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Nonsynaptic Neurotransmitter Effects on Developing Spinal Cord Circuitry

非突触神经递质对发育中的脊髓回路的影响

基本信息

批准号：
BB/E015352/1
负责人：
Jonathan McDearmid
金额：
$ 35.1万
依托单位：
University of Leicester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE015352%2F1
关键词：
Nonsynaptic Neurotransmitter Effects Developing Spinal

项目摘要

In the adult brain, nerve cells communicate by secreting neurotransmitters, small chemical messengers, at specialized junctions between cells called synapses. When neurotransmitter is secreted, it crosses the synapse and interacts with the apposing nerve cell which converts this chemical message into electrical information. In this way, information can rapidly spread between the 100 billion nerve cells of our brain so that complex computational tasks can be performed that allow us to receive, process and react to information from the world around us. Traditionally, it was believed that in the developing brain, before synaptic junctions form, neurotransmitters were not required for nerve cell signalling. However, we now know that this is not the case. Developing nerve cells secrete neurotransmitter before they establish synaptic contacts and a range of studies show profound neurotransmitter effects on the growth and maturation of developing nervous tissue. Whilst this work has provided important clues about how immature brain cells communicate, few whole organism studies have been undertaken. We will address this problem by studying neurotransmission during development of the zebrafish embryo. The zebrafish, a small freshwater cyprinid, is ideal for developmental studies because fertilization occurs externally so that steps during embryonic development can be easily studied. In addition, zebrafish embryos are transparent which means that we can visually identify and monitor nerve cells as they develop within a living embryo. Our work has three broad aims. The first is to understand whether neurotransmitters affect the excitability of developing nerve cells before synaptic junctions form. We will use specialized techniques to record electrical activity in immature nerve cells following exposure to neurotransmitters. This will allow us to define when cells first become responsive to chemical signalling and what kind of neurotransmitters are involved in these responses. Our second aim will be to determine if embryonic nerve cells use neurotransmitter to talk to one another in the absence of synaptic junctions. We will apply chemicals to block responses to secreted neurotransmitters and measure how this affects electrical activity of developing nerve cells. This will allow us to determine when nerve cells of the developing nervous system begin to communicate. Our final aim is to determine the role for immature neurotransmission in the zebrafish embryo. We will use molecular genetic methods to disrupt neurotransmitter signalling from the onset of development and determine how this affects assembly of the nervous system. We will focus on the nerve cell network that generates swimming as it can be used as a simple model network for the study of behaviour. In this way we will be able to examine how disruptions in transmitter signalling impact on the many aspects of nervous development, from the growth and maturation of individual cells through to the activity of nerve cell networks and the generation of behaviour. Our work will cast new light on the importance of embryonic neurotransmission and may provide important clues about how imbalances in neurotransmitter activity cause developmental disease.

在成年人的大脑中，神经细胞通过分泌神经递质，小的化学信使，在称为突触的细胞之间的专门连接处进行交流。当神经递质被分泌时，它穿过突触并与并列的神经细胞相互作用，后者将这种化学信息转化为电信息。通过这种方式，信息可以在我们大脑的1000亿个神经细胞之间快速传播，以便执行复杂的计算任务，使我们能够接收，处理和反应来自我们周围世界的信息。传统上，人们认为在发育中的大脑中，在突触连接形成之前，神经细胞信号传导不需要神经递质。然而，我们现在知道情况并非如此。发育中的神经细胞在它们建立突触接触之前分泌神经递质，并且一系列研究表明神经递质对发育中的神经组织的生长和成熟具有深远的影响。虽然这项工作为未成熟的脑细胞如何交流提供了重要线索，但很少有人进行整体生物体研究。我们将通过研究斑马鱼胚胎发育过程中的神经传递来解决这个问题。斑马鱼是一种小型淡水鲤科鱼类，是发育研究的理想对象，因为受精发生在外部，因此可以很容易地研究胚胎发育过程中的步骤。此外，斑马鱼胚胎是透明的，这意味着我们可以在活体胚胎内发育时视觉识别和监测神经细胞。我们的工作有三大目标。首先是了解神经递质是否会影响突触连接形成前发育中神经细胞的兴奋性。我们将使用专门的技术来记录暴露于神经递质后未成熟神经细胞的电活动。这将使我们能够确定细胞何时首次对化学信号产生反应，以及这些反应中涉及哪种神经递质。我们的第二个目标将是确定胚胎神经细胞是否在缺乏突触连接的情况下使用神经递质彼此交谈。我们将应用化学物质来阻断对分泌的神经递质的反应，并测量这如何影响发育中神经细胞的电活动。这将使我们能够确定发育中的神经系统的神经细胞何时开始开始交流。我们的最终目标是确定斑马鱼胚胎中未成熟神经传递的作用。我们将使用分子遗传学方法从发育开始就破坏神经递质信号传导，并确定这如何影响神经系统的组装。我们将专注于产生游泳的神经细胞网络，因为它可以用作行为研究的简单模型网络。通过这种方式，我们将能够研究递质信号传导的中断如何影响神经发育的许多方面，从单个细胞的生长和成熟到神经细胞网络的活动和行为的产生。我们的工作将为胚胎神经传递的重要性提供新的线索，并可能为神经递质活动的不平衡如何导致发育疾病提供重要线索。