Imaging the engram in mice

在人类大脑中，850亿个神经细胞通过数万亿个连接进行通信，使用复杂的电震动模式和100多种不同的化学物质。了解这个复杂系统如何工作的一种方法是在它执行正常功能时“观察”它。也就是说，了解大脑如何编码和存储信息的一种方法是在动物执行记忆任务时，在真实的时间内检查神经功能。 19世纪90年代，神经科学先驱圣地亚哥·拉蒙·卡哈尔（Santiago Ramón y Cajal）用显微镜检查了人脑细胞，并记录了大量紧密排列的细胞相互连接的网络，他将其描述为“令许多研究人员迷失自我的难以穿越的丛林”。然而，从那时起，显微镜技术取得了许多进步，现在研究人员可以“以思维的速度”检查啮齿动物的大脑功能。 以前的神经元活动是使用体内电生理技术来评估的，在这种技术中，电极或电线被植入大脑，当动物正在执行某种任务时，少量神经元的活动被记录下来。虽然这项技术为大脑活动与行为之间的关系提供了许多重要的见解，但很难准确确定哪个神经元在放电。接下来的创新使研究人员能够通过使用表达遗传编码的钙指示剂（在神经激活时发出荧光）的啮齿动物和使用双光子显微镜来真正看到大脑并监测神经元的放电。这种方法非常适合检查大脑表面神经元的活动，但需要动物被限制（头部固定在一个不可移动的显微镜上），这可能也会给动物带来压力。相比之下，所提出的微型显微镜，这是小到足以安装在一个鼠标的头部将有可能“观看”脑细胞的活动，而鼠标自由行为。然而，这种微型显微镜将能够在动物执行某种任务（记忆测试、社会互动或其他行为）时长期记录神经活动，而不会引起压力。 我们相信，这项有远见的技术将使研究人员能够刺激一个大脑区域，同时记录其他几个大脑区域的神经后果。这将使我们不仅能够了解大脑区域内的小部分神经元如何发挥作用，而且能够了解大脑的整体功能。这项技术将使我们能够创建大脑的动态地图，这对理解大脑功能至关重要。

In a human brain, 85 billion nerve cells communicate via trillions of connections using complex patterns of electrical jolts and more than 100 different chemicals. One way to understand how this complex system works is to “watch” it while it performs its normal functions. That is, one way to understand how the brain encodes and stores information is to examine neural function in real time while an animal performs a memory task. In the 1890s, the pioneering neuroscientist, Santiago Ramón y Cajal, microscopically examined human brain cells and wrote of massively interconnecting webs of tightly packed cells, which he described as “impenetrable jungles where many investigators have lost themselves”. Since that time, however, there have been numerous advances in microscopy which now allow researchers to examine rodent brain function “at the speed of thought”. Previously neuronal activity has been assessed using in vivo electrophysiological techniques in which electrodes or wires were implanted into the brain and activity of handfuls of neurons recorded while an animal is behaving some sort of task. Although this technique offered many important insights into how brain activity correlates with behaviour, it was difficult to determine exactly which neuron was firing. The next innovation allowed researchers to literally see into the brain and monitor neuronal firing by using rodents expressing genetically-encoded calcium indicators (which fluoresce upon neural activation) and using 2-photon microscopy. This approach can be well-suited for examining the activity of neurons on the surface of the brain, but requires that the animal be restrained (head-fixed to an immovable microscope), which likely also stresses the animal. In contrast, the proposed mini-microscope, which is small enough to be mounted on the head of a mouse will make it possible to “watch” brain cell activity and while the mouse freely-behaves. This mini-microscope, though, will enable chronic recording of neural activity while an animal is performing some sort of task (memory test, social interaction, or other behaviour) without inducing stress. We believe that this visionary technology will enable researchers to stimulate one brain region and record the neural consequences in several other brain regions at the same time. This will allow us to understand not only how small portions of neurons within a brain region function, but how the brain functions overall. This technology will allow us to create a dynamic map of the brain which is crucial to understanding brain function.