Investigating a placental origin for pregnancy and postpartum mood disorders:

产褥期精神病是一种非常罕见但严重的精神疾病，也是英国孕产妇死亡的主要间接原因。虽然这种疾病相对罕见，在英国每年影响大约800名妇女，但10-20%的妇女在怀孕期间会经历显著的情绪变化，如焦虑和抑郁。虽然在大多数情况下恢复了正常的情绪，但怀孕期间的慢性抑郁和焦虑与低出生体重有关，而产前和产后情绪障碍与儿童心理健康状况较差独立相关。这些关联的生物学相关性尚不清楚。母亲的情绪障碍是否会导致低出生体重和更差的结果，因为这些母亲采取了不太理想的生活方式？对儿童不利的行为、情绪和认知结果是否是由于这些疾病在子宫内的编程或纳塔尔后早期护理不良造成的？或者这些疾病都是一个潜在的生物学问题的表现？怀孕期间发生的一个关键变化是接触胎盘激素。胎盘是一个强大的内分泌器官，它能分泌大量的激素作用于母体，引起母体生理的变化，以确保安全和成功的怀孕。除了确保营养输送到胎儿，这些变化包括母性行为的诱导。因此，涉及异常激素信号的胎盘缺陷可能导致低出生体重婴儿和异常的母亲情绪。最近的研究表明印记基因在母亲情绪障碍中的作用。印记基因调节胎盘发育和胎儿生长。我们的实验模型研究表明，印记基因可能通过调节胎盘的内分泌室来影响母体行为。内分泌谱系产生胎盘催乳素，已显示其在啮齿动物中诱导母性行为。我们有试验数据表明，携带突变胎盘的雌性小鼠，由于印迹基因的遗传修饰而导致内分泌区室被破坏，表现出行为改变。在另一项初步研究中，我们发现产前抑郁症与胎盘印记基因和人类胎盘催乳素的表达之间存在关联。这提供了初步的数据来支持胎盘信号的表观遗传错误编程导致人类怀孕中母亲情绪障碍的假设。在拟议的研究中，我们将获得进一步的证据，胎盘可以使用我们现有的动物模型编程母亲的行为。同时，我们将从受抑郁和焦虑困扰的人类妊娠中鉴定胎盘中的基因变化。然后，我们将把这两个因素结合在一起，询问我们在人类胎盘中观察到的变化是否可以在动物模型中改变行为。小鼠无法模拟人类疾病的所有方面，特别是在复杂的认知行为方面，但我们可以确定因果关系，这将为异常母体行为的起源提供更深入的生物学见解，并可能支持开发预测产后情绪障碍的诊断工具，以进行早期干预。

Puerperal psychosis is a very rare but severe psychiatric illness and the leading indirect cause of maternal death in the UK. While this disorder is relatively rare, affecting approximately 800 women per annum in the UK, 10-20% of all women will experience significant mood changes during pregnancy, such as anxiety and depression. While in most cases normal mood is restored, chronic depression and anxiety during pregnancy is associated with low birth weight while both pre and postnatal mood disorders are independently associated with poorer mental health outcomes for children. The biological relevance of these associations is unclear. Do maternal mood disorders contribute to low birth weight and poorer outcomes because these mothers adopt less optimal lifestyles? Are the unfavorable behavioural, emotional and cognitive outcomes for children a result of the programming of these disorders in utero or poor post natal care early in life? Or are these disorders all manifestations of one underlying biological problem? A key change that occurs during pregnancy is exposure to placental hormones. The placenta is a powerful endocrine organ pumping out vast quantities of hormones acting on the mother to induce changes in maternal physiology required to ensure a safe and successful pregnancy. In addition to securing nutrient transport to the fetus, these changes include the induction of mothering behaviours. Thus a placental defect involving aberrant hormonal signaling could result in both a low birth weight baby and abnormal maternal mood. Recent studies suggest a role for imprinted genes in maternal mood disorders. Imprinted genes regulate placental development and fetal growth. Our studies from experimental models suggest that imprinted genes may influence maternal behaviour by regulating the endocrine compartment of the placenta. Endocrine lineages manufacture placental lactogens which have been shown to induce mothering behaviours in rodents. We have pilot data to show that female mice carrying mutant placenta with a disrupted endocrine compartment, induced by genetic modification of an imprinted gene, show altered behaviour. In another pilot study, we found an association between prenatal depression and placental expression of an imprinted gene and human placental lactogen. This provides preliminary data to support the hypothesis that the epigenetic misprogramming of placental signals contributes to maternal mood disorders in human pregnancies.In the proposed study we will obtain further evidence that the placenta can program maternal behaviour using our existing animal model. We will concurrently identify gene changes in the placenta from human pregnancies blighted by depression and anxiety. We will then bring these two elements together to ask whether the changes we observe in human placenta can drive altered behaviour in an animal model. Mice are not able to model all aspect of human disease, particularly with respect to complex cognitive behaviours, but we can determine causal relationships which will provide greater biological insight into the origins of abnormal maternal behaviour and may support the development of diagnostic tools predicting postnatal mood disorders for early intervention.