Cross-modality integration of sensory signals leading to initiation of locomotion

动物如果不能对它的感觉环境做出适当的反应，就会危及它的生存。如果我们试图抓住一只鸟，它要么飞起来，要么跑掉。大多数动物，像我们人类一样，在受到刺激时可以行走、奔跑、游泳或飞行。尽管与我们思考、交谈和学习的能力相比，这种反应看起来非常简单，但大脑和脊髓中神经回路启动运动的细节仍然知之甚少。在研究最深入的哺乳动物中，我们对大脑的区域和涉及的神经细胞类型有广泛的了解，但神经系统令人惊讶地复杂。为了简化问题，我们选择了一种非常小的动物，新孵化的青蛙蝌蚪，它的脊髓有人类头发那么粗。在这个阶段，大脑和脊髓中大约2000个神经细胞可能足以让蝌蚪在被触摸时游泳。经过多年的研究，我们已经将这些神经细胞分为不到20种类型，并定义了它们的解剖、特性、连接和它们形成的网络。关键的是，我们发现了大脑中一种神经细胞的一小部分，这种神经细胞负责产生驱动游泳的有节奏的神经系统活动。对这些细胞的实验性刺激可以导致游泳，而让它们安静下来可以阻止它。利用我们对蝌蚪神经系统的详细知识，我们已经完成了第一代计算机模型，展示了蝌蚪的神经细胞是如何生长的，以建立连接并组装控制游泳的网络。因此，与其他脊椎动物相比，我们对这种简单动物的行为和控制它的神经系统有非常详细的了解。我们现在的目标是利用这些关于蝌蚪的知识来询问它的大脑是如何以及在哪里做出开始游泳的决定的。这是可能的，因为我们独一无二地识别出了驱动游泳的脑神经细胞。我们将检验这一假设，即这些细胞也是做出游泳决定的神经细胞。在布里斯托尔的实验中，我们将测试有关触摸、光和蝌蚪必须考虑的其他感官的所有信号是否都会聚在这些细胞上。我们可以通过记录它们的电活动来直接做到这一点，并在监测蝌蚪是否会游泳的同时刺激它。使用其他成像方法，让活跃的细胞发光，我们将追踪信号如何沿着神经系统中连接不同类型刺激和控制游泳的神经细胞的路径逐个传递。与此同时，在圣安德鲁斯，我们将使用复杂的电记录方法和药理学来检查驱动游泳的神经细胞的详细特性。这将帮助我们了解它们是如何对感觉信号做出反应的，从休息时的沉默转变为游泳时的起搏器，就像驱动心跳的细胞一样。与此同时，普利茅斯研究小组将使用蝌蚪大脑和脊髓中神经细胞和网络的计算机模型，结合布里斯托尔和圣安德鲁斯的新发现，了解开始和产生游泳活动的基本要求。它们还将使我们能够将决策的理论模型扩展到神经细胞层面，这是最终做出决定的地方。共同的进化起源意味着，尽管蝌蚪神经系统很小很年轻，但它建立在与所有脊椎动物相同的原理上。因此，我们的发现应该会为控制运动的大脑网络是如何组织的提供更广泛的见解。在哺乳动物的大脑中，像我们人类一样，这些网络非常复杂，当它们出错时，它们会导致启动运动的严重问题，比如帕金森症。我们希望，对一个简单得多的系统的研究可以揭示隐藏在成人大脑中的核心原理。

An animal that fails to respond appropriately to its sensory environment jeopardises its survival. If we try to catch a bird it will fly or run off. Most animals, like ourselves, can walk, run, swim or fly when stimulated. Even though this response seems very simple compared to our ability to think, talk and learn, the details of the way nervous circuits in the brain and spinal cord initiate locomotion remain poorly understood. In mammals, which have been studied most intensively, we have a broad knowledge of the areas of the brain and types of nerve cells which are involved, but the nervous system is astonishingly complex. To simplify the problem, we chose a very small animal, the newly hatched frog tadpole whose spinal cord is the thickness of a human hair. At this stage, around 2000 nerve cells in the brain and spinal cord may be sufficient to allow the tadpole to swim when it is touched. Over many years of study, we have classified these nerve cells into less than 20 types and defined their anatomy, properties, connections and the networks they form. Critically, we have discovered a small population of one type of nerve cell in the brain which is responsible for producing the rhythmic nervous system activity driving swimming. Experimental stimulation of these cells can lead to swimming and silencing them can stop it. Using our detailed knowledge about the tadpole nervous system, we have completed a first generation computer model of how the tadpole's nerve cells grow to make the connections and assemble the networks controlling swimming. Compared to other vertebrate animals, we therefore have remarkably detailed knowledge about this simple animal's behaviour and the nervous system controlling it. Our aim now is to exploit this knowledge about the tadpole to ask how and where its brain makes the decision to start to swim. This is possible because, uniquely, we have identified the brain nerve cells which drive swimming. We will test the hypothesis that these are also the nerve cells which make the decision to swim. In experiments in Bristol we will test whether all the signals about touch, light and other senses which the tadpole must take into account, converge on these cells. We can do this directly by recording their electrical activity and stimulating the tadpole while monitoring whether or not it swims. Using additional imaging methods where active cells are made to emit light, we will trace how signals pass cell-by-cell along the pathways in the nervous system connecting different kinds of stimulus to the nerve cells controlling swimming. Meanwhile in St Andrews we will use sophisticated electrical recording methods and pharmacology to examine the detailed properties of the nerve cells driving swimming. This will help us understand how they respond to sensory signals by switching from silence at rest to acting as pacemakers during swimming, rather like the cells which drive the heartbeat. In parallel, the Plymouth team will use computer models of the nerve cells and networks in the tadpole brain and spinal cord, combining the new findings from Bristol and St Andrews to understand the basic requirements to start and generate swimming activity. They will also allow us to extend theoretical models of decision making down to the level of nerve cells, which is where decisions are ultimately made. A shared evolutionary origin means that although the tadpole nervous system is small and young, it is built on the same principles as all vertebrates. Our findings should therefore provide broader insights into how brain networks controlling locomotion are organised. In the brain of mammals, like ourselves, these networks are remarkably complex, and when they go wrong, they cause severe problems in initiating locomotion, like Parkinsonism. Our hope is that study of a much simpler system may uncover core principles which lie concealed in the adult brain.