The effect of early-life prebiotic feeding on adult rat hippocampal function, central and peripheral metabonomics and microbial metagenomics

科学家们已经证明，在我们的肠道中培养有益细菌可以改善一些大脑功能，比如记忆力。我们发现，当老鼠吃了一种叫做BGOS的化合物后，有益的肠道细菌就会生长，而且大脑海马区的两种分子水平也会增加，这两种分子分别是NMDA受体和BDNF。这些分子和海马体对记忆功能非常重要。我们还发现，出生后不久就吃BGOS的大鼠幼崽，成年后海马中的NMDA受体和BDNF水平高于幼年时不吃BGOS的动物。因此，我们想知道，在年轻时BGOS后，我们在老年大脑中看到的NMDA受体和BDNF的变化是否真的改变了大脑的功能。我们还感兴趣的是，当大鼠长大后，喂食BGOS是否会改变大脑和身体的化学过程，即新陈代谢。最后，我们想看看在幼年时被喂食BGOS的老鼠，与没有喂食BGOS的老鼠相比，长大后是否含有不同类型的肠道细菌。大鼠幼鼠3日龄时饲喂BGOS，此后每天1次，直至21日龄。在给它们注射BGOS的同时，幼崽将被允许和它们的母亲呆在一起，并进行母乳喂养。其他老鼠将被给予一种糖化合物（安慰剂），这种化合物类似于BGOS，但不会生长肠道细菌。当所有大鼠22天大时，将它们放入不同的笼子中，给予正常的成人食物和水，并允许它们生长。然后，我们将做四个不同的实验：1)当一些老鼠22、56、112或196天大时，我们将人道地杀死它们，并移除它们的大脑。分别饲喂BGOS和安慰剂的各年龄大鼠海马将被取出进行电生理检查。这是一种测量神经递质在脑细胞之间传递时在脑组织中产生的电活动的技术。科学家们已经证明，NMDA受体和BDNF水平的变化会改变海马体的电活动，影响记忆。因此，我们预测，与安慰剂喂养的动物相比，BGOS喂养增加了海马电活动。2)在幼年时喂食BGOS或安慰剂的大鼠，将在它们22、56、112或196天大时进行记忆测试。在这些测试中，这些动物将被放入迷宫中，在那里它们必须学习和记住如何获得食物奖励。海马体对这项测试很重要，科学家们已经证明，海马体中NMDA受体和BDNF水平的变化可以改变这个大脑区域的活动，以及老鼠的记忆能力。我们预测，在所有年龄段，喂食BGOS的老鼠都比喂食安慰剂的老鼠在记忆任务上表现得更好。3)我们将观察在所有年龄的大鼠的大脑、肝脏、血液和尿液中由新陈代谢产生的分子的浓度。我们将使用的方法被称为代谢组学，这是一种快速的方法，可以在一个样本中观察数千个分子，同时观察数百个样本，以检测新陈代谢的变化。我们将使用一种叫做宏基因组学的方法来测量所有年龄的老鼠粪便中不同类型的细菌及其数量。这种方法有点像代谢组学，只不过可以在一个样本中识别和计数数千种细菌，而不是代谢分子，并且可以同时处理数百个样本。这个实验将告诉我们，在幼年时服用BGOS是否会使有益的肠道细菌随着大鼠年龄的增长而继续生长。总的来说，这项研究将告诉我们，当身体和大脑变老时，早期喂养BGOS是否能改善记忆、新陈代谢和有益肠道细菌的生长。如果确实如此，那么在儿童体内培养含有BGOS的有益细菌可能会使他们在生活中更健康，并抵抗某些疾病。

Scientists have shown that growing good bacteria in our guts can improve some brain functions, such as memory. We have found that when rats eat a compound called BGOS, good gut bacteria grow and there is an increase in the levels of two molecules, called the NMDA receptor and BDNF, in a brain area called the hippocampus. These molecules and the hippocampus are very important for memory function. We have also found that rat pups that eat BGOS shortly after they are born, contain higher levels of NMDA receptors and BDNF in their hippocampus when they are adults compared to animals that did not eat BGOS when they were young. We therefore, wonder whether the changes in NMDA receptors and BDNF we see in the older brain after BGOS at a younger age, actually change the function of the brain. We are also interested in whether BGOS feeding in rat pups changes the chemical processes, called metabolism, in the brain and body when they get older. Finally, we would like to see if rats being fed BGOS at a young age, contain different types of gut bacteria when they get older, compared to rats that were not given BGOS.Rat pups will be fed with BGOS when they are 3 days old, and then once every day until they 21 days old. While they are given BGOS, the pups will be allowed to stay with their mothers and breast-feed. Other rats will be given a sugar compound (placebo) which is like BGOS but does not grow gut bacteria. When all the rats are 22 days old, they will be put into different cages, given normal adult food and water, and allowed to grow. We will then do four different experiments: 1) When some rats are 22, 56, 112 or 196 days old, they will be humanely killed and their brains removed. The hippocampus of rats at each age that were fed BGOS or placebo, will be taken out for electrophysiology. This is a technique that measures the electrical activity in brain tissue generated when neurotransmitters travel between brain cells. Scientists have shown that changes in the levels of NMDA receptors and BDNF change electrical activity in the hippocampus and affects memory. We therefore, predict that BGOS feeding increases hippocampus electrical activity compared to the hippocampus from placebo fed animals. 2) Rats that had been fed BGOS or placebo at a young age, will be subjected to memory tests when they are 22, 56, 112 or 196 days old. In these tests, the animals will be put into mazes where they have to learn and remember how to get a food reward. The hippocampus is important for this test, and scientists have shown that changes in the levels of NMDA receptors and BDNF in the hippocampus can change the activity of this brain area and how well a rat can remember. We predict that rats that had been fed BGOS will do the memory tasks better than placebo fed animals at all ages. 3) We will look at the concentration of molecules that are made from metabolism, in the brain, liver, blood and urine of all rats at all ages. The approach we will use is called metabonomics, which is a fast way to look at thousands of molecules in one sample, and hundreds of samples at the same time, in order to detect changes that tells us about metabolism. 4) We will use a method called metagenomics to measure the different type of bacteria, and their amounts in the droppings of all rats at all ages. This approach is a bit like metabonomics, except that thousands of bacteria, instead of metabolic molecules, can be identified and counted in one sample, and hundreds of samples can be processed together. This experiment will show us if taking BGOS at an early age will make good gut bacteria continue grow as the rat gets older. Overall, the study will tell us if BGOS feeding from an early age improves memory, metabolism and the growth of good gut bacteria as the body and brain get older. If it does, then growing good bacteria with BGOS in children might make them more healthy in life and resistant to some diseases.