Epigenetic mechanisms of behavioural, placental and cognitive impairment in a neurodevelopmental model for schizophrenia

疾病研究中的一个基本问题是，在关键发育时期经历的压力源如何影响成人疾病的发生或“规划”(Estes&McAllister 2016)。特别是，怀孕期间经历的压力源对后代发展认知障碍的倾向有影响(Knuessel等人。2014年)。目前尚不清楚这是否与直接影响子宫内大脑发育的变化有关，或者与母亲行为的改变有关，或者与这些因素的组合有关。此外，这种影响背后的机制仍然没有得到很好的界定。母体应激源在子代大脑和胎盘组织中引起表观遗传修饰(DNA甲基化和组蛋白修饰)，这可能是导致基因表达改变的关键候选机制，引起大脑发育变化，导致认知和行为障碍(Akbarian 2014)。此外，胎盘在母胎相互作用和胎儿适应性反应的调节中发挥关键作用，这可能导致以后疾病发展的倾向增加。胎盘的发育和功能受到母体应激源的影响，但这与子代认知障碍的关系尚不清楚。最近的全基因组关联研究已经确定了精神分裂症的危险因素基因，这些基因对胎盘形成有不利影响(Ursini等人。2017年)。这可能解释了后来发展为精神分裂症的患者早期生活并发症水平高的原因。我们预测，表观遗传机制调节母体应激源对胎盘功能的影响，从而影响认知发育。这项拟议的项目旨在研究表观基因组与环境的相互作用，这些相互作用与精神分裂症的发展有关。我们将使用多学科方法沿着将胎盘形态发育与后代行为特征联系起来的发育时间表绘制功能变化图。在精神分裂症的啮齿动物神经发育模型中，将进行胎盘形态发育的评估、分子阵列研究、脑和胎盘的表观基因组学和组织学分析以及亲子行为相互作用、认知和行为分析。因此，该项目提供了广泛的科学培训，涵盖哺乳动物疾病和行为研究、组织学、生理学、分子生物学、表观遗传学和基因表达分析。

A fundamental question in disease research is how stressors experienced during critical developmental periods influence the genesis or 'programming' of adult disease (Estes & McAllister 2016). In particular, stressors experienced during pregnancy have effects on the propensity to develop cognitive disorders in the offspring (Knuessel et al. 2014). Whether this relates to changes directly affecting brain development in utero, or altered maternal behaviour, or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined. Maternal stressors cause epigenetic modifications (DNA methylation and histone modifications) in offspring brain and placental tissue, which are likely to be key candidate mechanisms leading to altered gene expression, evoking developmental changes in the brain that result in cognitive and behavioural impairment (Akbarian 2014).Further, the placenta plays a crucial role in maternal-fetal interactions and the modulation of fetal adaptive responses that may lead to increased propensity to disease development later in life. Placental development and function is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2017). This may explain the high level of early life complications in patients who later develop schizophrenia. We predict that epigenetic mechanisms mediate the effects of maternal stressors on placental function and hence cognitive development. The proposed project seeks to investigate epigenome x environment interactions that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring behavioural traits. Evaluation of placental morphological development, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in a rodent neurodevelopmental model for schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses.