Early life adversity drives sex-specific anhedonia and meningeal immune gene expression through mast cell activation.
Early life adversity drives sex-specific anhedonia and meningeal immune gene expression through mast cell activation.
复制标题
早期的生活逆境通过肥大细胞的激活驱动特定性别的快感缺乏和脑膜免疫基因的表达。
DOI：
10.1016/j.bbi.2022.03.009
复制
发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
暴露在身体和/或心理虐待或忽视形式的早期生活逆境(ELA)中，增加了在以后的生活中发展精神和炎症性障碍的风险。有假设认为，暴露于ELA会导致持续的、低级别的炎症，通过放大应激处理脑网络和免疫系统之间的串扰而导致疾病易感性增加，但其机制在很大程度上仍未被探索。脑膜是围绕中枢神经系统(CNS)的一层由三层重叠的膜组成的膜--硬脑膜、蛛网膜和硬脑膜--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方面发挥关键作用。这些包括将脑脊液从大脑输送到颈深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有窗血管，以及丰富的常驻肥大细胞群，它们是免疫系统的主要调节者。采用新生母体分离加早期断奶(NMSEW)的ELA小鼠模型，探讨ELA对成年雄性和雌性C57BL/6小鼠的嗜糖行为、硬脑膜炎性标志物表达和肥大细胞组织学的影响。我们发现，NMSEW本身并不影响男性或女性的蔗糖偏好行为，但它增加了女性肥大细胞蛋白酶CMA1(Cma1)和炎性细胞因子TNFα(TNFα)编码基因的硬脑膜表达。当NMSEW与成年温和应激(这不会影响NH动物的行为或基因表达)相结合时，雌性动物表现出对蔗糖的偏好降低，脑膜cma1水平甚至更高。有趣的是，在暴露于成年应激之前，全身应用肥大细胞稳定剂酮替芬可以阻止NMSEW雌性个体蔗糖偏好的降低和cma1表达的增加，但有助于NMSEW雄性个体和NH雌性个体的应激诱导的蔗糖缺乏。最后，组织学分析显示，与男性相比，女性硬脑膜横窦中肥大细胞的基线激活水平增加，而在暴露于成人应激的男性和女性中，NMSEW增加了硬脑膜顶间区域的肥大细胞数量和硬脑膜矢状窦区域的肥大细胞激活水平。综上所述，我们的结果表明，ELA诱导了脑膜免疫基因的长期变化，并提高了对成人应激诱导的行为和脑膜免疫反应的敏感性，这些作用可能是通过肥大细胞介导的。
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.
登录
查看更多内容
影响因子：
3.3
作者：
Brancato A;Bregman D;Ahn HF;Pfau ML;Menard C;Cannizzaro C;Russo SJ;Hodes GE
通讯作者：
Hodes GE
影响因子：
7.7
作者：
Absinta M;Ha SK;Nair G;Sati P;Luciano NJ;Palisoc M;Louveau A;Zaghloul KA;Pittaluga S;Kipnis J;Reich DS
通讯作者：
Reich DS
影响因子：
56.9
作者：
Allen, G;Buxton, RB;Courchesne, E
通讯作者：
Courchesne, E
影响因子：
15.1
作者：
Avitsur, Ronit;Hunzeker, John;Sheridan, John F.
通讯作者：
Sheridan, John F.
影响因子：
11
作者：
Baumeister D;Akhtar R;Ciufolini S;Pariante CM;Mondelli V
通讯作者：
Mondelli V