Vulnerability to neuroinflammation of brainstem ascending aminergic systems

描述(申请人提供)：本项目的总体目标是确定与正常衰老相关的慢性神经炎或通过注入脂多糖(LPS)而增强的慢性神经炎对大鼠脑干内上升的氨基能和胆碱能神经元的病理后果。阿尔茨海默病、病毒性脑炎、多发性硬化症、艾滋病和帕金森氏症患者的大脑中已被描述为一种促炎状态。目前提出的基本假设是，慢性神经炎的后果也是许多其他与年龄相关的退行性疾病的基础，这些疾病涉及SN中的多巴胺神经元、LC中的去甲肾上腺素神经元、RN中的5-羟色胺能神经元和LPT中的乙酰胆碱神经元。目前的提议旨在促进我们对这些脑干区域对这些神经系统年龄相关障碍的条件的选择性脆弱性的理解。提出的研究是基于这样一个假设，即这些神经元与年龄相关的损失的一个主要潜在问题是炎症诱导的细胞外谷氨酸升高和谷氨酸在NMDA通道上的作用。如果人们能够改变谷氨酸损伤或摧毁脆弱神经系统的能力，就会获得临床上的好处。这些研究将提供证据表明，靶向调节谷氨酸释放或其在突触或钙通道中的作用可能对可归因于脑部炎症或因脑部炎症而加重的急性和慢性神经退行性疾病产生临床益处。目的1将确定时间进程和局部变化，促炎生物标志物和病理。目的2研究谷氨酸在炎症诱导的脑干核团内神经元变性中的作用。AIM 3将监测向幼年、成年和老年大鼠第四脑室注射脂多糖后，上升系统离散核团内细胞外谷氨酸水平的每秒变化；这些变化将与每个胺能脑干核团表达的病理程度有关。

DESCRIPTION (provided by applicant): The overall goal of this project is to determine the pathological consequences of chronic neuroinflammation associated with normal aging or enhanced by the infusion of lipopolysaccharide (LPS) upon ascending aminergic and cholinergic neurons within the brainstem of rats. A pro-inflammatory state has been described in the brains of patients with Alzheimer's disease, viral encephalitis, multiple sclerosis, AIDS and Parkinson's disease. The principle hypothesis of the current proposal is that the consequences of chronic neuroinflammation also underlie numerous other age-related degenerative diseases that involve the dopamine neurons in the SN, norepinephrine neurons in the LC, serotonergic neurons in the RN and the acetylcholine neurons in the LPT. The current proposal is designed to advance our understanding of the selective vulnerability of these brainstem regions to conditions that characterize age-associated disorders of these neural systems. The proposed studies are based upon the hypothesis that a major underlying problem in the age-associated loss of these neurons is the inflammation-induced elevation in extracellular glutamate and action of glutamate at NMDA channels. Clinical benefits would be achieved if one could modify the ability of glutamate to injure or destroy vulnerable neural systems. These studies will provide evidence that targeting the regulation of glutamate release or its actions within the synapse or calcium channels may produce clinical benefit for acute and chronic neurodegenerative disorders attributable to or exacerbated by brain inflammation. Aim 1 will determine the time course and regional changes pro-inflammatory biomarkers and pathology. Aim 2 will investigate the role of glutamate in the inflammation-induced degeneration of neurons within these brainstem nuclei. Aim 3 will monitor second-by-second changes in extracellular glutamate levels within the discrete nuclei of the ascending systems following infusion of LPS into the 4th ventricle of young, adult and aged rats; these changes will be related to the degree of pathology expressed by each aminergic brainstem nuclei.