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，但这些并发症的机制尚不清楚。在这项提议中，我们提出了新的数据，表明老年小鼠的小胶质细胞在外周脂多糖（LPS）攻击后变得过度活跃，表现出白细胞介素(IL)-12和吲哚胺2,3双加氧酶（IDO）的过度诱导。此外，老年小鼠的这种放大的小胶质细胞反应与长期的疾病和抑郁样行为是平行的。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通路将色氨酸代谢成几种反应性中间体和谷氨酸受体激动剂，这些中间体可以影响行为并影响神经元重组。为了支持这一假设，我们展示了老年小鼠海马顶端树突长度减少的初步证据，与抑郁样行为相对应。综上所述，这些发现强调了理解小胶质细胞如何在老年大脑中激活失调的重要性。小胶质细胞调控的一个重要机制是fractalkine （FKN）系统。FKN在神经元上的互补表达和FKN受体（FKNR）在小胶质细胞上的互补表达建立了一个独特的系统，即神经元源性FKN抑制/调节小胶质细胞的激活。在这项提议中，我们提供了证据，证明FKN对小胶质细胞的调节受损可能是lps诱导的老年大脑小胶质细胞过度激活的基础。例如，老年小鼠大脑中FKN mRNA水平下降。此外，与成年小鼠相比，外周LPS注射导致老年小鼠FKNR mRNA的小胶质细胞特异性减少更大。这个为期5年的项目的目标是验证一个主要假设：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起小胶质细胞过度活跃（过度的细胞因子产生和IDO激活），从而导致长时间的抑郁样行为和海马树突萎缩。为了解决这些问题，我们提出了使用BALB/c小鼠衰老模型和FNKR-/-转基因小鼠小胶质细胞调节受损模型的三个具体目标。在第一个目标中，我们将确定受损裂裂蛋白（FKN/FKNR）相互作用与老年小鼠小胶质细胞过度活跃相关的程度。在第二个目标中，我们将确定在有或没有功能性FKNR的小鼠中，外周免疫挑战导致小胶质细胞过度活跃和抑郁样行为的程度。在最后的目的中，我们将确定小胶质细胞过度激活的衰减在多大程度上阻断了外周LPS刺激后老年小鼠长时间的抑郁样行为和海马树突萎缩。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，并且对于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具有潜在的重要意义。

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.