Interrogation of the role of transient interneuron circuits in the development of normal sensory activity in vivo.

我们理解大脑功能的一个主要障碍是，即使是最简单的行为也离不开细胞的多样性和数量。一种方法旨在通过研究控制发育中的大脑的规则来解决这个问题。其理由是，如果我们能够理解早期阶段的生物学过程——为我们大脑惊人的处理能力奠定基础的过程——那么我们也许可以将它们推断到更复杂的成人大脑。这种方法的另一个优点是，它使我们能够研究和剖析遗传和环境对大脑形成的相对贡献，这两者结合起来塑造了个体对世界的独特感知。然而，即使在这些形成阶段，在所有数以百万计的神经细胞中，仍然存在一个问题，即发育中的大脑中的单个神经细胞如何知道去哪里，以及它应该与哪些其他神经细胞形成连接？一种特殊的细胞类型-局部，抑制性神经细胞被称为中间神经元，面临着艰巨的任务，因为它们的起源与它们最终的功能位置完全不同。为了解决这个问题，这些细胞迁移和整合到正确的大脑回路中似乎主要是由遗传事件控制的。本质上，它们代表了电路的“硬连线”组件。正在进行的实验室研究表明情况确实如此。我们利用遗传学的力量来研究中间神经元对紧急大脑回路的贡献，通过这些研究揭示了中间神经元的某些亚型作为发育中的大脑的支架，限制了环境的影响，因此无论我们的早期生活经历如何，如果我们有正确的遗传程序，我们的大脑最终都会变得“正常”。此外，就像支架一样，这些特定的中间神经元回路是短暂的，所以我们不能在成人大脑中研究它们。不幸的是，从那时起，这个故事在很大程度上仍然是不完整的，我们对这些中间神经元在新生儿大脑中的实际功能的了解有限。我们认为解决这个问题至关重要，因为这个活动为我们随后的所有认知发展奠定了基础。因此，我们想确定(1)在正常大脑中，中间神经元对形成性大脑活动的确切贡献。我们想看看我们的支架中间神经元是否会随着大脑的发育而改变功能；我们想测试一下这个支架是否至关重要。我们将通过阻断支架的形成来实现这一目标，通过遗传学在发育早期促进成熟的大脑状态；(3)通过发展和评估对网络成熟的影响，在离散阶段直接改变暂态网络的性能。我们相信，后者将证明这种早期瞬态神经元中间回路对正常大脑发育的重要性。

A major obstacle to our understanding of brain function is the sheer diversity and number of cells that contribute to even the simplest of behaviours. One approach aims to tackle this problem by investigating the rules that govern the developing brain. The reasoning being that if we can understand the biology going on at early stages - processes that lay the foundations for the amazing processing power of our brains - then we can perhaps extrapolate them to the more complex adult brain. A further advantage of this approach is that it allows us to study and dissect the relative contribution of genetics and environment on brain formation, both of which combine to sculpt an individual's unique perception of the world. Yet even at these formative stages, amongst all the millions of nerve cells jostling for position there remains the question as to how an individual nerve cell in the developing brain know where to go and which other nerve cells it should form connections to? One particular cell type - local, inhibitory nerve cells termed interneurons, face a monumental task as their origin is completely distinct from their eventual site of function. To get round this challenge it appears that the migration and integration of these cells into the correct brain circuits is governed largely by genetic events. In essence they represent 'hard-wired' components of the circuit. Ongoing studies in the lab suggest that this is the case. We have used the power of genetics to interrogate the contribution of interneurons to emergent brain circuits and through these studies have revealed that certain subtypes of interneuron act as a scaffold for the developing brain, constraining the impact of the environment so that no matter what our early life experience are, should we have the right genetic programmes, our brain will end up with being 'normal'. Moreover just like a scaffold these particular interneuron circuits are transient and so we cannot study them in the adult brain. Unfortunately from then on the story is still largely incomplete and we have a limited knowledge of what function these interneurons actually have in the newborn brain. We believe that resolving this is critically important because this activity lays the foundation for all of our subsequent cognitive development. As such we want to determine (1) the exact contribution of interneurons to formative brain activity in the normal brain. We want to see if our scaffold interneurons change function as the brain develops; (2) we want to test if this scaffold is critical. We will achieve this by blocking formation of the scaffold by using genetics to promote the mature brain state earlier in development; before (3) altering directly the performance of the transient network at discrete stages through development and assessing the consequences on network maturation. Our belief is that the latter will demonstrate the importance of this early transient interneuron circuit to normal brain development.