Age Neuroinflammation and Neurobehavioral Disorders

描述（由申请人提供）：最近的证据表明，小胶质细胞，大脑的先天免疫细胞，随着年龄的增长而变得更活跃。显著反应性小胶质细胞群的潜在后果是对免疫激活的神经炎症反应放大。我们最近的研究支持了这一前提，该研究表明，脂多糖（LPS）对先天免疫系统的外周刺激会导致老年BALB/c小鼠神经炎症细胞因子反应的夸大和疾病行为的延长。重要的是，过度或长期暴露于炎症细胞因子可能导致老年人的认知和行为并发症。在这项应用中，我们发现lps加剧了老年大脑中的炎症细胞因子反应，导致了长期的抑郁样行为，并与单胺类神经递质5-羟色胺（5-HT）的脑代谢受损有关，5-羟色胺是情绪和行为的关键调节剂。我们的研究结果还表明，大脑5-羟色胺代谢受损是吲哚胺2,3双加氧酶（IDO）活性升高的结果，IDO是一种分解色氨酸（TRP）的酶。TRP是5-HT合成中的限速氨基酸，因此升高的TRP分解代谢可以减少5-HT介导的神经传递，从而导致抑郁行为。因此，神经炎症反应的增强可能是老年人抑郁症相关并发症的基础。该项目的目的是验证这样一种假设，即老年人外周先天免疫系统的激活促进了海马体中延长的炎症反应，从而破坏了5-羟色胺的代谢，导致明显且持久的抑郁症状。为了解决这个问题，我们提出了使用衰老BALB/c小鼠模型的两个具体目标。在第一个目标中，我们将描述小胶质细胞活性的衰减是否可以防止lps诱导的神经炎症、5-羟色胺代谢受损和老年小鼠的抑郁样行为。在第二个目标中，我们将确定消除IDO活性是否可以逆转LPS刺激后老年小鼠的生化和行为缺陷。本研究的目的是了解衰老对抑郁症相关疾病的影响，以制定治疗干预策略，提高成功衰老的可能性。

DESCRIPTION (provided by applicant): Recent evidence indicates that microglia, innate immune cells of the brain, become more reactive with age. A potential consequence of a significant reactive microglia population is an amplified neuroinflammatory response to immune activation. This premise is supported by our recent study demonstrating that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) caused an exaggerated neuroinflammatory cytokine response and prolonged sickness behavior in aged BALB/c mice. Importantly, excessive or chronic exposure to inflammatory cytokines may be permissive to cognitive and behavioral complications in the elderly. In this application, we show that an LPS-exacerbated inflammatory cytokine response in the aged brain causes protracted depressive-like behavior and is associated with impaired brain metabolism of the monoamine neurotransmitter serotonin (5-HT), a critical regulator of mood and behavior. Our findings also indicate that this impaired brain 5-HT metabolism is a result of the heightened activity of indoleamine 2, 3 dioxygenase (IDO), an enzyme that catabolizes tryptophan (TRP). TRP is the rate limiting amino acid in 5-HT synthesis, so elevated TRP catabolism could reduce 5-HT-mediated neurotransmission leading to depressive behavior. Thus, a heightened neuroinflammatory response may underlie the depressive- related complications that frequently occur in the elderly. The objective of this project is to test the hypothesis that activation of the peripheral innate immune system in the aged promotes a prolonged inflammatory response in the hippocampus that disrupts 5-HT metabolism causing pronounced and long-lasting depressive symptoms. To address this issue, we propose two specific aims using an aged BALB/c mouse model. In the first aim we will delineate if attenuation of microglial activity prevents LPS-induced neuroinflammation, impaired 5-HT metabolism, and depressive-like behavior in aged mice. In the second aim we will determine if abrogation of IDO activity reverses these same biochemical and behavioral deficits in aged mice following LPS challenge. The goal of this proposal is to understand the effects of aging on depressive disorders associated with illness to develop strategies for therapeutic intervention to improve the likelihood of successful aging.