Mechanisms of plasticity specification during an embryonic critical period.

在形成时期的短暂经历，被称为“关键时期”，对我们的大脑功能有持久的影响。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，这决定了神经网络的表现。重要的是，在关键时期发生的错误往往会被锁定，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（童年或青春期）出现的网络失调。相反，关键时期的临床干预可能非常有效；例如，关键时期神经元活动的短暂重新平衡可以永久地挽救突变的影响，否则会导致癫痫。因为关键时期对于神经系统是否获得正常功能至关重要，所以我们了解潜在的机制是很重要的。当研究复杂的神经系统时，这些问题非常难以研究，比如哺乳动物的感觉系统，而这些系统迄今为止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Richard Baines教授最近的工作表明，关键时期可能是普遍现象，包括昆虫在内的所有神经系统都存在。基于他们的发现，我们已经在果蝇的神经肌肉连接（神经-肌肉连接）中发现了一个明确的关键时期。这有许多优点，包括相对较大，以及易于访问和操作。通过许多实验室的工作（在其他情况下），我们现在可以在这些坚实的基础上进一步发展，并取得快速进展。例如，我们已经发现，以前研究过的几种形式的神经元可塑性（允许神经系统调节和学习的机制）是由胚胎发生后期的短暂关键时期经历调节的，有些在短暂的胚胎经历后被禁用。为了说明这一点，我们选择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，如果在胚胎后期的几个小时内短暂经历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）和行为方式（例如，不再能够以学习所必需的方式改变）。这反映在动物行为的层面上，动物被“卡住”了，无法适应环境的变化。科学地说，这是令人兴奋的；虽然考虑到气候变化，但观察到几度的差异对神经系统发育和动物行为所产生的巨大而持久的影响，是相当令人震惊的。我们现在计划利用这个高度易于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特性的机制（目标1）。其次，我们将研究短暂的经历是如何产生持久影响的。虽然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，但目前尚不清楚这一点。总之，我们已经确定了一个简化但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。所涉及的机制几乎肯定是保守的。因此，这项工作的结果可能对临床和生态环境都有影响。

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.