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，随着年龄的增长变得更具反应性。显著反应性小胶质细胞群体的潜在后果是对免疫激活的放大的神经炎症反应。我们最近的研究表明，脂多糖（LPS）的先天免疫系统的外周刺激引起了夸大的神经炎性细胞因子反应和长期的疾病行为在老年BALB/c小鼠的支持这一前提。重要的是，过度或长期暴露于炎性细胞因子可能会导致老年人的认知和行为并发症。在这个应用程序中，我们表明，在老年人的大脑中的LPS加剧炎症细胞因子反应导致长期抑郁样行为，并与受损的大脑代谢的单胺神经递质5-羟色胺（5-HT），情绪和行为的关键调节。我们的研究结果还表明，这种受损的脑5-HT代谢是吲哚胺2，3双加氧酶（IDO），一种分解代谢色氨酸（TRP）的酶的活性升高的结果。TRP是5-HT合成的限速氨基酸，因此升高的TRP催化剂可减少5-HT介导的神经传递，导致抑郁行为。因此，神经炎症反应增强可能是老年人经常发生的抑郁相关并发症的基础.本项目的目的是验证老年人外周先天免疫系统激活促进海马中长时间炎症反应的假设，该炎症反应破坏5-HT代谢，导致明显和持久的抑郁症状。为了解决这个问题，我们提出了两个具体的目标，使用老年BALB/c小鼠模型。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-HT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IDO活性的消除是否逆转LPS攻击后老年小鼠中这些相同的生物化学和行为缺陷。该提案的目标是了解衰老对与疾病相关的抑郁症的影响，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.