Neuropeptide function in a decentralised nervous system

神经肽是“信使分子”，使神经系统能够协调人类和其他动物的生理过程和行为。对神经肽的研究为我们的感觉和行为的生理机制的分子基础提供了重要的见解。例如，我们知道吗啡在人体中发挥其缓解疼痛的作用，因为它模拟了内源性神经肽-“内啡肽”的作用。虽然神经肽催产素在人类和其他动物的社会行为神经机制中的作用的发现导致它被标记为“爱和信任的激素”。但是，在地球上动物生命的进化史上，这些关键的行为分子调节器是什么时候起源的呢？这个问题已经被证明是困难的，因为神经肽只由短串的氨基酸组成。因此，当将人类中的神经肽与存在于例如远亲的“模型”无脊椎动物如果蝇中的神经肽进行比较时，由于氨基酸序列差异，鉴定神经肽之间的关系是具有挑战性的。然而，随着DNA测序成本的下降，在越来越广泛的动物中识别神经肽编码基因已经变得可行，这为神经肽信号系统的进化史提供了重要的新见解。特别是，它一直是从各种海洋无脊椎动物的DNA序列数据的可用性，提供了关键的“丢失的部分”在“拼图”的神经肽的进化。例如，促甲状腺激素释放激素（TRH）在调节人类生长方面起着关键作用，直到最近才被认为只存在于脊椎动物中。但我们的研究表明，TRH型神经肽也存在于棘皮动物（例如海胆，海星）中，这表明TRH的进化历史比迄今为止认为的要古老得多。该项目的目的是调查和确定常见的欧洲海星Asterias rubens中神经肽的生理/行为作用。为什么是这个物种，为什么是现在？首先，作为棘皮动物，该物种属于与脊椎动物相同的动物界（后口动物）的分支，因此它提供了脊椎动物和原口无脊椎动物（如果蝇）的充分表征的神经肽系统之间的“缺失环节”。其次，海星和其他棘皮动物有一个没有大脑的五向体（一个“分散”的神经系统），这为确定神经肽系统如何用于控制生理/行为过程提供了一个独特的背景。第三，红海星是欧洲沃茨中非常丰富的物种，这使得它很容易获得用于实验研究。第四，利用新的DNA测序技术，我们最近确定了在该物种神经系统中表达的约16，000个基因的序列，其中包括许多神经肽基因。因此，我们现在第一次能够全面研究神经肽在棘皮动物中的功能。通过使用一系列技术研究红海星中神经肽的表达和作用（见技术摘要），我们将i）。发现神经肽在海星中的生理作用，首次全面了解神经肽系统如何用于调节棘皮动物的生理过程和行为，棘皮动物是一种五向对称的动物，具有分散的神经系统，但没有大脑ii）。通过将我们的发现与其他动物（脊椎动物和其他无脊椎动物）中神经肽功能的知识进行比较，确定棘皮动物中神经肽功能的保守/多样化程度。

Neuropeptides are "messenger molecules" that enable nervous systems to co-ordinate physiological processes and behaviour in humans and other animals. Research on neuropeptides has provided important insights on the molecular basis of the physiological mechanisms that underlie how we feel and behave. For example, we know that morphine exerts its pain-relieving effect in humans because it mimics the action of endogenous neuropeptides - the "endorphins". Whilst discovery of the actions of the neuropeptide oxytocin in neural mechanisms of social behaviour in humans and other animals have led to it being labeled as the "hormone for love and trust". But when did these key molecular regulators of behaviour originate in the evolutionary history of animal life on earth? Answering this question has proven to be difficult because neuropeptides are comprised of only short strings of amino acids. Thus, when comparing neuropeptides in humans with those present in, for example, a distantly related "model" invertebrate such as the fruit fly Drosophila, identifying of relationships between neuropeptides is challenging because of amino acid sequence divergence. However, with the falling cost of DNA sequencing it has become feasible to identify neuropeptide-encoding genes in an increasingly wide range of animals, and this has provided important new insights on the evolutionary history of neuropeptide signaling systems. In particular, it has been the availability of DNA sequence data from a variety of marine invertebrates that has provided critical "missing pieces" in the "jigsaw puzzle" of neuropeptide evolution. For example, the hormone thyrotropin-releasing hormone (TRH), which has a key role in regulating growth in humans, was until recently thought to occur only in vertebrates. But our research has revealed that TRH-type neuropeptides also occur in echinoderms (e.g. sea urchins, starfish), demonstrating that TRH has a much more ancient evolutionary history than hitherto thought. The aim of this project is to investigate and determine the physiological/behavioural roles of neuropeptides in the common European starfish Asterias rubens. Why this species and why now? Firstly, as an echinoderm, this species belongs to the same branch of the animal kingdom (deuterostomes) as vertebrates and therefore it provides a "missing link" between the well-characterised neuropeptide systems of vertebrates and protostomian invertebrates such as Drosophila. Secondly, starfish and other echinoderms have a pentaradial body plan without a brain (a "decentralized" nervous system), providing a unique context in which to determine how neuropeptide systems are used to control physiological/behavioural processes. Thirdly, Asterias rubens is a very abundant species in European waters, which makes it easy to obtain for experimental studies. Fourthly, using new DNA sequencing technology, we have recently determined the sequences of ~16,000 genes that are expressed in the nervous system of this species, including many neuropeptide genes. Thus, we are now for the first time able to comprehensively investigate neuropeptide function in this echinoderm species. By investigating neuropeptide expression and action in Asterias rubens using a range of techniques (see Technical Summary), we will i). discover the physiological roles of neuropeptides in starfish, providing for the first time comprehensive insights on how neuropeptide systems are used to regulate physiological processes and behaviour in echinoderms, pentaradially symmetrical animals that have a decentralized nervous system without a brain ii). determine to what extent there has been conservation/diversification of neuropeptide function in echinoderms, by comparison of our findings with knowledge of neuropeptide function in other animals (vertebrates and other invertebrates).