Integration strategies of GABAergic interneuron subtypes in the normal and dysfunctional neonatal cerebral cortex

我们的大脑对我们是谁是根本-管理过程，如学习，记忆和语言，这些行动的中心是一个巨大的细胞阵列，其多样性已被证明是我们理解大脑功能和功能障碍的障碍。解决这个难题的一种方法是调查并尝试理解控制发育中的大脑的规则，因为这为我们大脑惊人的处理能力奠定了基础。然而，即使在这个阶段，在所有争夺位置的神经细胞中，发育中的大脑中的单个神经细胞如何知道该去哪里，以及它应该与哪些其他神经细胞形成连接？毕竟，某些细胞类型不能做到这一点往往会导致行为方面的可怕后果，并被认为是癫痫、精神分裂症和自闭症等几种严重神经系统疾病的基础。目前，我们将前脑中的神经细胞分为两类：兴奋性锥体细胞和称为中间神经元的局部抑制性神经细胞。虽然后者只是大脑细胞总数的一小部分，但它们对正常功能至关重要。这个建议的基础是一种新的方法，依赖于遗传学的力量来询问中间神经元对大脑活动的贡献，并在复制与精神分裂症相关的一些分子缺陷的模型中剖析它们何时以及如何出错。目的：了解简单的早期大脑，这将（1）为更复杂的成熟大脑建立一套规则;（2）为更好地理解这些与中间神经元相关的神经系统疾病提供基础。由于发育中的大脑的动态性质和靶向特定细胞的困难，这种方法在过去很难实现。为了克服这一点，我们将利用对细胞身份至关重要的基因。我们最近的研究结果表明，细胞的命运在胚胎早期就被指定为对遗传密码的响应，遗传密码通过级联检查点产生成人中存在的多样性。我们已经开始破解这个密码，现在能够确定中间神经元在何时何地诞生。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，我们对特定类别的中间神经元如何在新生儿大脑中发挥作用的知识有限。这一点很重要，因为精神分裂症等几种神经系统疾病与一种或两种细胞类型的缺陷有关。使用我们已经知道的代码位，我们可以一次又一次地识别相同的细胞，更有效地定位我们的研究，并提出关于选择中间神经元对发育中的大脑的作用的重要问题。我们拥有记录单个细胞的技术，并将它们的活动与周围大脑区域的活动联系起来。我们希望利用我们的策略来跟踪某些细胞，揭示它们对早期大脑功能的贡献，并揭示这些细胞是如何以及何时被引导承担特定角色的。我们的初步数据表明，在出生后早期的一个关键窗口期，在此期间，我们可能能够使用药理学或基于细胞的治疗手段进行干预，以恢复一定程度的正常性的新兴功能网络。通过进一步解决这个问题，我们将有基石来更详细地探索新生儿大脑，了解胚胎中的一个简单细胞层如何成熟为令人惊讶的复杂成人大脑，并可能为新型治疗干预打开大门，这些干预措施可以缓解一系列与中间神经元缺陷相关的神经发育状况。

Our brains are fundamental to whom we are - governing processes such as learning, memory and language, and central to these actions is a huge array of cells whose diversity has proven to be an obstacle to our understanding of brain function and conversely dysfunction. One approach to resolving this conundrum is to investigate and try and understand the rules that govern the developing brain as this lays the foundation for the amazing processing power of our brains. Yet even at this stage, amongst all nerve cells jostling for position how does an individual nerve cell in the developing brain know where to go and which other nerve cells it should form connections to? After all, failure of certain cell types to do just that often results in dire consequences in terms of behaviour and is thought to underpin several severe neurological conditions including epilepsy, schizophrenia and autism. At present we define two categories of nerve cell in the forebrain: excitatory pyramidal cells and local, inhibitory nerve cells termed interneurons. Although the latter are only a minor component of the total number of cells in the brain, they are critical to normal function. The basis of this proposal is a novel approach reliant on the power of genetics to interrogate the contribution of interneurons to emergent brain activity and dissect when and how they might go wrong in models that replicate some of the molecular deficiencies associated with schizophrenia. The purpose: to gain an understanding of the simple, early brain that will (1) establish a set of rules for the more complex mature brain; (2) provide the foundation for a better understanding of these interneuron-related neurological conditions. This approach has proven hard to pursue in the past due to the dynamic nature of the developing brain and the difficulty in targeting specific cells. To overcome this, we will make use of genes crucial for cell identity. Our recent findings have revealed that the fate of a cell is specified early on in the embryo in response to a genetic code, which acts through a cascade of checkpoints to generate the diversity present in the adult. We have begun to crack this code and are now able to pinpoint where and when interneuron are born. Unfortunately from then on the story is still largely incomplete and we have a limited knowledge of how specific classes of interneuron become functional in the newborn brain. This is important because several neurological conditions such as schizophrenia have been linked to deficits in just one or two cell types. Using the bits of code we already know we can identify the same cells time and time again, target our research more effectively and ask important question as to the role of select interneurons to the developing brain. We have the technology to record from individual cells and relate their activity to that of the surrounding brain regions. We hope to use our strategy to follow certain cells, unravel their contribution to early brain function and reveal how and when these cells are directed to assume a particular role. Our initial data points to a critical window early in postnatal life during which we may be able to intervene using either pharmacological or cell based therapy means to restore a degree of normality to the emergent functional network. By resolving this further we will have the cornerstone to probe the newborn brain in more detail, understand how a simple layer of cells in the embryo matures into the amazingly complex adult brain and perhaps open the door to novel therapeutic interventions that could alleviate a range of neurodevelopmental conditions associated with interneuron deficits.