Ensuring quality maternal care in an adverse environment

哺乳动物怀孕期间的一个至关重要的适应是母亲护理的诱导。产妇护理对新生儿的生存至关重要，产妇护理的撤销或质量差的产妇护理可能导致不良的行为和代谢结果在以后的生活。重要的是，产前逆境，如不理想的饮食或压力，可以影响产妇护理的质量。因此，了解母亲护理是如何诱导的，以及母亲的环境如何影响母亲护理的诱导是至关重要的。有证据表明，胎盘在指导母亲照顾新生儿方面发挥着作用。胎盘是妊娠的一个短暂器官，在将营养物质转移到生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，它制造激素，使母体系统充满，以诱导成功，健康怀孕所需的变化。研究表明，其中一些激素，胎盘催乳素，可能会引起产妇护理。考虑到胎盘的这种作用，胎盘功能障碍可能导致孕产妇护理不良。我们已经确定了一个名为Phlda 2的基因，它对这些胎盘激素的产生很重要。Phlda 2通过调节胎盘内分泌室的大小来调节胎盘激素的量。Phlda 2的转基因过表达导致较小的内分泌隔室。暴露于具有这种小得多的内分泌隔室的胎盘的小鼠母亲在怀孕期间表现出母体大脑中的基因表达和神经发生的变化，并且对后代的母亲护理较差，即使它们本身不是Phlda 2突变体。Phlda 2是一个印记基因，其表达受表观遗传标记调控。值得注意的是，Phlda 2的表达在胎盘中改变，以响应两种不同的次优母体饮食，这两种饮食以前被认为与不良的母体护理有关。这使我们相信，一个次优的产妇饮食可能有助于通过改变胎盘中的Phlda 2的表达，从而减少暴露的母体大脑胎盘催乳素的产妇护理差。在这项研究中，我们将使用各种现有的实验模型和技术来验证这一假设，首先询问我们是否可以通过在饮食模型中操纵胎盘Phlda 2的表达来恢复产妇护理，然后通过探索最初关注胎盘催乳素信号转导的机制，通过母体催乳素受体。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生物成像正在进行的母体神经发生。该工具的一个相当大的优势是能够多次对同一只动物进行成像，从而大大减少了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孕产妇护理是如何诱导的，而且还有助于我们了解这一过程如何受到孕产妇环境的影响，以及我们如何能够恢复孕产妇护理--这些工作将与实验动物、家畜和农业动物的福利以及人类健康广泛相关。

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.