Layer 1 interneurons as master regulators of prefrontal cortex circuit development

大脑包含数百种单独的细胞类型，它们必须连接在一起才能形成正常的功能网络。如果这个过程正常发生，它会提高我们学习、感知、移动、计划和推理的能力。在这一过程失败的情况下，它可能会导致毁灭性的神经发育障碍，如自闭症和精神分裂症。为了了解大脑的发育，我们必须创建一个不同年龄的大脑的接线图，并弄清楚它何时以及如何变化。这项提议旨在通过观察关键细胞类型如何在精确的发育时期调节电路形成来确定两者。大脑成熟的时间很重要，因为在不同的大脑结构中，大脑成熟的速度不同。青春期与我们从事抽象思维、逻辑和计划等更高层次认知任务的能力的出现有关。这与大脑前额叶皮质区域的电路变化不谋而合。尽管我们有重要的证据表明前额叶皮质在青春期发生变化，但我们仍然不清楚这种变化是如何发生的。根据我和其他人之前的研究，我预测某些关键细胞类型可能是前额叶皮质发育的主要调节因素。这些细胞被称为第一层中间神经元，并显示独特的连接模式，使它们能够控制本地电路中大量细胞的活动。这种连接被预测为帮助第一层中间神经元调节前额叶皮质网络的各个组成部分之间的连接，称为突触的形成。这表明，如果我们在前额叶皮质发育的关键时期，如青春期，破坏L1中间神经元在网络中发挥正常作用的能力，将导致前额叶皮质网络形成和功能的长期变化。这些细胞类型对大量神经元的潜在强大影响导致了我的假设，即这些细胞作为前额叶皮质局部发育的速度和大小的主要调节细胞。在BBSRC的这项建议中，我将通过结合一系列复杂的遗传工具来测试这一假设，以激活或沉默青春期L1中间神经元的活动，并确定对前额叶皮质局部和远程回路的影响。这些研究的发现将加强我们对健康衰老过程中正常大脑发育背后的机制的理解。通过揭示这些新细胞类型调节前额叶皮质成熟的潜力，我们还将揭示新的治疗靶点，可用于控制神经发育障碍患者前额叶回路的成熟，帮助恢复正常的网络成熟和功能。因此，这项工作有望在我们理解这一重要大脑区域的成熟方面取得关键进展。

The brain contains many hundreds of individual cell types which must be connected together to form a normal functional network. If this process occurs normally, it gives rise to our ability to learn, to sense, to move, to plan and to reason. In instances where this process fails it can give rise to devastating neurodevelopmental disorders, such as autism and schizophrenia. To understand brain development we must create a wiring diagram of the brain at different ages and figure out when and how it changes. This proposal aims to determine both by looking at how key cell types regulate circuit formation during precise periods of development. The when is important because brain maturation occurs at different speeds in different brain structures. The period of adolescence is linked to the emergence of our ability to engage in higher-level cognitive tasks such as abstract thought, logic and planning. This coincides with changes in the circuitry of a brain region called the prefrontal cortex. Although we have significant evidence to suggest that the prefrontal cortex changes during adolescence, we still do not understand how this occurs. Based on previous studies by myself and others I predict that certain key cell types may function as master regulators of development within the prefrontal cortex. These cells are known as layer 1 interneurons and display unique connectivity patterns that allow them to control the activity of a huge number of cells within the local circuit. This connectivity is predicted to help layer 1 interneurons regulate the formation of connections, termed synapses, between individual components of the prefrontal cortex network. This suggests that if we disrupt the ability of L1 interneurons to perform their normal role in the network during key periods of prefrontal cortex development, such as adolescence, it will cause long-term changes to prefrontal cortex network formation and function. The potentially powerful influence of these cell types over a large number of neurons has led to my hypothesis that these cells function as master regulators of the rate and magnitude of prefrontal cortex local development.In this BBSRC proposal I will test this hypothesis by combining an array of sophisticated genetic tools to either activate or silence the activity of L1 interneurons during adolescence and determine the impact on the local and long-range circuits of the prefrontal cortex. The findings that emerge from these studies will strengthen our understanding of the mechanisms behind normal brain development during healthy ageing. By shedding light on the potential of these novel cell types to regulate prefrontal cortex maturation, we will also reveal new therapeutic targets that could be used to control the maturation of prefrontal circuits in patients suffering from neurodevelopmental disorders, helping to restore normal network maturation and function. This work is therefore poised to make key advances in our understanding of the maturation of this important brain region.