Laboratório de Investigações em Neurodegeneração e Infecção, Hospital João de Barros Barreto, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil.
Neuroscience. 2013 May 15;238:280-96. doi: 10.1016/j.neuroscience.2013.02.019. Epub 2013 Feb 27.
It has been demonstrated that rat litter size affects the immune cell response, but it is not known whether the long-term effects aggravate age-related memory impairments or microglial-associated changes. To that end, we raised sedentary Wistar rats that were first suckled in small or large litters (6 or 12pups/dam, respectively), then separated into groups of 2-3 rats from the 21st post-natal day to study end. At 4months (young adult) or 23months (aged), all individual rats were submitted to spatial memory and object identity recognition tests, and then sacrificed. Brain sections were immunolabeled with anti-IBA-1 antibodies to selectively identify microglia/macrophages. Microglial morphological changes in the molecular layer of the dentate gyrus were estimated based on three-dimensional reconstructions. The cell number and laminar distribution in the dentate gyrus was estimated with the stereological optical fractionator method. We found that, compared to young rat groups, aged rats from large litters showed significant increases in the number of microglia in all layers of the dentate gyrus. Compared to the microglia in all other groups, microglia in aged individuals from large litters showed a significantly higher degree of tree volume expansion, branch base diameter thickening, and cell soma enlargement. These morphological changes were correlated with an increase in the number of microglia in the molecular layer. Young adult individuals from small litters exhibited preserved intact object identity recognition memory and all other groups showed reduced performance in both spatial and object identity recognition tasks. We found that, in large litters, brain development was, on average, associated with permanent changes in the innate immune system in the brain, with a significant impact on the microglial homeostasis of aged rats.
已经证实，大鼠窝仔数会影响免疫细胞反应，但尚不清楚长期影响是否会加剧与年龄相关的记忆障碍或与小胶质细胞相关的变化。为此，我们饲养了久坐的 Wistar 大鼠，这些大鼠首先在小窝（每窝 6 只幼仔）或大窝（每窝 12 只幼仔）中哺乳，然后从出生后第 21 天开始分成 2-3 只大鼠一组进行研究。在 4 个月（年轻成年）或 23 个月（老年）时，所有个体大鼠均接受空间记忆和物体身份识别测试，然后处死。脑切片用抗 IBA-1 抗体进行免疫标记，以选择性地识别小胶质细胞/巨噬细胞。基于三维重建，估计齿状回分子层中小胶质细胞的形态变化。使用体视学光学分割器方法估计齿状回的细胞数量和层分布。我们发现，与年轻大鼠组相比，大窝仔大鼠的所有齿状回层中的小胶质细胞数量均显著增加。与所有其他组的小胶质细胞相比，大窝仔老年大鼠的小胶质细胞树突体积扩张、树突基干直径增粗和细胞体增大程度更高。这些形态变化与分子层中小胶质细胞数量的增加相关。小窝仔的年轻成年大鼠表现出完好的完整物体身份识别记忆，而所有其他组在空间和物体身份识别任务中的表现均有所下降。我们发现，在大窝仔中，大脑发育平均与大脑中先天免疫系统的永久性变化相关，对老年大鼠的小胶质细胞稳态有重大影响。
