Maternal Immune Effects on Neurobehavioral Development

描述(由申请人提供)：精神分裂症等精神疾病发展的一个重要假说是两次命中假说。最近的证据表明，母体免疫激活可能是疾病发生的“第一次打击”，而对后代的后续应激源则是疾病发病的额外次级诱因(“第二次打击”)。这些证据很大程度上是针对先天免疫反应。因此，在目前的一组研究中，有人建议确定怀孕小鼠的T细胞激活是否会作为发育中的胚胎的初始敏感剂；这可能会使产后和青春期后的未来应激源对维持正常行为更加不稳定。诱导T细胞活化将涉及使用细菌T细胞超抗原(SAG)，如葡萄球菌肠毒素A和B(SEA；SEB)，它们在体内激活T细胞并诱导高水平的细胞因子。此外，它们还激活下丘脑-垂体-肾上腺(HPA)轴、皮质和边缘脑区，并改变认知和情感行为。这项研究将围绕一个特定的目标，即调查SEA对怀孕小鼠的免疫效应，并确定这是否对雄性和雌性后代的认知和感觉运动行为功能产生影响。此外，青春期后的慢性心理应激状态(“二次打击”)也将强加于来自海洋或注射盐水的母亲的男性和女性后代的子代。被评估的认知功能将包括(I)在Morris水迷宫(MWM)中的空间导航学习，其中将包括工作记忆部分，以及(Ii)反应抑制的操作性学习任务。此外，小鼠将接受脉冲前抑制(PPI)测试，该测试测量感觉运动门控，这是精神分裂症缺乏的一种神经机制。最后，为了探索与焦虑和抑郁相关的行为变化，将对小鼠进行开阔场地行为、高架加迷宫(EPM)和蔗糖消耗(以测试快感丧失)的测试。这些研究将有助于理解T细胞在宫内环境中对大脑发育的影响，以及这对正常神经行为发育和心理应激源的行为适应所带来的风险。

DESCRIPTION (provided by applicant): A prominent hypothesis for the development of psychiatric diseases, such as schizophrenia, is the two-hit hypothesis. Recent evidence suggests that maternal immune activation may represent the “first hit”, whereas subsequent stressors to the offspring serve as additional secondary precipitants (“second hit”) of disease onset. Much of this evidence is for innate immune responses. Therefore, in the present set of studies, it is proposed to determine whether T cell activation in pregnant mice will serve as an initial sensitizing agent in the developing embryo; this may render future stressors in the postpartum and postpubertal periods more destabilizing to maintenance of normal behavior. Induction of T cell activation will involve the use of bacterial T cell superantigens (SAgs), such as Staphylococcal enterotoxins A and B (SEA; SEB), which activate T cells in vivo and induce high levels of cytokines. In addition, they activate the hypothalamic-pituitary-adrenal (HPA) axis, cortical and limbic brain regions, and alter cognitive and emotional behaviors. The study will encompass a single specific aim, which will investigate the immunologic effects of SEA in pregnant mice, and determine whether this exerts an influence on cognitive and sensorimotor behavioral functions of male and female offspring. Furthermore, postpubertal conditions of chronic psychogenic stress (the “second hit”) will also be imposed on subsets of male and female offspring from SEA or Saline-injected mothers. Cognitive functions to be assessed will include (i) spatial navigation learning in the Morris water maze (MWM), that will include a working memory component, and (ii) an operant learning task of response-inhibition. In addition, mice will be subjected to a test of prepulse inhibition (PPI), which measures sensorimotor gating, a neural mechanism deficient in schizophrenia. Finally, to probe for anxiety-related and depression-like behavioral changes, mice will be tested for open field behavior, the elevated plus maze (EPM), and sucrose consumption (to test anhedonia). These studies will contribute to an understanding of T cell mediated effects on brain development in the intrauterine environment, and the risk this represents for normal neurobehavioral development and behavioral adaptation to psychogenic stressors.