Coding in healthy and diseased neurons

健康和患病神经元的编码

• 批准号: RGPIN-2014-06204
• 负责人: Longtin, Andre
• 金额: $ 5.83万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630197
• 关键词: Coding; healthy; diseased; neurons

Our nervous system gathers information from the environment, resulting in perceptions and appropriate behaviours. There are exciting unresolved fundamental questions about how this information is acquired and processed. This proposal uses mathematics to address three such fundamental questions. 1) How do temperature sensors work? Studying how the "experts" do it may reveal fundamental organization principles for all senses. We will investigate how snakes can detect extremely small temperature changes in their environment (due e.g. to prey). They measure heat though specialized infrared cameras on their head. They can respond to changes in the thousandth of a degree range. Work in the mid 80's suggested that this sense operates near the limit allowed by the background noise, which hampers signal detection. Since then however, extremely temperature-sensitive ion channels known as TRP receptors has been discovered in thermal sensing neurons. New electrical synchronization phenomena have also been discovered in these neurons. The proposed research will establish, using neural modeling, how important synchronization and TRP receptors are to the thermal sensitivity. This adds a fundamental link in the chain from the infrared optics of the cameras to the higher brain levels that together process infrared and visual images. 2) What is the relation between nerve damage and degradation of information flow? Nerves are a collection of "wires" known as "axons" coming out of single neurons. Fast propagation of information down a nerve, in the form of electrical pulses, relies on myelin. This myelin is made up of specialized cells that wrap around the axon, except at tiny 1 micron gaps called nodes of Ranvier. The myelin modifies the electrical properties of the axon "cable" in a way that pulses quickly jump from node to node. It also insulates one axon from the other. Myelin thins out in diseases like multiple sclerosis (MS). Recently the damage from MS can be quantified at high resolution by state-of-the-art "CARS" microscopy. My colleagues at U. Laval have provided me with images at different stages of the disease in a mouse. Our work proposes to understand and predict functional deficits in these nerves from the images. This involves modeling propagation in healthy and demyelinated single axons and axon bundles. 3) How are brain rhythms altered by stimuli? Debates rage over how rhythms are generated and what they mean. Certain brain rhythms are thought to be important for our ability to pay attention to a stimulus. Our work proposes a simple novel mechanism that can be tested in weakly electric fish brains. Paradoxically, we predict that the rhythm arises in a cell that receives a random signal plus a delayed version of that signal (such "feedforward" circuitry abounds). This will be analyzed in detail using a theory we have recently developed for the activity of cells in networks. This theory will also be expanded to explain how brain rhythms can align themselves to stimulation, a phenomenon missing in certain diseases. The work is theoretical and computational. We formulate predictive mathematical models that are simple enough to explain neural phenomena with a minimal number of biological ingredients. The work will make careful use of existing biological data, and benefit from collaborations with experimentalists. The modeling also serves the purpose of making predictions about function - via theoretical analyses or in silico experiments - which can be tested in new experiments. This research will deepen our knowledge of brain circuit function. It may also lead to novel technologies (e.g. neural prosthetics) based on newly found principles, including technologies to repair faulty circuits or to sense heat.

我们的神经系统从环境中收集信息，从而产生感知和适当的行为。关于这些信息是如何获得和处理的，还有一些令人兴奋的悬而未决的根本问题。这项提议使用数学来解决三个这样的基本问题。1)温度传感器如何工作？研究“专家”如何做到这一点可能会揭示所有意义上的基本组织原则。我们将研究蛇是如何探测到环境中极小的温度变化(例如由于猎物)的。它们通过头上戴着的特殊红外摄像机测量热量。他们可以对百分之一度范围内的变化做出反应。S在80年代中期的工作中提出，这种感觉工作在背景噪声允许的极限附近，这阻碍了信号检测。然而，从那时起，在热敏神经元中发现了被称为Trp受体的极端温度敏感的离子通道。在这些神经元中也发现了新的电同步现象。这项拟议的研究将利用神经模型来确定同步性和色氨酸受体对热敏性的重要性。这在从摄像机的红外光学到共同处理红外和视觉图像的更高大脑水平的链中增加了一个基本环节。2)神经损伤与信息流退化有什么关系？神经是由单个神经元发出的被称为“轴突”的“电线”的集合。信息以电脉冲的形式沿神经快速传播依赖于髓鞘。这种髓鞘是由包裹在轴突周围的特殊细胞组成的，除了被称为兰维尔结节的微小1微米间隙。髓鞘以一种脉冲快速从一个节点跳到另一个节点的方式改变轴突“电缆”的电学特性。它还将一个轴突与另一个轴突隔绝。在多发性硬化症(MS)等疾病中，髓鞘会变薄。最近，多发性硬化症的损害可以通过最先进的“汽车”显微镜以高分辨率进行量化。我在拉瓦尔大学的同事向我提供了小鼠疾病不同阶段的图像。我们的工作是从图像中了解和预测这些神经的功能缺陷。这涉及到对健康和脱髓鞘的单一轴突和轴突束中的传播进行建模。3)刺激是如何改变大脑节律的？关于节奏是如何产生的，以及它们的含义，争论非常激烈。某些大脑节律被认为对我们注意刺激的能力很重要。我们的工作提出了一种简单而新颖的机制，可以在弱电的鱼脑中进行测试。矛盾的是，我们预测，节奏是在接收随机信号加上该信号的延迟版本的细胞中产生的(这种“前馈”电路比比皆是)。这将使用我们最近开发的关于网络中细胞活动的理论进行详细分析。这一理论还将被扩展，以解释大脑节律如何与刺激保持一致，这是某些疾病中缺失的现象。这项工作既是理论的，也是计算的。我们建立了预测数学模型，这些模型足够简单，可以用最少的生物成分来解释神经现象。这项工作将仔细利用现有的生物数据，并受益于与实验者的合作。该模型还用于通过理论分析或电子实验对功能进行预测，这些预测可以在新的实验中进行测试。这项研究将加深我们对大脑回路功能的认识。它还可能导致基于新发现的原理的新技术(例如神经假体)，包括修复有故障的电路或感应热量的技术。