Age Neuroinflammation and Neurobehavioral Disorders

描述(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加活跃。显著的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性反应。我们最近的一项研究支持了这一假设，该研究表明，外周内毒素(LPS)刺激BALB/c小鼠的先天免疫系统可导致过度的神经炎性细胞因子反应和延长的疾病行为。重要的是，过度或长期接触炎性细胞因子可能会导致老年人的认知和行为并发症。在这一应用中，我们表明，在老年大脑中，内毒素加剧的炎性细胞因子反应会导致长期的抑郁样行为，并与大脑中单胺类神经递质5-羟色胺(5-HT)的代谢受损有关，5-羟色胺是情绪和行为的关键调节因子。我们的发现还表明，大脑5-羟色胺代谢受损是吲哚胺2，3双加氧酶(IDO)活性增强的结果，IDO是一种分解色氨酸(Trp)的酶。色氨酸是5-羟色胺合成的限速氨基酸，因此色氨酸分解代谢的升高可能会减少5-羟色胺介导的神经传递，从而导致抑郁行为。因此，神经炎性反应增强可能是老年人经常发生的抑郁症相关并发症的基础。该项目的目的是验证一种假说，即老年人外周天然免疫系统的激活促进了海马区长期的炎症反应，从而扰乱了5-羟色胺的代谢，导致明显而持久的抑郁症状。为了解决这个问题，我们利用老龄BALB/c小鼠模型提出了两个特定的目标。在第一个目标中，我们将描述小胶质细胞活性的减弱是否可以防止脂多糖诱导的神经炎症、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，我们将确定在脂多糖攻击后，IDO活性的取消是否可以逆转老龄小鼠同样的生化和行为缺陷。这项建议的目标是了解衰老对与疾病相关的抑郁障碍的影响，以制定治疗干预策略，以提高成功老龄化的可能性。

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.