Neuroimmunology of Age-Associated Depressive Disorders

描述（由申请人提供）：过度或长时间暴露于外周感染可能导致老年人的认知和行为并发症。我们最近报道了脂多糖（LPS）对先天免疫系统的外周刺激导致老年Balb/c小鼠脑炎症细胞因子反应的夸大和疾病行为的延长。虽然短暂暴露于细胞因子对宿主对病原体的反应是有益的，但过度或长时间暴露于细胞因子会导致无数的神经行为并发症，包括情绪、认知和抑郁症。在这里，我们提供了新的证据，证明这种LPS加剧的老年小鼠大脑中的炎症细胞因子反应促进了抑郁样行为，即使在LPS的急性效应已经解决后，这种行为也很明显。此外，我们的初步研究结果表明，LPS刺激后这些与年龄相关的抑郁样症状与细胞因子介导的吲哚胺2,3 -二氧合酶（IDO）活性增加和大脑中5-羟色胺（5-HT）代谢改变有关。在这个应用中，我们将测试一个假设，即老年人的外周先天免疫系统的激活促进了大脑中夸大的炎症反应，破坏了神经递质血清素的正常代谢，导致明显和持久的抑郁样症状。为了解决这个问题，我们提出了使用老年小鼠模型的两个具体目标。在第一个目标中，我们将使用两种不同的行为测试来描述LPS刺激小鼠的抑郁样行为：强迫游泳和蔗糖偏好，并确定神经炎症途径是否与这些与年龄相关的行为改变有关。在第二个目标中，我们将描述老年小鼠在LPS刺激后延长的抑郁样症状是否是大脑中色氨酸（TRP）和5-羟色胺代谢受损的结果。这个项目的成功完成将使我们更好地理解细胞因子与老年人抑郁症之间的关系。众所周知，老年人伴随疾病或感染的情绪和抑郁障碍的发生率较高；然而，所涉及的机制尚不清楚。为了解决这个问题，我们使用BALB/c小鼠衰老模型设计了行为和生化实验，以确定大脑中与年龄相关的变化是否允许外周先天免疫系统激活后抑郁症的发作。我们推测，大脑中炎症细胞因子反应的增强破坏了正常的血清素代谢，导致了长期的抑郁症状。

DESCRIPTION (provided by applicant): Excessive or prolonged exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have recently reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated brain inflammatory cytokine response and prolonged sickness behavior in aged Balb/c mice. While transient exposure to cytokines is beneficial in the host's response to a pathogen, excessive or prolonged exposure is associated with a myriad of neurobehavioral complications including mood, cognitive, and depressive disorders. Here, we provide novel evidence that this LPS-exacerbated inflammatory cytokine response in the brain of aged mice promotes depressive-like behaviors that are evident even after the acute effects of LPS have been resolved. Furthermore, our preliminary findings suggest that these age-related depressive-like symptoms following LPS challenge are associated with increased cytokine-mediated indoleamine 2, 3-dioxgenase (IDO) activity and altered serotonin (5-HT) metabolism in the brain. In this application, we will test the hypothesis that activation of peripheral innate immune system in the aged promotes an exaggerated inflammatory response in the brain that disrupts the normal metabolism of the neurotransmitter serotonin causing pronounced and prolonged depressive-like symptoms. To address this issue, we propose two specific aims using an aged mouse model. In the first aim we will characterize depressive-like behavior in mice challenged with LPS using two distinct behavioral tests: forced swimming and sucrose preference, and determine if neuroinflammatory pathways are associated with these age-related alterations in behavior. In the second aim we will delineate if prolonged depressive-like symptoms in aged mice following LPS challenge are a consequence of impaired tryptophan (TRP) and 5-HT metabolism in the brain. Successful completion of this project will yield a better understanding of the relationship between cytokines and depression in the aged. It is known that the elderly have a higher incidence of mood and depressive disorders concomitant with illness or infection; however, the mechanisms involved are not well understood. To address this issue we have designed behavioral and biochemical experiments using a BALB/c mouse model of aging to determine if age-associated changes in the brain are permissive to the onset of depression following activation of the peripheral innate immune system. We hypothesize that a heightened inflammatory cytokine response in the brain disrupts normal serotonin metabolism and results in long- lasting depressive symptoms.