Saavedra Luis Miguel, Fenton Navarro Bertha, Torner Luz
Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, Mexico.
Neuroimmunomodulation. 2017;24(4-5):242-255. doi: 10.1159/000485383. Epub 2018 Jan 13.
Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15.
Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively.
LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1β, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1β protein, but these were attenuated in MS-LPS pups.
Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.
早年生活应激（ELS）会增加成年后患精神病理障碍的易感性，这些障碍伴有脑部炎症过程。然而，早年的双重打击（应激和免疫）如何影响神经免疫系统的反应尚不清楚。在此，我们研究了周期性母婴分离（MS）后给予脂多糖（LPS）对出生后第15天（PN15）海马CA3区和齿状回胶质细胞以及细胞因子释放的影响。
雄性幼鼠接受MS（每天3小时，PN1 - 14）。MS组和对照组幼鼠在PN14接受单次LPS注射（1mg/kg体重）。1小时后对它们进行旷场试验。分别在LPS注射后90分钟（PN14）或PN15处死幼鼠，进行细胞因子或免疫组织学分析。
LPS降低了处理组幼鼠的运动能力并诱导了高皮质酮水平。MS或LPS降低了海马CA3区和齿状回的小胶质细胞密度并激活了小胶质细胞。小胶质细胞激活在MS - LPS组幼鼠中最高。MS或LPS使CA3区和齿状回的星形胶质细胞密度轻度降低，但在MS - LPS组幼鼠中降低最大。LPS增加了血浆白细胞介素（IL）-1β、肿瘤坏死因子-α和IL - 6以及海马IL - 1β蛋白的分泌，但在MS - LPS组幼鼠中这些分泌减弱。
虽然MS和LPS激活了神经免疫细胞，但应激通过一种尚未明确的适应性机制减弱了海马和外周对LPS的细胞因子反应。这些结果提供了关于应激和炎症神经生物学的信息。
