The effect of D-alanine and a prebiotic on rat brain N-methyl-D-aspartate (NMDA) receptors and executive function

D-丙氨酸和益生元对大鼠脑 N-甲基-D-天冬氨酸 (NMDA) 受体和执行功能的影响

• 批准号: BB/I00792X/1
• 负责人: Jeremy Spencer
• 金额: $ 3.03万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI00792X%2F1
• 关键词: effect; alanine; prebiotic; rat; brain

The NMDA glutamate receptor is important for brain functions such as memory and problem solving. A naturally occurring chemical called D-alanine can activate this receptor and may control the way we think, but its levels in the brain are quite low. We have often wondered whether increasing the amounts of D-alanine in the brain would activate the NMDA receptor more, and therefore make the thinking processes work better. Animals and people can drink a lot of D-alanine in water without making them feel ill. We have found that when rats drink D-alanine for a couple of weeks, it causes chemical changes to the NMDA receptor in the brain. Scientists have shown that the sorts of changes we see, make the NMDA receptor more active. We therefore want to prove that D-alanine increases NMDA receptor function, and if this also improves thinking. This information will be useful to people who are interested in stopping the decrease in brain function which happens as the brain gets older or when it is affected by an illness. We will feed rats with D-alanine for two and eight weeks and see if they are better at problem solving than animals not given the compound (controls). This will be done with the attentional set-shifting task which basically tests how many go's it takes the rats to work out where food is buried, by using the information they were taught before the actual test. After the tests we will use standard methods to measure chemical changes to NMDA receptors and the amounts of other brain molecules which sometimes change when the receptor is active. All this information should tell us if D-alanine helps the thinking process, and if it is related to certain chemical alterations in the brain. In separate experiments, rats will be fed with D-alanine as before, and while they are asleep we will measure their brain electrical activity produced by adding the chemical NMDA. We believe that the brains of D-alanine fed rats compared to controls will have more electrical activity after adding NMDA because, the NMDA receptor is more active in these animals. Scientists have known for a while that D-alanine in our bodies actually comes from the good bacteria in our guts. Some drinks and yoghurts, called prebiotics, make these bacteria grow more, and this makes us healthy because the bugs help breakdown the food we eat. When we fed rats with a prebiotic called fructo-oligosaccharide (FOS), we saw the same changes in the NMDA receptor in the brain as we previously saw with D-alanine feeding. We now want to see if FOS feeding does actually increase levels of D-alanine in the brain, and if it changes rat behaviour and brain electrical activity. Finally, we will add D-alanine to isolated brain cells (cell culture) and measure chemical changes to the NMDA receptor. If nothing happens, we will know that D-alanine can only change NMDA receptor chemistry when the brain is in the body. This means that other molecules, pathways and brain areas, which are not present in cell culture, are needed for D-alanine to affect the receptor. We will also test if D-alanine added to cells affect other chemicals without causing changes in NMDA receptor chemistry. Overall, the study will tell us if the thinking process and NMDA receptor activity can be increased after drinking D-alanine or a prebiotics. This is important to know because a lot of people take prebiotics with their food, and it is possible that these, or just D-alanine alone, can help brain function as we get older or develop a brain disease.

NMDA谷氨酸受体对大脑功能如记忆和解决问题很重要。一种叫做D-丙氨酸的天然化学物质可以激活这种受体，并可能控制我们的思维方式，但它在大脑中的水平很低。我们经常想知道，增加大脑中D-丙氨酸的数量是否会更多地激活NMDA受体，从而使思维过程更好地工作。动物和人可以喝大量的D-丙氨酸而不会感到不适。我们发现，当大鼠连续几周饮用D-丙氨酸时，它会导致大脑中NMDA受体发生化学变化。科学家们已经证明，我们看到的各种变化，使NMDA受体更加活跃。因此，我们想证明D-丙氨酸增加NMDA受体功能，如果这也改善思维。这些信息将有助于那些有兴趣阻止大脑功能下降的人，这种情况发生在大脑变老或受到疾病影响时。我们将用D-丙氨酸喂养大鼠两周和八周，看看它们是否比没有给予化合物的动物（对照组）更善于解决问题。这将通过注意力转移任务来完成，该任务基本上是通过使用实际测试前教授的信息来测试老鼠需要多少次才能找到食物埋在哪里。在测试之后，我们将使用标准方法来测量NMDA受体的化学变化以及当受体活跃时有时会发生变化的其他脑分子的数量。所有这些信息应该告诉我们D-丙氨酸是否有助于思维过程，以及它是否与大脑中的某些化学变化有关。在单独的实验中，将像以前一样给大鼠喂食D-丙氨酸，当它们睡着时，我们将测量它们的脑电活动，这些脑电活动是通过添加化学物质NMDA产生的。我们相信，与对照组相比，D-丙氨酸喂养的大鼠的大脑在添加NMDA后将具有更多的电活动，因为NMDA受体在这些动物中更活跃。科学家们已经知道了一段时间，我们体内的D-丙氨酸实际上来自我们肠道中的有益细菌。一些饮料和酸奶，称为益生元，使这些细菌生长更多，这使我们健康，因为这些细菌有助于分解我们吃的食物。当我们用一种叫做低聚果糖（FOS）的益生元喂养大鼠时，我们看到大脑中NMDA受体的变化与我们以前用D-丙氨酸喂养时看到的相同。我们现在想看看FOS喂养是否真的会增加大脑中D-丙氨酸的水平，以及它是否会改变大鼠的行为和脑电活动。最后，我们将向分离的脑细胞（细胞培养物）中加入D-丙氨酸，并测量NMDA受体的化学变化。如果什么都没有发生，我们将知道D-丙氨酸只能改变NMDA受体的化学物质时，大脑在体内。这意味着D-丙氨酸需要其他分子、途径和脑区（细胞培养物中不存在）来影响受体。我们还将测试添加到细胞中的D-丙氨酸是否会影响其他化学物质，而不会引起NMDA受体化学物质的变化。总的来说，这项研究将告诉我们，在饮用D-丙氨酸或益生元后，思维过程和NMDA受体活性是否会增加。知道这一点很重要，因为很多人在食物中服用益生元，当我们变老或患上脑部疾病时，这些益生元，或者仅仅是D-丙氨酸，可能有助于大脑功能。

项目成果

Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine.

• DOI: 10.1016/j.neuint.2013.10.006
• 发表时间: 2013-12
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Savignac HM;Corona G;Mills H;Chen L;Spencer JP;Tzortzis G;Burnet PW
• 通讯作者: Burnet PW