-born neurons in the dentate gyrus (DG) play critical roles in learning, memory, depression, and anxiety. Both Alzheimer's disease (AD) and epilepsy are associated with marked alterations in neurogenesis, which may contribute to cognitive and psychiatric symptoms that are key features of both diseases. Recurrent seizures, which are characteristic of both AD and epilepsy, may critical in the (dys)-regulation of neurogenesis and downstream cognitive impairments. Acute seizure activity stimulates neurogenesis in rodents and humans, but chronic epilepsy is associated with decreased neurogenesis. Why acute and chronic seizures are associated with opposing effects on neurogenesis, and how this affects cognition, is unknown. Recent findings that neural stem cells in the mouse DG are "disposable" rather than self-renewing may provide an explanation. Upon exiting the quiescent state, these adult DG neural stem cells undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons, and then terminally differentiate into astrocytes. This "disposable stem cell" model accounts for the age-related disappearance of DG neural stem cells, appearance of new astrocytes, and age-related decline in neurogenesis. Such a model would predict that the robust increases in neurogenesis triggered by acute seizures accelerate division-coupled depletion of the neural stem cell pool, leading to reduced neurogenic potential in conditions with recurrent seizures such as AD and epilepsy. Our preliminary data support the hypothesis that loss of DG neural stem cells is accelerated in transgenic mice expressing human amyloid precursor protein (APP), a well-characterized model of AD with spontaneous seizures, and that accelerated loss affects specific cognitive functions that are regulated by adult- born DG neurons. We found similar results in the kainate model of epilepsy; moreover, treatment of APP mice with an anti-epileptic drug appeared to delay the rate of loss, supporting a role for seizures. Building on these preliminary studies, in Aim 1, we will establish that the DG neural stem cell pool undergoes accelerated division-coupled depletion that is commensurate with seizure activity and cognitive deficits in APP mice; in Aim 2 we will determine whether treatment with an anti-epileptic drug prevents depletion of the DG neural stem cell pool and ameliorates performance on a DG-dependent behavioral task; in Aim 3 we will assess whether pharmacologically-induced seizures in wild-type mice also induce division-coupled depletion of the DG neural stem cell pool and deficits in DG function. Determining if seizures accelerate division-coupled depletion of the DG neural stem cell pool will shed new light on understanding the processes that drive both normal use, and pathological depletion, of neural stem cells. The answer will have a major impact on determining the stages of neurogenesis that are most advantageous to focus on for therapeutic strategies. This is an essential step in achieving two major long-term goals: 1) prevent pathological effects of conditions that impact neurogenesis, 2) harness the power of neurogenesis as a treatment for devastating conditions like AD and epilepsy.

描述（由申请人提供）：齿状回（DG）中的成年神经元在学习，记忆，抑郁和焦虑中起关键作用。阿尔茨海默氏病（AD）和癫痫都与神经发生的明显改变有关，这可能导致两种疾病的关键特征的认知和精神病症状。复发性癫痫发作是AD和癫痫的特征，在（DYS）调节神经发生和下游认知障碍中可能至关重要。急性癫痫活性刺激啮齿动物和人类的神经发生，但慢性癫痫与神经发生降低有关。为什么急性和慢性癫痫发作与对神经发生的相反影响以及这对认知的影响如何相关。最近的发现，小鼠DG中的神经干细胞是“一次性”而不是自我更新的结果，可以提供解释。退出静态状态后，这些成年DG神经干细胞会经历一系列不对称的分裂，以产生注定成为神经元的后代，然后终止分化为星形胶质细胞。这种“一次性干细胞”模型解释了DG神经干细胞与年龄相关的消失，新星形胶质细胞的出现以及与年龄相关的神经发生下降。这样的模型将预测，急性癫痫发作触发的神经发生的强大增加加速了神经干细胞池的分裂耦合耗竭，从而导致在复发性癫痫发作（如AD和癫痫）的情况下，神经发生潜力降低。我们的初步数据支持以下假设：在表达人淀粉样蛋白前体蛋白（APP）的转基因小鼠中，DG神经干细胞的丧失是加速的，这是一种自发性癫痫发作的AD特征良好模型，并且加速损失会影响成人BORN DG神经元调节的特定认知功能。我们在癫痫的海谷酸酯模型中发现了类似的结果。此外，用抗癫痫药对APP小鼠的治疗似乎延迟了损失率，从而支持癫痫发作。在这些初步研究的基础上，在AIM 1中，我们将确定DG神经干细胞池经历加速的分裂耦合耗竭，与App Mice中的癫痫发作活性和认知缺陷相称。在AIM 2中，我们将确定使用抗癫痫药的治疗是否可以防止DG神经干细胞池的耗竭并改善DG依赖性行为任务的性能；在AIM 3中，我们将评估野生型小鼠的药理诱导的癫痫发作是否还会诱导DG神经干细胞池的分裂偶联耗竭和DG功能的缺陷。确定癫痫发作是否加速了DG神经干细胞池的分裂偶联耗竭，将为了解驱动正常使用和病理耗尽的神经干细胞的过程提供新的启示。答案将对确定神经发生阶段的阶段产生重大影响，而神经发生阶段最有利地专注于治疗策略。这是实现两个主要长期目标的重要步骤：1）防止影响神经发生的疾病的病理影响，2）利用神经发生作为对AD和癫痫等毁灭性疾病的治疗方法。