The role of the descending dopaminergic projection in spinal development and regeneration

脊髓中的神经细胞(神经元)可能在损伤后丢失。在运动神经元疾病中，脊髓中的运动神经元也会死亡，导致进行性瘫痪和死亡。这些情况不可逆转的原因是，在人类脊髓中，干细胞无法再生神经元。相反，我们已经证明，斑马鱼即使在成年鱼身上也能再生运动神经元和其他神经元。因此，阐明允许这些动物完成这些艰巨任务的信号是很重要的。我们最近描述了一种信使分子多巴胺，能够在细胞培养中增加斑马鱼和人类胚胎干细胞中运动神经元的生成，表明斑马鱼和人类之间的这种信号有一定程度的相似。在这里，我们想要找出多巴胺是否只作用于产生运动神经元的干细胞，以及干细胞内负责运动神经元产生的哪些信号参与其中。此外，我们将确定这种多巴胺信号如何使胚胎在发育过程中出现正确的运动模式，以及在运动神经元丧失后，是否可以利用多巴胺来改善游泳功能。因此，我们的研究旨在找到新的分子信号级联，这些信号对于了解脊椎动物脊髓是如何发育的，以及这些发育信号在损伤或变性神经元丢失后如何重新部署可能是重要的，这可能最终为损伤或疾病患者脊髓的细胞替代治疗提供信息。此外，我们的研究表明，在胚胎发育的关键阶段作用于多巴胺信号的精神活性药物可能会导致胚胎脊髓功能的永久性变化。这可能会为未来关于怀孕早期使用药物的潜在有害后果的研究提供信息。

Nerve cells (neurons) in the spinal cord may be lost after injury. In motor neuron diseases, motor neurons in the spinal cord also die, leading to progressive paralysis and death. The reason for the irreversibility of these conditions is that in the human spinal cord, stem cells fail to regenerate neurons. In contrast, we have shown that the zebrafish regenerates motor neurons and other neurons even in adults. It is therefore important to elucidate the signals that allow these animals such formidable tasks. We have recently described that a messenger molecule, dopamine, is able to augment the generation of motor neurons in zebrafish and in human embryonic stem cells in cell culture, indicating a degree of similarity of this signal between zebrafish and humans. Here we want to find out whether dopamine acts only on stem cells that generate motor neurons and which signals inside the stem cells, responsible for motor neuron generation, are involved. Moreover, we will determine how this dopamine signal allows correct movement patterns of the embryo to emerge during development and whether dopamine can be harnessed to improve swimming function after a loss of motor neurons. Our research thus aims to find new cascades of molecular signals that may be important to understand how the spinal cord in vertebrates develops and how these developmental signals can be re-deployed after injury or degenerative neuron loss, which may ultimately inform cell replacement therapies in injured or diseased patient spinal cords. Moreover, our research indicates that psycho-active drugs that act on dopamine signalling during critical phases of embryonic development may lead to permanent changes in spinal cord function of the embryo. This may inform future research into potentially harmful consequences of drug use during early stages of pregnancy.