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Understanding the role of dopamine in vertebrate motor control

了解多巴胺在脊椎动物运动控制中的作用

基本信息

批准号：
BB/N010140/1
负责人：
Jonathan McDearmid
金额：
$ 44.58万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN010140%2F1
关键词：
Understanding role dopamine vertebrate motor

项目摘要

Nerve cells (neurons) communicate by secreting neurotransmitters, small chemical messengers, at tiny junctions between cells called synapses. Dopamine is a specialised messenger molecule that alters the way other neurons processes information. In the normal brain, dopamine controls information processing in neurons that affect movement, attention and motivation. However, disturbances in dopamine release can have devastating effects on brain function. For example, disorders such as schizophrenia, Parkinson's disease and restless leg syndrome are linked to imbalances in dopamine secretion. For this reason, dopamine secreting neurons are a major focus of bioscience research. Our understanding of dopamine function comes mainly from the study of neurons in the midbrain, a brain region that coordinates many of our sensory and motor functions. However, dopamine releasing neurons are also found in the diencephalon, a region responsible for processing sensory information, regulating motivation and controlling other body functions. A specific group of these cells extend long outgrowths (axons) into the spinal cord where they communicate with networks of neurons responsible for generation of movements such as walking, running and swimming. These dopamine neurons are thought to facilitate and stabilise locomotor behaviours, but their specific roles have not been properly analysed, and little is known about the specific mechanisms by which they might exert their effects in the spinal cord. One key reason why the roles of these cells are not well understood is because most studies have been conducted on isolated pieces of spinal cord tissue that cannot generate naturally-occurring movements.We are using zebrafish larvae to determine how dopamine neurons affect naturally-occurring forms of locomotion. These tiny larval fish contain a full complement of dopamine neurons, yet lack bone tissue and skin pigments. These features mean that we can observe, record from and experimentally manipulate neurons in intact, living fish that can produce natural swimming patterns. Our preliminary work with this model has provided some exciting new insights into the possible role for diencephalic dopamine neurons in controlling the frequency and intensity of swimming: different groups of spinal cord neurons are activated at different speeds of swimming, with cells in one region used to produce slow, weak movements and those in another region used for fast, intense movements. We have found that laser removal of spinally-projecting dopamine neurons reduces the activity in spinal cells used for fast, intense movements. Thus, we suspect that dopamine precisely regulates the production of more intense forms of locomotor behaviour. We will test this suggestion by using a laser to selectively remove the dopamine neurons of interest. We will then record the electrical activity patterns of spinal cord neurons involved in the generation of swimming. This will allow us to study loss of dopamine signals in the spine affects nerve cells used for low and high speed movements. Once we have identified the cell types that dopamine affects, we will make recordings of the electrical activity of these individual neurons to examine the mechanisms underlying these changes. Finally, we will use high speed video motion capture to understand how removal of dopamine neurons affects the movements of freely-behaving zebrafish. In completing this work we aim to shed important new light on the fundamental processes underpinning vertebrate motor control. Moreover, as spinal cord-projecting dopamine neurons have been implicated in disorders such as Parkinson's disease and restless leg syndrome, our finding may help us to better understand dopamine-related diseases that can have debilitating effects on locomotor behaviour.

神经细胞（神经元）通过分泌神经递质，小的化学信使，在细胞之间的微小连接处称为突触。多巴胺是一种特殊的信使分子，它改变了其他神经元处理信息的方式。在正常的大脑中，多巴胺控制着影响运动、注意力和动机的神经元的信息处理。然而，多巴胺释放的紊乱可能对大脑功能产生破坏性影响。例如，精神分裂症、帕金森病和不宁腿综合征等疾病都与多巴胺分泌失衡有关。因此，多巴胺分泌神经元是生物科学研究的主要焦点。我们对多巴胺功能的理解主要来自对中脑神经元的研究，中脑是一个协调我们许多感觉和运动功能的大脑区域。然而，间脑中也发现了多巴胺释放神经元，间脑是负责处理感觉信息、调节动机和控制其他身体功能的区域。这些细胞中的一个特定群体将长的突起（轴突）延伸到脊髓中，在那里它们与负责产生运动（如行走，跑步和游泳）的神经元网络进行通信。这些多巴胺神经元被认为促进和稳定运动行为，但它们的具体作用尚未得到适当的分析，并且对它们在脊髓中发挥作用的具体机制知之甚少。这些细胞的作用尚未被很好地理解的一个关键原因是，大多数研究都是在无法产生自然运动的孤立脊髓组织上进行的，我们正在使用斑马鱼幼虫来确定多巴胺神经元如何影响自然发生的运动形式。这些微小的幼鱼含有完整的多巴胺神经元，但缺乏骨组织和皮肤色素。这些特征意味着我们可以观察、记录和实验性地操纵完整的、可以产生自然游泳模式的活鱼的神经元。我们对该模型的初步研究为间脑多巴胺神经元在控制游泳频率和强度方面的可能作用提供了一些令人兴奋的新见解：不同的脊髓神经元组在不同的游泳速度下被激活，一个区域的细胞用于产生缓慢，弱的运动，而另一个区域的细胞用于快速，强烈的运动。我们发现，激光去除脊髓投射多巴胺神经元会降低用于快速、剧烈运动的脊髓细胞的活性。因此，我们怀疑多巴胺精确地调节了更强烈形式的运动行为的产生。我们将通过使用激光选择性地去除感兴趣的多巴胺神经元来测试这一建议。然后，我们将记录参与游泳产生的脊髓神经元的电活动模式。这将使我们能够研究脊柱中多巴胺信号的丢失对用于低速和高速运动的神经细胞的影响。一旦我们确定了多巴胺影响的细胞类型，我们将记录这些单个神经元的电活动，以研究这些变化背后的机制。最后，我们将使用高速视频运动捕捉来了解多巴胺神经元的去除如何影响自由行为的斑马鱼的运动。在完成这项工作，我们的目标是揭示重要的新的光的基本过程的脊椎动物运动控制的基础。此外，由于脊髓投射多巴胺神经元与帕金森病和不宁腿综合征等疾病有关，我们的发现可能有助于我们更好地了解可能对运动行为产生衰弱影响的多巴胺相关疾病。