Ensuring quality maternal care in an adverse environment

在哺乳动物怀孕期间，一个至关重要的适应是母体护理的诱导。产妇护理对新生儿的生存至关重要，放弃产妇护理或质量不佳的产妇护理可能会在以后的生活中造成不良的行为和代谢后果。重要的是，产前逆境，如不理想的饮食或压力，可能会影响产妇护理的质量。因此，了解产妇护理是如何诱导的以及产妇环境如何影响产妇护理的诱导是至关重要的。有一些证据表明，胎盘在指导母亲照顾她的新生儿方面发挥了作用。胎盘是妊娠的一个暂时性器官，在将营养物质转移到成长中的胎儿中起着关键作用。胎盘也是一个超级内分泌器官，它制造的荷尔蒙充斥着母体系统，引发成功、健康怀孕所需的变化。研究表明，其中一些荷尔蒙，即胎盘催乳素，可能会引发产妇护理。考虑到胎盘的这一拟议作用，胎盘功能障碍可能会导致产妇护理不善。我们已经确定了一种名为Phlda2的基因，它对这些胎盘激素的产生非常重要。Phlda2通过调节胎盘内分泌室的大小来调节制造的胎盘荷尔蒙的数量。转基因过表达Phlda2会导致内分泌室变小。暴露在胎盘中的小鼠母亲在怀孕期间表现出母体大脑中基因表达和神经发生的变化，并表现出对后代的糟糕的母体照顾，尽管她们本身并不是Phlda2的突变。Phlda2是一个印迹基因，其表达受表观遗传标记的调控。值得注意的是，Phlda2的表达在胎盘中的表达发生了变化，以回应两种不同的次优产妇饮食，这两种饮食以前被认为与糟糕的产妇护理有关。这使我们相信，不理想的母体饮食可能会改变胎盘中Phlda2的表达，从而减少母体大脑对胎盘催乳素的暴露，从而导致产妇护理不善。在这项研究中，我们将使用现有的各种实验模型和技术来验证这一假说，首先询问我们是否可以通过在饮食模型中操纵胎盘Phlda2的表达来恢复母体护理，然后通过探索最初侧重于通过母体催乳素受体的胎盘催乳素信号转导的机制。我们还将开发一种基于红外荧光素酶的新型成像工具，以询问我们是否可以纵向地对正在进行的母体神经发生进行生物成像。这个工具的一个相当大的优势将是能够多次成像同一动物，大大减少我们研究所需的动物数量。这项工作不仅有助于我们从根本上了解母体护理是如何产生的，而且这一过程可能如何受到母体环境的影响，以及我们如何能够恢复母体护理-这项工作将与实验动物、家畜和农业动物的福利以及人类健康有着广泛的相关性。

A critically important adaptation during the mammalian pregnancy is the induction of maternal care. Maternal care is vitally important for the survival of the newborn and the withdrawal of maternal care or poor quality maternal care can result in adverse behavioural and metabolic outcomes later in life. Importantly, prenatal adversities such as suboptimal diet or stress can influence the quality of maternal care. Consequently, understanding how maternal care is induced and how the maternal environment influences the induction of maternal care is of paramount importance.There is some evidence that the placenta plays a role in instructing the mother to care for her newborns. The placenta is a transient organ of pregnancy that plays a key role in transferring nutrients to the growing fetus. The placenta is also a super endocrine organ that manufactures hormones that flood the maternal system to induce the changes required for a successful, health pregnancy. Studies suggest that some of these hormones, the placental lactogens, may induce maternal care. Given this proposed role for the placenta, placental dysfunction could contribute to poor maternal care. We have identified a gene called Phlda2 that is important for the production of these placental hormones. Phlda2 regulates the amount of placental hormones that are manufactured by regulating the size of the placental endocrine compartment. Transgenic over expression of Phlda2 results in a smaller endocrine compartment. Mouse mothers exposed to placenta with this much smaller endocrine compartment exhibit changes in gene expression and neurogenesis in the maternal brain during pregnancy and poor maternal care of their offspring, even though they themselves are not mutant for Phlda2. Phlda2 is an imprinted gene whose expression is regulated by epigenetic marks. Remarkably, expression of Phlda2 is altered in the placenta in response to the two different suboptimal maternal diets that have previously been linked to poor maternal care. This leads us to believe that a suboptimal maternal diet may contribute to poor maternal care by altering the expression of Phlda2 in the placenta and thus reducing exposure of the maternal brain to placental lactogens. In this study, we will use a variety of existing experimental models and techniques to test this hypothesis first asking whether we can restore maternal care by manipulating placental expression of Phlda2 in a dietary model, and then by exploring the mechanism initially focusing on placental lactogen signaling via the maternal prolactin receptor. We will also develop a novel imaging tool based on infrared luciferase, to ask whether we can longitudinally bioimage ongoing maternal neurogenesis. A considerable advantage of this tool will be the ability to image the same animal multiple times substantially reducing the number of animals required for our studies.This work is important not just in helping us to fundamentally understand how maternal care is induced but also how this process may be influenced by the maternal environment, and how we might be able to restore maternal care - work that will have wide relevance to the welfare of experimental, domestic and agricultural animals as well as human health.