Behavioural and developmental consequences of maternal immune activation in offspring

基础疾病研究中的一个基本问题是，在关键时期经历的应激源如何影响成人疾病的发展。特别是，怀孕期间经历的压力源已被证明对后代发展认知障碍的倾向有影响。但这是因为直接影响子宫内大脑发育的变化，还是因为母亲为了应对压力而改变了父母的行为，还是两者兼而有之？此外，这种影响背后的机制是什么？胎盘在母胎相互作用和胎儿在子宫内的适应性反应中起着关键作用，这可能导致在以后的生活中疾病发展的倾向。先前的研究表明，胎盘发育受到母体应激源的影响，但尚不清楚这是否以及如何导致子代的认知障碍。拟议的项目试图通过应用多学科方法绘制发育时间表上的功能变化图，将胎盘形态发育与后代特征联系起来，通过结合啮齿动物模型系统中的实验研究、胎盘形态发育评估以及父母-后代行为相互作用、认知和行为分析来实现。这将与组织学研究和分子阵列研究相结合。这还将得到生物信息学部分的补充，以揭示胎盘功能和相关行为障碍的已知候选者的生物途径和遗传网络。因此，该项目提供广泛的科学培训，将涵盖哺乳动物疾病和行为研究、组织学、生理学、分子生物学、遗传学和生物信息学。

One of the fundamental questions in basic disease research is how stressors experienced during critical periods influence the development of adult disease. In particular, stressors experienced during pregnancy have been shown to have effects on the propensity to develop cognitive disorders in offspring. But is this because of a change directly affecting brain development in utero or is it because mothers change their parental behaviour in response to stressors, or a combination? Further, what are the mechanisms underlying such effects? The placenta plays a critical role in maternal-fetal interactions and fetal adaptive responses in utero which may lead to a propensity to disease development later on in life. Prior work has indicated that placental development is affected by maternal stressors, but it remains unclear whether and how this may result in cognitive impairment in offspring. The proposed project seeks to answer these questions by applying a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring traits, achieved by combining experimental studies in a rodent model system with evaluation of placental morphological development, together with parent-offspring behavioural interactions, cognitive and behavioural analyses. This will be combined with histological investigations and molecular array studies. This will also be complemented by a bioinformatics component to unravel the biological pathways and genetic networks of known candidates for placental function and associated behavioural impairments. The project therefore offers broad scientific training that will cover mammalian disease and behaviour research, histology, physiology, molecular biology, genetics and bioinformatics.