Bonasera Stephen J, Arikkath Jyothi, Boska Michael D, Chaudoin Tammy R, DeKorver Nicholas W, Goulding Evan H, Hoke Traci A, Mojtahedzedah Vahid, Reyelts Crystal D, Sajja Balasrinivasa, Schenk A Katrin, Tecott Laurence H, Volden Tiffany A
Division of Geriatrics, University of Nebraska Medical Center, Durham Research Center II, Omaha, NE 68198, USA.
Monroe-Meyer Institute, University of Nebraska Medical Center, Durham Research Center II, Omaha, NE 68198, USA.
Aging (Albany NY). 2016 Sep 20;8(9):2153-2181. doi: 10.18632/aging.101040.
We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules. However, these changes do not localize to microglia, the major CNS immunocyte. Consistent with a neuronal role, there is a marked age-related increase in excitatory synapses over the cerebellum and hypothalamus. Functional imaging of these regions is consistent with age-related synaptic impairments. These studies suggest that aging reactivates a developmental program employed during embryogenesis where immune molecules guide synapse formation and pruning. Renewed activity in this program may disrupt excitatory neurotransmission, causing significant behavioral deficits.
我们描述了基于脑区和遗传背景的与年龄相关的分子和神经元变化，这些变化会破坏运动能力或能量平衡。与年轻小鼠相比，老年C57BL/6小鼠表现出明显的运动（而非能量平衡）障碍。相比之下，老年BALB小鼠表现出明显的能量平衡（而非运动）障碍。小脑或下丘脑基因表达的与年龄相关的变化伴随着这些表型。衰老会引起免疫模式识别受体和细胞粘附分子的上调。然而，这些变化并不局限于主要的中枢神经系统免疫细胞——小胶质细胞。与神经元作用一致，小脑和下丘脑的兴奋性突触随年龄增长显著增加。这些区域的功能成像与年龄相关的突触损伤一致。这些研究表明，衰老重新激活了胚胎发育过程中使用的一个发育程序，其中免疫分子指导突触形成和修剪。该程序的重新激活可能会破坏兴奋性神经传递，导致显著的行为缺陷。
