目的:我们旨在研究小胶质细胞活性和小胶质细胞FDG摄取对代谢连接的影响,因为小胶质细胞的活化状态决定了FDG-PET的改变。代谢连通性是指相互作用的代谢脑区域的概念,并且在神经退行性疾病中处理复杂的脑代谢网络方面受到越来越多的关注。然而,代谢连接的潜在来源仍有待阐明。
方法:我们分析了通过FDG-PET扫描的区域间相关系数(ICCs)测量的代谢网络,在WT小鼠和在颗粒蛋白前体(Grn)或在骨髓细胞2(Trem2)敲除(-/-)上表达的触发受体(-/-)以及双突变Grn-/-/Trem2-/-小鼠中。我们选择了这些啮齿动物模型,因为它们代表了Grn-/-小鼠中与疾病相关的小胶质细胞相反的小胶质细胞特征,而Trem2-/-小鼠中的小胶质细胞则处于稳态状态;然而,两者都导致大脑葡萄糖摄取降低。小胶质细胞对代谢网络的直接影响通过在两个不同年龄的WT小鼠中使用CSF1R抑制剂消除小胶质细胞来进一步确定。在全球平均尺度区域FDG吸收图中,将24个预先建立的感兴趣体积应用并分配给皮质或皮质下网络。计算所有区域对的ICC,并在组比较之前进行z-转化。神经元的FDG摄取,小胶质细胞,通过评估单细胞示踪剂摄取(scradiotracing),在Grn-/-和WT小鼠中确定星形胶质细胞。
结果:由CSF1R抑制引起的小胶质细胞耗竭导致代谢连通性的强烈降低,该代谢连通性由研究的两个年龄的WT小鼠的平均皮质ICC的降低定义(6-7m;p=0.0148,9-10m;p=0.0191),当与媒介物处理的年龄匹配的WT小鼠相比时。Grn-/-,当与WT小鼠相比时,Trem2-/-和Grn-/-/Trem2-/-小鼠均显示减少的FDG-PET信号。然而,在分析代谢网络时,当在皮质(p<0.0001)和海马(p<0.0001)网络中与WT小鼠相比时,在Grn-/-小鼠中观察到ICC显著增加。相比之下,当与WT相比时,Trem2-/-小鼠在代谢连通性方面没有显示出显著的改变。此外,Grn-/-/Trem2-/-小鼠的代谢连接增加被完全抑制。Grn-/-小鼠表现出神经元FDG摄取的严重损失(-61%,p<0.0001),这将细胞脑FDG摄取的分配转移到小胶质细胞(Grn-/-vs.22%在WT中)。
结论:存在,缺席,小胶质细胞的激活对小鼠大脑的代谢连通性有很大影响。增强的代谢连通性与增加的小胶质细胞FDG分配相关。
OBJECTIVE: We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.
METHODS: We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG-PET scans in WT mice and in mice with mutations in progranulin (Grn) or triggering receptor expressed on myeloid cells 2 (Trem2) knockouts (-/-) as well as in double mutant Grn-/-/Trem2-/- mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn-/- mice and microglia locked in a homeostatic state in Trem2-/- mice; however, both resulting in lower glucose uptake of the brain. The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn-/- and WT mice via assessment of single cell tracer uptake (scRadiotracing).
RESULTS: Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6-7 m; p = 0.0148, 9-10 m; p = 0.0191), when compared to vehicle-treated age-matched WT mice. Grn-/-, Trem2-/- and Grn-/-/Trem2-/- mice all displayed reduced FDG-PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn-/- mice when compared to WT mice in cortical (p < 0.0001) and hippocampal (p < 0.0001) networks. In contrast, Trem2-/- mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn-/- mice was completely suppressed in Grn-/-/Trem2-/- mice. Grn-/- mice exhibited a severe loss of neuronal FDG uptake (- 61%, p < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn-/- vs. 22% in WT).
CONCLUSIONS: Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation.