SSA:Neuronal control of mitochondrial trafficking down long-range axons

为了支持突触传递的能量需求，神经元在其高度分支和非常长的轴突上有成千上万的线粒体。在神经元的整个生命周期中，它必须解决一个独特的细胞生物学问题，即将这些线粒体运送到正确的轴突位置。我们知道线粒体在轴突内移动，线粒体的分布在许多神经系统疾病中受到影响，这告诉我们这是一个高度调控的重要过程。然而，我们不知道神经元是如何控制大脑轴突中的线粒体运动的，也不知道这是如何影响它们的整体分布的。在这个项目中，我们将结合神经元线粒体的体内双光子成像和计算模型来解决神经元活动如何控制线粒体在轴突中的传递和分布，这是大脑中每个神经元的基础。在阿什比实验室，我们开发了体内双光子显微镜技术，可以在几分钟到几天的时间内跟踪活体小鼠大脑神经元中的单个线粒体。在这个项目中使用这些方法将使我们能够定义线粒体是如何在轴突上移动的，以及这种运动是如何被神经元活动控制的。然后，我们将测试这些局部运输规则是否可以解释线粒体最终如何分布在轴突上。为了做到这一点，我们将扩展O'Donnell实验室以前的方法，我们将建立解剖学上真实的神经元的复杂计算模型，模拟线粒体在整个轴突树中的运输。通过将体内测量的力量和大规模的计算模型结合起来，我们将定义神经元如何克服挑战，确保它们在正确的位置拥有正确数量的线粒体，以维持其功能。这是一个跨学科的项目，建立在Ashby和do 'Donnell实验室之间的密切合作基础上。该项目的性质意味着学生将接受广泛的技术技能培训，从尖端成像到体内实验技能和计算神经科学编码。

To support the energy demands of synaptic transmission, neurons have many thousands ofmitochondria located along their highly branched and very long axons. Throughout a neuron's entirelifetime, it must solve the unique cell biological problem of delivering these mitochondria to thecorrect axonal locations. Mitochondria are known to move around within axons and mitochondrialdistribution is affected in many neurological diseases, which tells us that that this is a highly regulatedand important process. However, we do not how neurons control mitochondrial movement in axonswithin the brain, or how this influences their overall distribution. In this project, we will combine invivo 2-photon imaging of neuronal mitochondria with computational modelling to solve how neuronalactivity controls the delivery and distribution of mitochondria in axons that is fundamental to everyneuron in the brain.In the Ashby lab, we have developed in vivo 2-photon microscopy techniques to track individualmitochondria in neurons of the living mouse brain over the course of minutes through to days. Usingthese approaches in this project will allow us to define how mitochondria move around functioningaxons and how that movement is controlled by neuronal activity. We will then test whether theselocal trafficking rules can explain how mitochondria end up distributed across the axon. To do this,extending previous approaches by the O'Donnell lab, we will build sophisticated computationalmodels of anatomically real neurons that simulate the trafficking of mitochondria across the entireaxonal tree. By pulling together the power of the in vivo measurements and the large scale of thecomputational models, we will define how neurons overcome the challenge of ensuring they have theright numbers of mitochondria in the right place to maintain their function.This is an interdisciplinary project that is built on the close collaboration between the Ashby andO'Donnell labs. The nature of the project means that the student will receive training in a wide-rangeof technical skills ranging from cutting edge imaging to in vivo experimental skills and coding forcomputational neuroscience.