RUI: Peripheral Glucose Regulation Influences on Memory Modulation

许多药物已被证明可以增强实验室动物和人类学习和记忆的认知过程。 在被认为是记忆调节剂的物质中，有几种通过增加大脑中葡萄糖的摄取和利用来产生有益的效果。 葡萄糖是大脑的主要燃料来源，也是合成多种神经递质的底物。 肾上腺素（EPI）是解释外周作用记忆调节剂如何影响记忆的理论的重要组成部分。 根据一种观点，认知增强药物直接或间接作用于肾上腺，肾上腺释放EPI。 尽管EPI是外周作用的并且不穿过血脑屏障，但EPI的释放导致随后从肝脏释放葡萄糖。 葡萄糖的增加可能会进入大脑，影响学习和记忆的神经系统。 然而，有证据表明，一些外周作用的认知增强剂通过一种不依赖于葡萄糖的机制起作用。 一种这样的物质是L-葡萄糖。 L-葡萄糖是一种外周作用的葡萄糖类似物，不会导致血糖水平升高。 此外，L-葡萄糖在外周注射时增强啮齿动物的记忆力，但直接注射大脑时则不然。 本提案中概述的实验提供了外周记忆增强剂L-葡萄糖可能利用的机制的证据。 假设是L-葡萄糖利用直接的神经连接（通过迷走神经从肝脏到大脑）作为影响CNS和记忆存储过程的一种方式。

Lay SummaryMany drugs have been shown to enhance the cognitive processes that underlie learning and memory in laboratory animals and humans. Among the substances that have been implicated as memory modulators, several produce their beneficial effect by increasing glucose uptake and utilization in brain. Glucose is the major source of fuel for brain and acts as a substrate for the synthesis of several neurotransmitters. Epinephrine (EPI) is a vital component in the theory most often advanced in explaining how peripherally-acting memory modulators affect memory. According to one view, cognitive enhancing drugs act directly or indirectly upon the adrenal glands, which release EPI. Although EPI is peripherally acting and does not cross the blood-brain barrier, the release of EPI results in the subsequent release of glucose from liver. Increased amounts of glucose may enter brain and affect the neural systems underlying learning and memory. There is evidence, however, that some peripherally-acting cognitive enhancers act via a mechanism independent of glucose. One such substance is L-glucose. L-glucose is a peripherally acting glucose analog that does not cause an increase in blood-glucose levels. Furthermore, L-glucose enhances memory in rodents when injected peripherally but not when injected directly in brain. The experiments outlined in this proposal provide evidence of a mechanism that may be utilized by peripheral memory enhancer, L-glucose. The hypothesis is that L-glucose utilizes direct neural connections (liver to brain via the vagus nerve) as a way to affect the CNS and memory storage processes.