Neuroinflammation and Behavior in the Aged

描述（由申请人提供）：急性认知障碍在老年急诊科患者中很常见，通常由与中枢神经系统无关的感染引起。认知障碍导致自我护理的失败，并与住院治疗增加和恢复延迟有关。本应用程序提供的初步数据表明，正常衰老与神经炎症增加有关，当脂多糖（LPS）激活外周先天免疫系统时，健康老年小鼠的大脑中会发生夸张的炎症反应。我们认为，这种现象可能是老年患者普遍存在的认知缺陷的基础，并解释了为什么感染是神经退行性疾病发展的危险因素。在这个应用中，我们将直接测试外周先天免疫系统的激活在老年大脑中产生夸大的炎症反应，导致严重和长期的认知功能缺陷和海马锥体神经元形态的变化。我们在老年小鼠模型中提出了四个具体目标来解决这一假设。为了确定患有全身性感染的老年人的大脑炎症是否加剧，在第一个目标中，将给成年和老年小鼠注射LPS，并在使用激光捕获显微解剖技术获得的海马组织中测量炎症细胞因子，并通过免疫组织化学染色定位细胞因子阳性的小胶质细胞。我们将特别关注海马体，因为它对衰老很敏感，并参与认知障碍，这在老年全身性感染患者中很明显。第二个目标是通过评估老年小鼠在几项海马体依赖性测试中的表现来确定过度炎症反应的行为后果；目标三将通过确定LPS和重组细胞因子对海马锥体神经元形态的影响来探索行为变化的根源。最后，在第四个目标中，我们将抑制LPS刺激的老年小鼠大脑中的炎症细胞因子，以确定这是否会抑制与年龄相关的神经行为缺陷加剧和神经回路减少的迹象。当前文献中的一个主要难题是，在感染解决和细胞因子恢复正常后，老年人的行为缺陷仍然存在很长时间。因此，我们认为了解炎症细胞因子对介导认知行为的大脑区域神经元形态的影响至关重要。为了提高“成功”衰老的可能性，需要更好地了解衰老如何影响与全身性感染相关的神经行为并发症。

DESCRIPTION (provided by applicant): Acute cognitive impairment is common in elderly emergency department patients and frequently results from infections that are unrelated to the CNS. Cognitive impairment leads to a failure in self-care and is associated with increased hospitalization and delayed recovery. Preliminary data presented in this application indicate that normal aging is associated with increased neuroinflammation and that an exaggerated inflammatory response occurs in the brain of healthy aged mice when lipopolysaccharide (LPS) activates the peripheral innate immune system. We believe that this phenomenon may underlie the cognitive deficits that are highly prevalent in elderly patients and explain why infection is a risk factor for development of neurodegenerative diseases. In this application, we will directly test the hypothesis that activation of the peripheral innate immune system produces an exaggerated inflammatory response in the aged brain that causes severe and prolonged deficits in cognitive function and changes in hippocampal pyramidal neuron morphology. We propose four specific aims in an aged mouse model to address the hypothesis. To determine if inflammation in the brain of older adults with a systemic infection is exacerbated, in the first aim adult and aged mice will be given LPS i.p. and inflammatory cytokines will be measured in hippocampal tissue obtained using laser capture microdissection techniques, and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention will be paid to the hippocampus because it is sensitive to aging and involved in cognitive disorders that are evident in elderly patients with systemic infections. The second aim will determine the behavioral consequences of the exaggerated inflammatory response in aged mice by assessing their performance in several hippocampal-dependent tests; and aim three will explore the root of the behavioral changes by determining the effects of LPS and recombinant cytokines on hippocampal pyramidal neuron morphology. Finally in the fourth aim we will inhibit inflammatory cytokines in the brain of aged mice that are challenged with LPS to determine if this inhibits the age-associated exacerbation of neurobehavioral deficits and indications of diminished neuronal circuitry. One of the major conundrums in the current literature is that behavioral deficits persist in the elderly long after the infection has been resolved and cytokines returned to normal. Therefore, we contend that understanding the effects of inflammatory cytokines on morphology of neurons in brain areas that mediate cognitive behavior is critical. A better understanding of how aging influences the neurobehavioral complications associated with systemic infections is needed to improve the likelihood for "successful" aging.