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.

项目摘要（完整重写）急性认知功能障碍（包括ir妄）是一种高度普遍的神经精神病学老年人，尤其是患有痴呆症患者的全身性炎症并发症。除了延长住院外，急性全身性炎症发作还增加了随后痴呆并加速现有痴呆症的风险。尽管经济和公共卫生要求，系统性炎症的病理生理机制 - 诱发的急性认知功能障碍和持久的脑损伤知之甚少。我们有以前证明，当叠加在现有的神经退行性病理学，在与妄想相关的认知领域（Davis等，2015），并加速了长期下降（Cunningham等，2009）。乙酰胆碱（ACH）是一种神经调节剂在注意力和认知功能以及基本的胆碱能神经元中的重要作用前脑在阿尔茨海默氏病中显着退化。我们最近证明了基本前脑胆碱能系统中的现有神经变性导致更严重全身施用细菌内毒素后急性认知功能障碍（LPS; Field ET Al。，2012）。巨噬细胞谱系细胞也可以通过ACH调节，在这里我们强调胆碱能前脑的损失导致前脑小胶质细胞的启动人群显示出夸张的IL-1β对随后的炎症刺激的反应。我们建议这种胆碱能和随之而来的炎症易感性会显着影响在短期认知/神经生理学以及长期认知和神经病理学上系统性炎症的结果。我们将通过管理直接解决这一假设 LPS或多微生物败血症（Cecal结扎和穿刺； CLP）与免疫靶向的小鼠基本前脑胆碱能系统的变性。在AIM1中，我们将证明夸张的小胶质细胞，星形胶质细胞和神经元对全身注射的反应并证明烟碱受体在这些作用中的作用。在AIM 2中，我们将同时使用LP和CLP耦合具有独特的实时体内大脑监测乙酰胆碱和关键决定剂神经元功能：氧，葡萄糖，乳酸，时间同步进行行为测试以询问急性认知变化的神经生理基础和大脑的机制伤害导致长期认知障碍。在AIM3中，我们将检查差异效果（在降压素能和正常小鼠上）的某些药物干预措施急性医疗环境。我们共同认为，这些研究将对我们的了解全身注射过程中发生的急性认知功能障碍和加剧与衰老和痴呆症相关的认知下降。