CRCNS:Mechanisms of Axonal Gradient Detection

描述（由申请人提供）：正确的大脑功能需要正确的大脑线路。建立适当连接的一个重要步骤是引导轴突在发育中的大脑中长距离找到正确的目标。轴突使用的一个关键类型的引导线索是吸引因子或排斥因子的浓度梯度。在过去的十年里，人们发现了许多以这种方式引导轴突的新分子。然而，到目前为止，我们对轴突探测和响应梯度的精确机制仍然知之甚少。更好地理解这些机制将使我们能够更好地理解(1)神经系统是如何正常构建的；(2)为什么轴突在发育过程中有时会错靶；(3)基因缺失和突变对布线的影响；(4)如何在损伤后促进轴突再生到合适的目标。该项目的目标是通过建立梯度检测和轴突定向运动的计算模型，对梯度中的轴突行为进行机械理解。我们将研究两种类型的模型。第一种是基于梯度检测受到受体结合过程中不可避免的随机噪声的限制。这些模型假设一个小的球形传感装置，并对这种传感装置可以检测到的最小可检测梯度陡度进行预测。第二种类型的模型解决了丝状足在轴突梯度感知和运动中发挥的独特作用。该模型基于丝状足作为某种独立的传感装置的想法，正是它们的组合动力学决定了梯度检测的阈值和轴突遵循的轨迹。该项目的一个关键组成部分是，计算模型将使用研究人员最近开发的一种新的定量实验方法直接进行测试和约束。该分析允许在胶原凝胶中建立精确控制形状的稳定分子梯度。该系统将采用神经生长因子梯度诱导背根神经节轴突。将使用不同NG陡峭度的指数形梯度来确定轴突可以检测到的最小梯度陡峭度作为绝对浓度的函数，并将定量分析这些梯度中的轴突轨迹。

DESCRIPTION (provided by applicant): Correct brain function requires correct brain wiring. An important step in the establishment of appropriate connectivity is the guidance of axons over long distances in the developing brain to find their correct targets. A crucial type of guidance cue axons use is concentration gradients of attractive or repellent factors. Over the past decade many new molecules have been discovered that guide axons in this way. However, as yet we still have very little understanding of the precise mechanisms by which axons detect and respond to gradients. A better understanding of these mechanisms would enable us to understand better (1) how the nervous system is normally constructed, (2) why axons sometimes mistarget during development, (3) the effect of gene deletions and mutations on wiring, and (4) how to encourage axonal regeneration to appropriate targets after injury. The goal of this project is to develop a mechanistic understanding of axonal behavior in gradients by building computational models of gradient detection and directed movement for axons. Two types of models will be investigated. The first type is based on the idea that gradient detection is limited by inevitable stochastic noise in the receptor binding process. These models assume a small, spherical sensing device, and make predictions about the minimum detectable gradient steepness that such sensing devices can detect. The second type of model addresses the unique role that filopodia play in axonal gradient sensing and movement. The model is based on the idea that filopodia act as somewhat independent sensing devices, and it is their combined dynamics that determines the threshold for gradient detection and the trajectories that axons follow. A crucial component of the project is that the computational modeling will be directly tested and constrained using a new, quantitative experimental assay the investigators have recently developed. The assay allows stable molecular gradients of precisely controlled shape to be established in a collagen gel. The system used will be the guidance of dorsal root ganglion axons by gradients of Nerve Growth Factor (NG). Exponentially-shaped gradients of varying steepness of NG will be used to determine the minimum gradient steepness axons can detect as a function of absolute concentration, and the trajectories of axons in these gradients will be quantitatively analyzed.