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。阿尔茨海默病（AD）和癫痫都与神经发生的显著改变有关，这可能导致认知和精神症状，这些症状是这两种疾病的关键特征。反复发作是AD和癫痫的特征，可能在神经发生和下游认知障碍的（dys）调节中起关键作用。急性癫痫发作活动刺激啮齿动物和人类的神经发生，但慢性癫痫与神经发生减少有关。为什么急性和慢性癫痫发作与神经发生的相反作用有关，以及这如何影响认知，尚不清楚。最近的研究结果表明，小鼠DG中的神经干细胞是“一次性的”，而不是自我更新，这可能提供了一个解释。在退出静止状态时，这些成年DG神经干细胞经历一系列不对称分裂以产生注定成为神经元的分裂后代，然后终末分化为星形胶质细胞。这种“一次性干细胞”模型解释了DG神经干细胞的年龄相关性消失、新星形胶质细胞的出现以及神经发生的年龄相关性下降。这样的模型将预测，由急性癫痫发作触发的神经发生的稳健增加加速了神经干细胞库的分裂偶联耗竭，导致在具有复发性癫痫发作的病症（例如AD和癫痫）中神经发生潜力降低。我们的初步数据支持这一假设，即在表达人淀粉样前体蛋白（APP）的转基因小鼠中，DG神经干细胞的损失加速，这是一种具有自发性癫痫发作的AD模型，并且加速损失影响由成年出生的DG神经元调节的特定认知功能。我们在红藻氨酸癫痫模型中发现了类似的结果;此外，用抗癫痫药物治疗APP小鼠似乎可以延迟损失率，支持癫痫发作的作用。在这些初步研究的基础上，在目标1中，我们将确定DG神经干细胞库经历加速的分裂偶联耗竭，这与APP小鼠的癫痫发作活动和认知缺陷相称;在目标2中，我们将确定用抗癫痫药物治疗是否防止DG神经干细胞库的耗竭并改善DG依赖性行为任务的表现;在目标3中，我们将评估野生型小鼠中药理学诱导的癫痫发作是否也诱导DG神经干细胞库的分裂偶联耗竭和DG功能的缺陷。确定癫痫发作是否加速DG神经干细胞库的分裂偶联耗竭将为理解驱动神经干细胞正常使用和病理性耗竭的过程提供新的线索。答案将对确定神经发生的阶段产生重大影响，这些阶段是最有利于治疗策略的重点。这是实现两个主要长期目标的重要一步：1）预防影响神经发生的疾病的病理影响，2）利用神经发生的力量作为AD和癫痫等破坏性疾病的治疗方法。