Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- dura mater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on sucrose preference behavior, dura mater expression of inflammatory markers and mast cell histology in adult male and female C57Bl/6 mice. We found that NMSEW alone does not affect sucrose preference behavior in males or females, but it increases the dura mater expression of the genes coding for mast cell protease CMA1 (cma1) and the inflammatory cytokine TNF alpha (tnf alpha) in females. When NMSEW is combined with an adult mild stress (that does not affect behavior or gene expression in NH animals) females show reduced sucrose preference and even greater increases in meningeal cma1 levels. Interestingly, systemic administration of the mast cell stabilizer Ketotifen before exposure to adult stress prevents both, reduction in sucrose preference an increases in cma1 expression in NMSEW females, but facilitates stress-induced sucrose anhedonia in NMSEW males and NH females. Finally, histological analyses showed that, compared to males, females have increased baseline activation levels of mast cells located in the transverse sinus of the dura mater, where the meningeal lymphatics run along, and that, in males and females exposed to adult stress, NMSEW increases the number of mast cells in the interparietal region of the dura mater and the levels of mast cell activation in the sagittal sinus regions of the dura mater. Together, our results indicate that ELA induces long-term meningeal immune gene changes and heightened sensitivity to adult stress-induced behavioral and meningeal immune responses and that these effects could mediated via mast cells.

以身体和/或心理虐待或忽视的形式暴露于早年逆境 (ELA) 会增加在以后的生活中患上精神疾病和炎症性疾病的风险。据推测，暴露于 ELA 会导致持续的低度炎症，通过放大压力处理大脑网络和免疫系统之间的串扰，导致疾病易感性增加，但其机制在很大程度上仍未得到探索。脑膜是一层围绕中枢神经系统 (CNS) 的三层重叠膜 - 硬脑膜、蛛网膜和脑膜 - 具有独特的特征，使它们能够在协调大脑和外周免疫系统之间的免疫运输中发挥关键作用. 这些包括将脑脊液从大脑输送到颈深部淋巴结的淋巴管网络、允许分子从血液进入中枢神经系统的开窗血管，以及丰富的常驻肥大细胞群，免疫系统的主要调节剂系统。我们使用由新生儿母体分离加早期断奶 (NMSEW) 组成的 ELA 小鼠模型，试图探索 ELA 对成年雄性和雌性 C57Bl/6 小鼠蔗糖偏好行为、炎症标志物的硬脑膜表达和肥大细胞组织学的影响. 我们发现 NMSEW 单独不影响男性或女性的蔗糖偏好行为，但它增加了编码肥大细胞蛋白酶 CMA1 的基因的硬脑膜表达（以及丰富的常驻肥大细胞群，是免疫系统的主要调节剂。我们使用由新生儿母体分离加早期断奶 (NMSEW) 组成的 ELA 小鼠模型，试图探索 ELA 对成年雄性和雌性 C57Bl/6 小鼠蔗糖偏好行为、炎症标志物的硬脑膜表达和肥大细胞组织学的影响. 我们发现 NMSEW 单独不影响男性或女性的蔗糖偏好行为，但它增加了编码肥大细胞蛋白酶 CMA1 的基因的硬脑膜表达（以及丰富的常驻肥大细胞群，是免疫系统的主要调节剂。我们使用由新生儿母体分离加早期断奶 (NMSEW) 组成的 ELA 小鼠模型，试图探索 ELA 对成年雄性和雌性 C57Bl/6 小鼠蔗糖偏好行为、炎症标志物的硬脑膜表达和肥大细胞组织学的影响. 我们发现 NMSEW 单独不影响男性或女性的蔗糖偏好行为，但它增加了编码肥大细胞蛋白酶 CMA1 的基因的硬脑膜表达（成年雄性和雌性 C57Bl/6 小鼠的硬脑膜炎症标志物表达和肥大细胞组织学。我们发现 NMSEW 单独不影响男性或女性的蔗糖偏好行为，但它增加了编码肥大细胞蛋白酶 CMA1 的基因的硬脑膜表达（成年雄性和雌性 C57Bl/6 小鼠的硬脑膜炎症标志物表达和肥大细胞组织学。我们发现 NMSEW 单独不影响男性或女性的蔗糖偏好行为，但它增加了编码肥大细胞蛋白酶 CMA1 的基因的硬脑膜表达（cma1 ) 和女性的炎症细胞因子 TNF alpha ( tnf alpha )。当 NMSEW 与成人轻度压力（不影响 NH 动物的行为或基因表达）相结合时，雌性表现出蔗糖偏好降低，脑膜cma1水平甚至更高。有趣的是，在暴露于成人应激之前全身施用肥大细胞稳定剂酮替芬可以防止两者，减少蔗糖偏好和增加cma1在 NMSEW 女性中表达，但在 NMSEW 男性和 NH 女性中促进应激诱导的蔗糖快感缺乏。最后，组织学分析表明，与男性相比，女性增加了位于硬脑膜横窦的肥大细胞的基线激活水平，脑膜淋巴管在此运行，并且在暴露于成人压力的男性和女性中，NMSEW增加硬脑膜顶叶间区肥大细胞的数量和硬脑膜矢状窦区肥大细胞的激活水平。总之，我们的结果表明 ELA 诱导长期脑膜免疫基因变化和对成人应激诱导的行为和脑膜免疫反应的敏感性增强，并且这些作用可以通过肥大细胞介导。