BrainSight: Imaging of neural codes over the lifecourse

你所有的行为、思想、感觉和记忆都是由大脑中相互连接的神经细胞网络中的活动引起的。大脑活动每时每刻都在变化，但可以维持几分钟的思考，持续数小时的感觉或持续数年的记忆。大脑是如何做到这一点的？我们的目标是破译这些机制，以准确地理解我们的大脑是如何思考的。从长远来看，这是了解大脑如何出错的必要一步。要实现这一雄心，我们必须能够在一个人的整个生命过程中，稳定地、重复地记录神经细胞的活动。虽然人类还不能应对这一挑战，但现在可以使用一种最先进的技术在实验室大鼠和小鼠身上实现这一挑战：可以在大脑内部成像的头戴式微型显微镜(Hmmm)。HMM的重量约为1便士的一半，但包含了标准显微镜的所有基本部件。这种体积小、重量轻的HMMM可以暂时连接到大鼠或小鼠的头部，而不会阻碍它的行为。因此，当动物睡着、醒着或执行行为任务时，我们可以使用HMMM对神经细胞的活动进行成像，这些神经细胞被设计成产生荧光蛋白。数百个神经细胞可以同时成像，使我们能够捕捉整个大脑回路活动的规模和复杂性。此外，HMM可以被移除并返回到完全相同的位置，这样就可以跟踪相同细胞活动随时间的变化，例如，当动物学习新技能或记住过去的事件时。最后，只需增加一个额外的LED光源，HMMM不仅可以为神经细胞成像，还可以打开或关闭经改造产生光激活蛋白质的细胞组。通过这种方式，我们可以记录和修改精确时刻的大脑活动，以了解改变大脑活动的结构是否会影响行为。该项目将在布里斯托尔大学建立一个核心的HMMM设施，由12个致力于大脑功能互补方面的国际公认的研究小组共享。通过利用我们的集体专业知识，我们将有能力解决现代神经科学前沿的重大问题。该项目的具体目标包括：确定大脑中处理基于事件的记忆的不同特征的部分(即什么、地点和时间)。了解情绪如何影响决策。破译快速眼动睡眠的目的。定义在睡眠期间调节大脑活动的大脑回路的元素(即神经细胞的类型)。识别活动模式，使我们能够学习复杂的动作。了解神经化学物质多巴胺、去甲肾上腺素和乙酰胆碱如何调节触觉、运动和我们对世界的期望。我们团队和其他人的发现表明，这些不同的大脑功能需要多个大脑区域之间的沟通，每个区域提供不同的信息或调节另一个区域的活动。这个项目的一个主要目标是通过使用多个HMMM来记录相互连接的大脑回路内部和之间的活动，从而促进对这种交流的理解。这是以前从未做过的，这将使我们了解大脑结构之间的沟通是如何通过不同的大脑状态和行为来改变的。

All your behaviours, thoughts, feelings and memories are caused by activity within interconnected networks of nerve cells in the brain. Brain activity changes every second, yet can sustain thoughts over minutes, feelings that persist for hours or memories that last for years. How does the brain achieve this? Our goal is to decipher these mechanisms to understand precisely how our brains think. In the long run, this is a necessary step towards understanding how brains go wrong.To realise this ambition we must be able to record the activities of nerve cells stably and repeatedly over time, throughout the life-course of an individual. While this challenge cannot yet be met in humans, it can now be achieved in laboratory rats and mice using a state-of-the-art technology: head-mounted miniaturised microscopes (HMMM) that can image inside the brain. HMMMs weigh about half as much as 1 penny but contain all the essential parts of a standard microscope. This small size and low weight allows HMMMs to be temporarily connected to the head of a rat or mouse without impeding its behaviour. As a result, we can use HMMMs to image the activities of nerve cells engineered to produce fluorescent proteins, while the animal is asleep, awake or performing behavioural tasks. Hundreds of nerve cells can be imaged at once, allowing us to capture the scale and complexity of activity throughout brain circuits. Additionally, HMMMs can be removed and returned to exactly the same place, so that changes in the activities of the same cells can be tracked across time, for example as the animal learns a new skill or remembers a past event. Finally, by simply adding an extra LED light source, the HMMM can not only image nerve cells, but also switch on or off groups of cells engineered to produce light activated proteins. In this way, we can record and modify brain activity at precise moments to understand whether changing the structure of brain activity can influence behaviour. This project will establish a core HMMM facility at the University of Bristol that will be shared between 12 internationally recognised research groups working on complementary aspects of brain function. By harnessing our collective expertise we will be equipped to tackle big questions at the forefront of modern neuroscience. Specific aims of the project include: Determining the parts of the brain that process different features of event-based memories (i.e. what, where and when). Understanding how emotions influence decision-making. Deciphering the purpose of REM sleep. Defining elements of brain circuits (i.e. types of nerve cell) that regulate brain activity during sleep. Identifying patterns of activity in that allow us to learn complex movements. Understanding how the neurochemicals dopamine, noradrenaline and acetylcholine modulate sense of touch, movement and our expectations of the world. Discoveries by our team and others have shown that these diverse brain functions require communication between multiple brain areas, with each area contributing different information or modulating activity in the other. An overarching goal of this project is to advance understanding of this communication by using multiple HMMMs to record activity within and between interconnected brain circuits. This has not been done before, and will allow us to understand how communication between brain structures is modified across different brain states and behaviours.