Early-life stress (ELS) is considered a relevant etiological factor for neurodegenerative and mental disorders. In the present study, we hypothesized that ELS may persistently and sex dependently influence blood–brain barrier (BBB) integrity and function during critical periods of brain development and consequently determine susceptibility to and sex-related prevalence of chronic diseases in adult life. We used the maternal separation (MS) procedure in rats to model ELS and evaluated BBB permeability and gene expression of selected tight junction (TJ) proteins, glucose transporter type 1 (Slc2a1) and aquaporin 4 (Aqp4) in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR) and hippocampus of juvenile and adult rats. Serum concentrations of a peripheral marker of BBB function (S100β) and proinflammatory cytokines were also assessed. We observed developmental sealing of the BBB and sex differences in the permeability of the BBB and the mRNA expression of TJ proteins and Slc2a1. Adult females showed lower BBB permeability and higher levels of Cldn3, Cldn5, Ocln, and Slc2a1 in the mPFC and dSTR than males. MS temporarily increased BBB permeability in the dSTR of juvenile males and affected mRNA expression of the majority of studied proteins related to BBB function in age-, region- and sex-dependent manners. Additionally, MS sex dependently decreased serum S100β levels and did not affect proinflammatory cytokine concentrations. In general, our study did not reveal a clear or strong negative effect of MS on BBB integrity. However, the results suggest that ELS may induce adaptive/maladaptive changes or compensatory mechanisms within the BBB of unknown yet consequences.

中文翻译：

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早期生活压力和性行为对幼年和成年大鼠血脑屏障通透性和完整性的影响

早期生活压力 (ELS) 被认为是神经退行性疾病和精神障碍的相关病因。在本研究中，我们假设 ELS 可能在大脑发育的关键时期持续和性别依赖性地影响血脑屏障 (BBB) 的完整性和功能，从而确定成年生活中慢性病的易感性和与性别相关的患病率。我们在大鼠中使用母体分离 (MS) 程序来模拟 ELS，并评估选定紧密连接 (TJ) 蛋白、葡萄糖转运蛋白 1 ( Slc2a1 ) 和水通道蛋白 4 ( Aqp4 ) 的 BBB 通透性和基因表达) 在幼年和成年大鼠的内侧前额叶皮层 (mPFC)、背侧纹状体 (dSTR) 和海马中。还评估了 BBB 功能外周标志物 (S100β) 和促炎细胞因子的血清浓度。我们观察到 BBB 的发育封闭和 BBB 通透性的性别差异以及 TJ 蛋白和Slc2a1的 mRNA 表达。成年女性显示较低的 BBB 通透性和较高水平的Cldn3、Cldn5、Ocln和Slc2a1在 mPFC 和 dSTR 中比男性。MS 暂时增加了少年男性 dSTR 中 BBB 的通透性，并以年龄、地区和性别依赖的方式影响了与 BBB 功能相关的大多数研究蛋白质的 mRNA 表达。此外，MS 性别依赖性降低血清 S100β 水平并且不影响促炎细胞因子浓度。总的来说，我们的研究没有揭示 MS 对 BBB 完整性的明显或强烈的负面影响。然而，结果表明，ELS 可能会在 BBB 内引起适应性/适应不良的变化或补偿机制，其后果尚不清楚。