Mechanisms of plasticity specification during an embryonic critical period.

发育过程中的短暂经历，也就是所谓的“关键期”，会对我们的大脑功能产生持久的影响。顾名思义，关键期对神经系统的发育至关重要；在这些发育阶段，神经细胞的功能特性被指定，这些特性决定了网络的运行方式。重要的是，在关键时期发生的错误通常仍处于锁定状态，无法纠正。许多神经发育障碍，包括癫痫、精神分裂症和自闭症谱系障碍，现在被认为是在关键时期(儿童或青春期)出现的网络失调。相反，关键时期的临床干预可能被证明是非常有效的；例如，关键时期神经元活动的瞬时重新平衡可以永久挽救否则将导致癫痫的突变的影响。由于关键时期对神经系统是否获得正常功能至关重要，因此我们了解其潜在机制是非常重要的。在研究复杂的神经系统时，这些问题是非常困难的，例如哺乳动物的感觉系统，到目前为止，这些系统一直是首选的模型系统。令人兴奋的是，我们的合作者，曼彻斯特大学的理查德·贝恩斯教授最近的研究表明，关键时期可能是普遍现象，对包括昆虫在内的所有神经系统来说都是常见的。基于他们的发现，我们在果蝇的神经肌肉连接(神经-肌肉连接)处发现了一个明确的临界期。这有许多优点，包括相对较大，以及易于访问和操作。我们通过许多实验室的工作(在其他情况下)表现得非常好，现在可以在这些坚实的基础上再接再厉，取得快速进展。例如，我们已经发现，以前研究的几种形式的神经元可塑性(允许神经系统调整和学习的机制)在胚胎发育后期受到瞬时关键期经验的调节，其中一些在短暂的胚胎经历后被禁用。为了说明这一点，我们选择将温度作为这种动物在野外通常会遇到的刺激，范围从18-29摄氏度。令人兴奋的是，我们发现，如果在胚胎发育后期的几个小时内经历18度或29度的“极端”，这将显著改变神经细胞的发育方式(例如，它们的生长)和它们的行为方式(例如，不再能够以被认为是学习所必需的方式改变)。这反映在动物的行为层面上，动物被“卡住”，无法适应环境的变化。从科学上讲，这是令人兴奋的；尽管考虑到气候变化，观察几度的差异可能对神经系统发育和动物行为产生的戏剧性、持久的影响，是相当令人震惊的。我们现在计划利用这个高度易处理的实验系统的优势来确定瞬时临界期指定重要神经细胞属性的机制(目标1)。第二，我们将研究瞬时经历如何产生持久的影响。这一点目前还不清楚，尽管我们的初步数据表明，表观遗传机制是改变和维持基因表达变化的一种手段。总而言之，我们已经确定了一个简化但功能强大的实验模型系统，用它来研究对我们对神经系统发育的一般理解很重要的基本问题。几乎可以肯定，所涉及的机制是保守的。因此，这项工作的成果可能会对临床和生态环境产生影响。

Transient experiences during formative periods of development, called 'critical periods', have lasting impact on how our brains function. As indicated by the name, critical periods are of fundamental importance to the development of nervous systems; during these developmental phases functional properties of nerve cells are specified, which determine how networks perform. Importantly, errors that occur during a critical period often remain locked in, unable to be corrected. Many neurodevelopmental disorders, including epilepsy, schizophrenia and autism spectrum disorder, are now thought of as network mis-adjustments that arise during critical periods (of childhood or adolescence). Conversely, clinical interventions during the critical period could prove highly effective; for example, transient re-balancing of neuronal activity during the critical period can permanently rescue the effects of mutations that would otherwise cause epilepsy. Because critical periods are so pivotal in whether or not a nervous system gains normal function, it is important that we understand the underlying mechanisms.These questions are exceedingly difficult to investigate when working with complex nervous systems, such as mammalian sensory systems, which thus far have been the go-to model systems. Excitingly, recent work by our collaborators, Prof. Richard Baines, University of Manchester, has shown that critical periods are probably universal phenomena, common to all nervous systems, including insects. Building on their findings, we have discovered an explicit critical period at the neuromuscular junctions (nerve-muscle connection) in the fruitfly, Drosophila. This has many advantages, including being comparatively large, as well as easy to access and manipulate. Having been extremely well characterised (in other contexts) through the work of many laboratories, we can now build on these solid foundations and make rapid progress. For example, we have already discovered that several forms of previously studied neuronal plasticity (mechanisms that allow nervous systems to adjust and learn) are regulated by transient critical period experience in late embryogenesis, and that some are disabled following brief embryonic experiences. To illustrate, we have chosen to work with temperature as a stimulus this animal would normally encounter in the wild, ranging from 18-29 degrees centigrade. Excitingly, we find that if the 'extremes' of either 18 or 29 degrees are transiently experienced for a few hours as late embryos, this markedly changes how nerve cells develop (e.g., their growth) and how they behave (e.g., no longer able to change in ways thought necessary for learning). This is mirrored at the level of animal behaviour, animals being 'stuck' and unable to adapt to changes in their environment. Scientifically, this is exciting; though in view of climate change, observing the dramatic, lasting effects that a difference of a few degrees can have on nervous system development and animal behaviour, is quite alarming. We now plan to use the advantages of this highly tractable experimental system to identify the mechanisms by which transient critical periods specify important nerve cell properties (Objective 1).Second, we will investigate how it is that transient experiences can have lasting effects. This is currently not understood, though our preliminary data point to epigenetic mechanisms as a means of changing and maintaining changes in gene expression. In summary, we have identified a simplified, but powerful experimental model system with which to investigate fundamental questions that important to our general understanding of nervous system development. The mechanisms involved are almost certainly conserved. The output from this work is therefore likely to have impact in both clinical as well as ecological settings.