Early life stress from allergic dermatitis causes depressive-like behaviors in adolescent male mice through neuroinflammatory priming
Early life stress from allergic dermatitis causes depressive-like behaviors in adolescent male mice through neuroinflammatory priming
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DOI：
10.1016/j.bbi.2020.09.013
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发表时间：
2020-11-01
影响因子：
15.1
通讯作者：
Sekiguchi, Masayuki
中科院分区：
文献类型：
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作者：
Hashimoto, Okito;Kuniishi, Hiroshi;Sekiguchi, Masayuki
过敏性皮炎（AD），与瘙痒和瘙痒有关，是生命早期的主要应激性疾病之一。AD还通过神经免疫相互作用影响神经精神障碍和发育障碍的发病率。据我们所知，没有报告使用动物模型评估幼儿皮炎对以后生活中精神疾病的影响。在这里，我们开发了一个恶唑酮（Ox）诱导的AD模型在早期的雄性C57 BL/6 J小鼠的耳朵反复挑战，从出生后的天（PD）2 PD 30。在PD 30时，Ox处理的耳朵显着增厚并表现出表皮增生，同时耳组织中辅助性T细胞因子2、白细胞介素（IL）-4和IL-13的表达增加。此外，Ox处理小鼠的血清免疫球蛋白E水平和血清皮质酮水平高于对照小鼠。尽管OX处理的PD 40小鼠既没有表现出行为异常，也没有表现出脑中促炎细胞因子表达的增加，这项研究显示，在基础条件下，他们经历了杏仁核中CD 200 R1表达的下调，并且额外的脂多糖（LPS）给药诱导了增强的神经炎症反应，因为引发效应伴随着Iba-1-杏仁核和海马区有阳性小胶质细胞。此外，Ox-treated PD 40小鼠在LPS给药后24 h表现出抑郁样行为，而对照小鼠没有。有趣的是，吲哚胺2，3-双加氧酶和犬尿氨酸3-单加氧酶的表达，犬尿氨酸代谢途径的关键限速酶，在LPS给药后4小时，在Ox-treated小鼠的海马，前额皮质和杏仁核中上调。基于这些结果，我们认为AD的早期生活压力增加了青少年大脑对全身炎症的易感性，导致抑郁行为伴犬尿氨酸代谢异常。
Allergic dermatitis (AD), associated with pruritus and itchiness, is one of the major stressful conditions early in life. AD also influences the incidence of neuropsychiatric disorders and developmental disorders through neuroimmune interactions. To the best of our knowledge, there is no report that assesses the effects of early childhood dermatitis on psychiatric disorders later in life using an animal model. Here, we developed an oxazolone (Ox)-induced AD model in the early life of male C57BL/6J mice whose ears were challenged by Ox repeatedly from postnatal days (PD) 2 to PD30. On PD30, the Ox-treated ears were remarkably thickened and showed epidermal hyperplasia coupled with increased expression of T helper 2 cytokines, interleukin (IL)-4, and IL-13 in the ear tissue. Additionally, serum immunoglobulin E levels and serum corticosterone levels were higher in the Ox treated mice than those in the control mice. Although Ox-treated PD40 mice showed neither behavioral abnormalities nor increases in pro-inflammatory cytokine expression in the brain, this study revealed that they experienced downregulation of CD200R1 expression in the amygdala under basal conditions and that additional lipopolysaccharide (LPS) administration induced enhanced neuroinflammatory reaction as the priming effect was accompanied by an increase of Iba-1-positive microglia in the amygdala and hippocampus. Furthermore, the Ox-treated PD40 mice showed depressive-like behaviors 24 h after LPS administration, whereas the control mice did not. Interestingly, the expression of indoleamine 2,3-dioxygenase and kynurenine 3-monooxygenase, key rate-limiting enzymes of the kynurenine metabolism pathway, was upregulated in the hippocampus, prefrontal cortex, and amygdala of the Ox-treated mice 4 h after LPS administration. Based on these results, we suggest that early life stress from AD aggravates susceptibility to systemic inflammation in the adolescent brain, leading to depressive behaviors with abnormal kynurenine metabolism.