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

在理解疾病机制并因此改进治疗方面的一个基本未知数是，在关键发育期经历的压力源如何影响成人疾病的发生或“编程”（Estes &麦卡利斯特2016）。特别是，妊娠期间经历的压力可能会增加后代在整个生命周期中发生认知障碍的可能性（Knuessel et al. 2014）。这是最有可能的，这诱导了一个脆弱性，导致社会压力在青春期经历加剧现有的表型和神经病理学。这是否与直接影响子宫内大脑发育的变化、母亲行为的改变、青少年大脑发育或这些因素的组合有关，目前尚不清楚。此外，这些影响的机制仍然不明确。母体压力导致表观遗传修饰胎盘组织和后代大脑中的DNA甲基化和组蛋白修饰，可能是导致基因表达改变的关键候选机制，从而导致大脑中的发育变化，导致认知和行为障碍（Akbarian 2014）。胎盘在母胎相互作用中起着至关重要的作用，胎儿适应性反应的调节可能导致在以后的生活中对神经精神疾病发展的易感性增加。胎盘发育受到母体压力的影响，但这与后代认知障碍的联系尚不清楚。最近的全基因组关联研究已经确定了对胎盘形成产生不利影响的精神分裂症风险因素基因（Ursini et al. 2018），并且已经确定了胎盘重量减轻与精神分裂症风险增加之间的联系（Wahlbeck et al. 2001）。我们认为，表观遗传机制介导的影响，母体压力对胎盘功能，导致改变大脑发育和后来受损的认知发展。拟议的项目利用了我们最近建立的母体免疫激活大鼠模型（Murray et al. 2019），并试图研究与精神分裂症发展相关的表观基因组与环境的相互作用。我们将使用多学科的方法来绘制沿着发育时间轴的功能变化，该时间轴将胎盘形态和功能发育与胎儿大脑发育和青少年环境条件与后代行为特征联系起来。将在我们的精神分裂症啮齿动物神经发育模型中进行胎盘形态发育和功能评价、分子阵列研究、脑和胎盘中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。这个多学科项目将适合具有相关背景的候选人，他们希望将自己的技能应用于使用尖端技术的重大研究问题。改变的行为表型与母体暴露于给予妊娠母鼠的病毒模拟物聚肌苷酸-聚胞苷酸（Poly I：C）相关，该病毒模拟物可诱导mIA（“首次”击中）。第二个“打击”涉及青春期经历的社会压力（母亲分离）。由于多学科项目团队（Neill，Hager，Harte，Gigg和Glazier）的广泛而独特的技能，学生将获得众多不同的体内技能。

A fundamental unknown in understanding mechanisms of disease, and therefore improving therapy, 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 may increase the likelihood of the offspring developing cognitive disorders across the lifespan (Knuessel et al. 2014). It is most likely that this induces a vulnerability which leads to social stressors experienced during adolescence exacerbating an existing phenotype and neuropathology. Whether this relates to changes directly affecting brain development in utero, altered maternal behaviour, adolescent brain development or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined. Maternal stressors result in epigenetic modifications (DNA methylation and histone modifications) in placental tissue and offspring brain, and are likely to be key candidate mechanisms leading to altered gene expression and thus developmental changes in the brain resulting in cognitive and behavioural disturbances (Akbarian 2014).The placenta plays a crucial role in maternal-fetal interactions, the modulation of fetal adaptive responses may lead to an increased susceptibility to development of neuropsychiatric disease later in life. Placental development 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. 2018) and a link between reduced placenta weight and increased risk for schizophrenia has been identified (Wahlbeck et al. 2001). We propose that epigenetic mechanisms mediate the effects of maternal stressors on placental function leading to altered brain development and later impaired cognitive development. The proposed project capitalizes on our recently established rat model of maternal immune activation (Murray et al. 2019) and seeks to investigate epigenome-by-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 and functional development with fetal brain development and adolescent environmental conditions to offspring behavioural traits. Evaluation of placental morphological development and function, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in our rodent neurodevelopmental model of 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. This multidisciplinary project will suit candidates with relevant backgrounds who wish to apply their skills to a significant research question using cutting-edge technologiesThis project involves the use of a 'two-hit stressor' neurodevelopmental model for schizophrenia in rats. Altered behavioral phenotypes are associated with maternal exposure to the viral mimetic polyinosinic-polycytidylic acid (Poly I:C) given to pregnant dams which induces mIA ('first' hit). A second 'hit' involves a social stressor experienced during adolescence (maternal separation). Numerous and varied in vivo skills will be acquired by the student due to the extensive and unique skills set of the multidisciplinary project team (Neill, Hager, Harte, Gigg and Glazier).