Networks of neural dynamics: Knowledge-discovery for experimental neuroscience

当你思考和行动时，你的大脑正在发生什么？细胞正在发射微小的电脉冲，活动的小尖峰，遍及整个大脑。一些细胞群同时发出这些尖峰信号，它们都会对突然的噪音或手臂的摆动做出反应。在其他组中，尖峰信号以固定的顺序出现在细胞中，记住你刚刚从前门到公交车站的路径。从根本上说，大脑是通过协调细胞间的活动来工作的。因此，当细胞停止精确协调时，大脑就不再正常工作。在癫痫发作时，整个大脑皮层的细胞都变得同步，活动的波动淹没了肌肉的精细控制。在痴呆症中，细胞间同步性的丧失阻碍了对过去事件的可靠回忆。我的研究目标是使我们能够发现和分析脑细胞的协调活动。神经科学家现在能够记录来自数百个独立细胞的尖峰信号，一次记录几个小时，来自整个大脑。然而，在没有能力分析这些记录的情况下，由此产生的数据山正在增长。我们有许多方法来比较两个细胞的活动，但很少有方法来比较数百个细胞的活动。我们有更少的方法来发现在每个记录中协调发生的时间，或者发现哪些细胞参与，或者发现协调是由同时的尖峰、尖峰序列还是更复杂的东西组成的。如果没有这些方法，这些记录就无法揭示单个细胞的协同活动告诉我们关于大脑功能和功能障碍的信息。我将开发能够记录并自动解决所有这些问题的分析方法：找出细胞何时一起活跃，它们属于哪个组，以及协调的活动采取什么形式。我将把这些方法应用于神经科学研究的三个领域，试图通过同时记录许多细胞来研究健康和疾病中的大脑。首先，我们将与康斯坦斯·哈蒙德博士在马赛的实验室一起，分析他们对发育中的大鼠纹状体的记录，这是一个大型前脑系统，对动作的控制和学习都是至关重要的。我们将使用我的方法来了解健康纹状体的协调活动是如何在怀孕和婴儿时期发展起来的，然后了解遗传和环境因素是如何破坏这种正确的发育的，从而导致青少年出现纹状体障碍，比如抽动症。其次，与希德·维纳博士在巴黎的实验室一起，我们将分析他们从学习在迷宫中解决空间导航任务的大鼠的前脑中获得的记录。我们将使用我的方法来理解学习过程中整个前脑的协调活动是如何发展的。特别是，我们将分析在对任务做出正确决定之前突然开始的广泛协调是如何依赖于多巴胺的，以及在睡眠期间重复协调活动如何导致性能改善。从第一个方面，我们可以更好地了解前脑中异常的多巴胺是如何扰乱工作记忆和决策的，就像精神分裂症患者一样；从第二个方面，我们可以更好地理解糟糕的睡眠质量如何影响学习。第三，与拉斯穆斯·彼得森博士在曼彻斯特的实验室一起，我们将分析老鼠大脑中央细胞对胡须运动的反应，并分析它们的记录。彼得森博士的实验室对这些细胞进行研究，以了解基本的“神经密码”，即每个脉冲所携带的信息。他们已经发现，一些细胞对单一的运动特征，如胡须的位置或速度，会发出尖峰信号，而其他细胞只会对这些特征的复杂组合发出尖峰信号。我们将使用我的方法来理解这些单细胞编码在协调时是如何结合在一起的，从而形成感官信息的“种群编码”。

What is happening in your brain when you think and act? Cells are firing tiny electrical pulses, little spikes of activity, all across the brain. Some groups of cells emit these spikes at the same time, all of them responding to sudden noise, or to the swinging of your arm. In other groups, the spikes occur in a fixed sequence across the cells, remembering the path you just took from the front door to the bus-stop. Fundamentally, the brain works by co-ordinating activity between its cells. So when cells stop being precisely co-ordinated, the brain stops working properly. In an epileptic fit, the cells across the cortex all become synchronised and waves of activity drown out the fine control of the muscles. In dementia, the loss of synchronisation between cells prevents reliable recall of past events. The goal of my research is to enable us to find and analyse the co-ordinated activity of brain cells. Neuroscientists are now able to record the spikes from hundreds of separate cells, for hours at a time, from all across the brain. Yet the resulting data mountain is growing without the ability to analyse those recordings. We have many methods for comparing the activity of two cells, but few for comparing the activity of hundreds. We have even fewer methods for finding when in each recording the co-ordination happens, or for finding which cells are taking part, or for finding if the co-ordination is made up of simultaneous spikes, a sequence of spikes, or something more complex. Without these methods, these recordings cannot reveal what co-ordinated activity of individual cells tells us about how the brain functions and dysfunctions. I will develop analysis methods that are able to take the recordings and automatically solve all these problems: finding when the cells are active together, which groups they belong to, and what form that co-ordinated activity takes. I will apply these methods to three areas of neuroscience research that seek to study the brain in health and disease by recording many cells at the same time. First, with Dr Constance Hammond's lab in Marseille, we will analyse their recordings of the developing rat striatum, a large forebrain system that is central to both the control and learning of actions. We will use my methods to understand how the co-ordinated activity in the healthy striatum develops over pregnancy and infancy, and then understand how genetic and environmental factors disrupt this correct development, leading to disorders of the striatum that appear in youth, like Tourette's syndrome. Second, with Dr Sid Wiener's lab in Paris, we will analyse their recordings from the forebrains of rats learning to solve spatial navigation tasks in mazes. We will use my methods to understand how co-ordinated activity across the forebrain develops during learning. Particularly we will analyse how the sudden onset of widespread co-ordination that precedes correct decisions on the task depends on dopamine, and how replays of co-ordinated activity during sleep lead to improved performance. From the first we can gain a better understanding of how abnormal dopamine in the forebrain, as in schizophrenics, disrupts working memory and decision-making; from the second we can gain a better understanding of how poor quality sleep can affect learning. Third, with Dr Rasmus Petersen's lab in Manchester, we will analyse their recordings from cells in the centre of the rat's brain that fire in response to movements of their whiskers. Dr Petersen's lab study these cells to understand the basic "neural code", the information that is carried by each spike. They have already found that some cells emit spikes in response to single features of movement, such as the whisker's position or velocity, whereas other cells emit spikes only to a complex mix of these features. We will use my methods to understand how these single cell codes combine when co-ordinated, forming the "population code" for sensory information.