Vulnerability to neuroinflammation of brainstem ascending aminergic systems

脑干上行胺能系统神经炎症的脆弱性

• 批准号: 8044396
• 负责人: Gary L. Wenk
• 金额: $ 30.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044396
• 关键词: Acetylcholine; Acquired Immunodeficiency Syndrome; Acute; Affect; Age; Alzheimer' s Disease; Animal Model; Attenuated; Behavior; Biological Markers; Brain; Brain Stem; Budgets; Calcium; Calcium Channel; Cell Nucleus; Cells; Chronic; Chronic Disease; Clinical; Cognitive; Data; Degenerative Disorder; Disease; Dopamine; Effectiveness; Elderly; Encephalitis; Enzymes; Foundations; Functional disorder; Future; Glutamate Receptor; Glutamates; Goals; Healthcare; Human; Impaired cognition; Inflammation; Inflammatory; Infusion procedures; Lipopolysaccharides; Medial; Memantine; Microelectrodes; Midbrain structure; Monitor; Multiple Sclerosis; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Norepinephrine; Parkinson Disease; Pathology; Patients; Pedunculopontine Tegmental Nucleus; Principal Investigator; Process; Rattus; Regulation; Research; Riluzole; Role; Series; Serotonin; Signal Transduction; Specificity; Substantia nigra structure; Synapses; System; Testing; Time; Ventral Tegmental Area; Viral Encephalitis; Vulnerable Populations; age related; aged; aging brain; base; behavior test; cholinergic neuron; design; dopaminergic neuron; dorsal raphe nucleus; excitotoxicity; extracellular; inhibitor/antagonist; injured; locus ceruleus structure; neuroinflammation; neuron loss; neuroprotection; neurotransmission; noradrenergic; normal aging; novel; prevent; programs; relating to nervous system; research study; response; uptake; young adult

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. PUBLIC HEALTH RELEVANCE: 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 underlie the progression of these age-related degenerative diseases. The experiments proposed will investigate the consequences of long term brain inflammation on specific nuclei that are critical for normal cognitive processes, particularly those that fail with normal aging. In addition, these experiments will investigate potential ways to reverse the effects of the inflammation.

描述（由申请人提供）：本项目的总体目标是确定与正常衰老相关的慢性神经炎症的病理后果，或通过输注脂多糖（LPS）增强大鼠脑干内上行胺能和胆碱能神经元。在阿尔茨海默病、病毒性脑炎、多发性硬化症、艾滋病和帕金森病患者的大脑中，已经描述了一种促炎状态。目前建议的主要假设是，慢性神经炎症的后果也是许多其他年龄相关性退行性疾病的基础，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中的多巴胺能神经元和LPT中的乙酰胆碱神经元。目前的建议旨在促进我们对这些脑干区域的选择性脆弱性的理解，这些脑干区域的条件是这些神经系统的年龄相关疾病的特征。提出的研究是基于这样的假设，即这些神经元的年龄相关性损失的一个主要的潜在问题是炎症诱导的细胞外谷氨酸的升高和谷氨酸在NMDA通道的作用。如果能够改变谷氨酸损伤或破坏脆弱神经系统的能力，将取得临床益处。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内的作用可能对可归因于脑炎症或因脑炎症加重的急性和慢性神经退行性疾病产生临床益处。目的1将确定促炎生物标志物和病理学的时程和区域变化。目的二探讨谷氨酸在炎症诱导的脑干核团神经元变性中的作用。目的3将监测LPS注入年轻、成年和老年大鼠第四脑室后，上行系统离散核团内细胞外谷氨酸水平的逐秒变化;这些变化将与脑干各胺能核团表达的病理程度相关。 公共卫生相关性：在阿尔茨海默病、病毒性脑炎、多发性硬化症、艾滋病和帕金森病患者的大脑中已经描述了促炎状态。目前建议的主要假设是，慢性神经炎症的后果是这些年龄相关性退行性疾病进展的基础。这些实验将研究长期大脑炎症对特定核团的影响，这些核团对正常认知过程至关重要，特别是那些随着正常衰老而失败的核团。此外，这些实验将研究逆转炎症影响的潜在方法。