Aging, Microglial Dysregulation and Depression

描述（由申请人提供）：在老年人中，外周感染与抑郁并发症的发生率较高相关，但这些并发症的潜在机制尚不清楚。在这个建议中，我们提出了新的数据表明，老年小鼠的小胶质细胞变得过度活跃后，外周脂多糖（LPS）的挑战，表现出夸张的诱导白细胞介素（IL）-12和吲哚胺2，3双加氧酶（IDO）。此外，这种放大的小胶质细胞反应在老年小鼠中被长期的疾病和抑郁样行为所抑制.过度的小胶质细胞特异性IDO诱导可能是一个关键事件，因为最近的研究表明，IDO是炎症介导的抑郁症的核心。IDO途径将色氨酸代谢成几种反应性中间体和谷氨酸受体激动剂，其可以影响行为以及影响神经元重构。在支持这一前提，我们显示了初步的证据，减少顶端树突长度在海马的老年小鼠在一个时间对应于抑郁样行为。总之，这些发现强调了了解小胶质细胞激活在老年大脑中如何失调的重要性。小胶质细胞调节的一个重要机制是Fractalkine（FKN）系统。神经元上FKN和小胶质细胞上FKN受体（FKNR）的互补表达建立了一个独特的系统，由此神经元衍生的FKN抑制/调节小胶质细胞活化。在这个建议中，我们提供的证据表明，受损的小胶质细胞调节FKN可能是这个LPS诱导的小胶质细胞过度激活的老年大脑的基础。例如，FKN mRNA水平在老年小鼠的脑中降低。此外，外周LPS注射导致老年小鼠FKNR mRNA的小胶质细胞特异性减少比成年小鼠更大。这个为期5年的项目的目的是测试一个主要假设：当FKN对小胶质细胞激活的调节受损时，外周先天免疫挑战会引发小胶质细胞过度活跃（细胞因子产生过多和IDO激活），从而导致长期的抑郁样行为和海马体树突萎缩。为了解决这些问题，我们提出了三个具体的目标，使用老化的BALB/c小鼠模型和受损的小胶质细胞调节的FNKR-/-转基因小鼠模型。在第一个目标中，我们将确定受损的fractalkine（FKN/FKNR）相互作用与老年小鼠小胶质细胞过度活跃的程度。在第二个目标中，我们将确定外周免疫攻击在多大程度上导致小胶质细胞过度活跃和抑郁样行为的小鼠与功能性FKNR或没有。在最后的目标，我们将确定在何种程度上衰减小胶质细胞过度激活块延长抑郁样行为和海马树突状萎缩的老年小鼠外周脂多糖的挑战。解决这些目标与理解小胶质细胞调节的年龄相关变化有关，并且在开发干预措施以防止导致长期神经行为并发症的长期神经炎症反应方面具有潜在的重要性。 公共卫生相关性：在老年人中，外周感染与认知和行为并发症的发生率较高有关，但所涉及的机制尚不清楚。我们认为这些炎症相关的并发症是由于老年大脑中小胶质细胞活化调节受损所致。在本申请中，我们将使用两种小鼠模型，一种是衰老模型，另一种是FKN依赖性小胶质细胞调节受损模型，以检验一个主要假设：当FKN对小胶质细胞活化的调节受损时，外周先天免疫激发小胶质细胞过度活跃（过度的细胞因子产生和IDO活化），导致长期的抑郁样行为和海马树突状细胞萎缩。因此，小胶质细胞过度活跃与长期IDO激活可能是老年人炎症相关抑郁症的基础。

DESCRIPTION (provided by applicant): In the elderly, peripheral infection is associated with higher incidence of depressive complications, but the mechanisms underlying these complications are unknown. In this proposal, we present novel data that indicates that microglia of aged mice become hyperactive following peripheral lipopolysaccharide (LPS) challenge, exhibiting exaggerated induction of interleukin (IL)-12 and indoleamine 2,3 dioxygenase (IDO). Moreover, this amplified microglial response in aged mice is paralleled by prolonged sickness and depressive- like behaviors. Excessive microglia-specific IDO induction may be a pivotal event as recent studies indicate that IDO is central to inflammatory-mediated depression. The IDO pathway metabolizes tryptophan into several reactive intermediates and glutamate receptor agonists that can impact behavior as well as influence neuronal restructuring. In support of this premise, we show preliminary evidence of decreased apical dendrite length in hippocampus of aged mice at a time corresponding with depressive-like behavior. Taken together, these findings underscore the importance of understanding how microglia activation is dysregulated in the aged brain. One significant mechanism for microglia regulation is the fractalkine (FKN) system. Complementary expression of FKN on neurons and FKN receptor (FKNR) on microglia establishes a unique system whereby neuron-derived FKN restrains/modulates microglia activation. In this proposal, we provide evidence that impaired microglia regulation by FKN may be the basis for this LPS-induced microglial hyperactivation in the aged brain. For example, FKN mRNA levels are decreased in the brain of aged mice. In addition, peripheral LPS injection causes a greater microglia-specific reduction in FKNR mRNA in aged mice than adults. The objective of this 5 year project is to test one major hypothesis: When FKN regulation of microglia activation is impaired, peripheral innate immune challenge elicits microglial hyperactivity (excessive cytokine production and IDO activation) that causes prolonged depressive-like behavior and hippocampal dendritic atrophy. To address these issues, we propose three specific aims using a BALB/c mouse model of aging and a FNKR-/- transgenic mouse model of impaired microglia regulation. In the first aim we will determine the degree to extent to which impaired fractalkine (FKN/FKNR) interactions are associated with microglial hyperactivity in aged mice. In the second aim we will ascertain the degree to which peripheral immune challenge causes microglial hyperactivity and depressive-like behavior in mice with or without functional FKNR. In the final aim, we will determine the extent to which attenuation of microglia hyperactivation blocks prolonged depressive-like behavior and hippocampal dendritic atrophy in aged mice after peripheral LPS challenge. Addressing these aims is relevant to understanding age-associated changes in microglia regulation and is potentially important in developing interventions to protect against prolonged neuroinflammatory responses that contribute to long- lasting neurobehavioral complications. PUBLIC HEALTH RELEVANCE: In the elderly, peripheral infection is associated with higher incidence of cognitive and behavioral complications but the mechanisms involved are not well understood. We propose that these inflammatory-related complications are caused by impaired regulation of microglia activation in the aged brain. In this application, we will use two mouse models, one of aging and one of impaired fractalkine (FKN)-dependent microglial regulation, to test one major hypothesis: When FKN regulation of microglia activation is impaired, peripheral innate immune challenge elicits microglial hyperactivity (excessive cytokine production and IDO activation) that causes prolonged depressive-like behavior and hippocampal dendritic atrophy. Thus, microglial hyperactivity with prolonged IDO activation may underlie inflammatory-related depression in the elderly.