Neuroinflammatory and cognitive consequences of losing cholinergic anti-inflammatory tone in the forebrain

前脑失去胆碱能抗炎张力的神经炎症和认知后果

基本信息

批准号：
9513986
负责人：
Colm Cunningham
金额：
$ 25.42万
依托单位：
TRINITY COLLEGE DUBLIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9513986
关键词：
Acceleration Acetylcholine Acute Address Adverse effects Aging Alzheimer&apos s Disease Animals Anti-Cholinergics Anti-inflammatory Anxiety Astrocytes Attention Behavior Blood Pressure Brain Brain Injuries Cell Lineage Cells Choline Chronic Cognition Cognitive Complication Confusion Coupled Delirium Dementia Economics Elderly Encephalitis Endotoxins Energy Metabolism Family Functional disorder Glucose Health High Prevalence Hippocampus (Brain)Hypersensitivity Impaired cognition Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Institutionalization Interleukin-1 Interleukin-1 beta Intervention Lead Length of Stay Lesion Measures Mediating Medical Medical Economics Medicine Memory Microglia Monitor Mus NGFR Protein Nerve Degeneration Neuromodulator Neurons Nicotinic Agonists Nicotinic Receptors Nitric Oxide Outcome Oxygen Pathology Patients Peripheral Pharmaceutical Preparations Pharmacology Population Predisposition Prosencephalon Proxy Public Health Quality of life Research Resolution Risk Risk Factors Role Severities System Time Tissues Transcript Vulnerable Populations aging population basal forebrain basal forebrain cholinergic neurons behavior test brain metabolism cecal ligation puncture chemokine cholinergic cognitive change cognitive function cognitive testing cost in vivo macrophage neurochemistry neuroinflammation neuropathology neurophysiology neuropsychiatry noradrenergic polymicrobial sepsis public health priorities receptor function response sedative

项目摘要

Project Summary (complete rewrite) Acute cognitive dysfunction (including delirium) is a highly prevalent neuropsychiatric complication of systemic inflammation in the elderly and, in particular, in those with dementia. As well as extending hospital stays, acute systemic inflammatory episodes also increase the risk for subsequent dementia and accelerate existing dementia. Despite these economic and public health imperatives, the pathophysiological mechanisms of systemic inflammation- induced acute cognitive dysfunction and lasting brain injury are poorly understood. We have previously demonstrated that systemic inflammation, when superimposed on existing neurodegenerative pathology, produces acute, fluctuating and reversible impairments in cognitive domains relevant to delirium (Davis et al., 2015) and accelerates the trajectory of long-term decline (Cunningham et al, 2009). Acetylcholine (ACh) is a neuromodulator with important roles in attention and cognitive function and the cholinergic neurons of the basal forebrain degenerate significantly in Alzheimer's disease. We have recently demonstrated that existing neurodegeneration in the basal forebrain cholinergic system leads to more severe acute cognitive dysfunction after systemic administration of bacterial endotoxin (LPS; Field et al., 2012). Macrophage lineage cells can also be modulated by ACh and here we highlight that loss of cholinergic forebrain ennervation leads to a priming of the forebrain microglial population to show exaggerated IL-1β responses to subsequent inflammatory stimulation. We propose that this cholinergic and consequent inflammatory predisposition significantly impacts on the short-term cognitive/neurophysiological, and long-term cognitive and neuropathological, outcomes of systemic inflammation. We will address this hypothesis directly by administering LPS or poly-microbial sepsis (cecal ligation and puncture; CLP) to mice with immunotargeted degeneration of the basal forebrain cholinergic system. In AIM1 we will demonstrate exaggered microglia, astroglial and neuronal responses to systemic inflammation and probe the role of nicotinic receptors in these effects. In AIM 2 we will use both LPS and CLP coupled with unique real-time in vivo brain monitoring of acetylcholine and of key determinants of neuronal function: oxygen, glucose, lactate, time-synced to behavioral testing to interrogate the neurophysiological underpinning of acute cognitive changes and the mechanisms of brain injury leading to long-term cognitive impairment. In AIM3 we will examine differential effects (on hypocholinergic versus normal mice) of some pharmacological interventions typical of the acute medical setting. Together we believe that these studies will significantly contribute to our understanding of acute cognitive dysfunction occurring during systemic inflammation and the exacerbation of ongoing cognitive decline relevant to aging and dementia.

项目总结（完全重写）急性认知功能障碍（包括谵妄）是一种非常普遍的神经精神疾病老年人，特别是痴呆症患者的全身炎症并发症。除了延长住院时间外，急性全身炎症发作也会增加尽管存在这些经济和风险，但仍存在随后发生痴呆的风险并加速现有痴呆的发生。公共卫生的当务之急，全身炎症的病理生理机制我们对引起的急性认知功能障碍和持久性脑损伤知之甚少。以前证明了全身炎症，当叠加到现有的神经退行性病理学，产生急性、波动性和可逆性损伤与谵妄相关的认知领域（Davis et al., 2015）并加速了长期衰退（Cunningham 等人，2009）。在注意力和认知功能以及基底胆碱能神经元中发挥重要作用我们最近证明，在阿尔茨海默病中，前脑会显着退化。基底前脑胆碱能系统中现有的神经变性导致更严重的全身施用细菌内毒素（LPS；Field 等）后出现急性认知功能障碍 al., 2012)。巨噬细胞谱系细胞也可以被乙酰胆碱调节，在这里我们强调这一点。胆碱能前脑神经支配的丧失导致前脑小胶质细胞的启动人群对随后的炎症刺激表现出夸张的 IL-1β 反应。提出这种胆碱能和随之而来的炎症倾向显着影响关于短期认知/神经生理学以及长期认知和神经病理学，我们将通过给药直接解决这一假设。 LPS 或多微生物败血症（盲肠结扎和穿刺；CLP）对免疫靶向小鼠我们将在 AIM1 中演示基底前脑胆碱能系统的退化。小胶质细胞、星形胶质细胞和神经系统对全身炎症和探针的过度反应在 AIM 2 中，我们将结合使用 LPS 和 CLP。具有独特的实时体内乙酰胆碱和关键决定因素的脑部监测神经功能：氧、葡萄糖、乳酸，与行为测试时间同步以询问急性认知变化的神经生理学基础和大脑机制在 AIM3 中，我们将研究不同的影响。（针对低胆碱能小鼠与正常小鼠）一些典型的药物干预措施我们相信这些研究将对我们的急性医疗环境做出重大贡献。了解全身炎症期间发生的急性认知功能障碍以及与衰老和痴呆相关的持续认知能力下降加剧。