The emergence and plasticity of a balance between excitation and inhibition along dendrites

大脑中的单个神经元可以接收来自数千个其他神经元的信号。每一个信号到达特定的部位，称为突触，这些突触分布在一个称为树突的树状结构上。然后，每个神经元必须根据这些输入信号决定是否生成自己的输出信号。因此，神经元对输入信号的整合对于确定信息如何流经大脑至关重要。然而，最近的证据表明，并非所有的突触都是一样的。突触的强度，即其影响输出信号生成的能力，可以根据树突上的位置而变化。更值得注意的是，神经元接受两种类型的输入：促进输出的兴奋性信号和阻止输出的抑制性信号。因此，神经元的行为受到这两种相反力量在空间和时间上如何相互作用的精确调节。不正确的平衡可能是癫痫、自闭症和精神分裂症等许多神经系统疾病的基础，这一事实强调了在兴奋和抑制之间建立和保持正确平衡的重要性。然而，我们对兴奋性和抑制性突触如何在成熟大脑的神经元中分布以及它们之间的相互作用如何影响神经元输出知之甚少。我们对兴奋性和抑制性突触的空间关系是如何随着大脑中神经元在发育过程中的连接而建立的，也不知道它们是如何随着动物生长而受到的感官体验的调节。这一点尤其重要，因为许多神经系统疾病是由于大脑发育异常而引起的。在这个提议中，我们将设计小鼠大脑中的神经元，使其表达不同颜色的荧光标记，以标记兴奋性和抑制性突触。这将使我们能够在单个神经元中可视化这两种类型的突触是如何分布的，以及这种分布在大脑布线过程中是如何发展的。我们还将研究兴奋性和抑制性输入的分布如何响应于导致神经元活动变化的经验（在这种情况下是视觉输入）的慢性变化而变化。这些荧光标记物也将作为一种指导，使我们能够选择性地激活已识别的突触，并提出具体的问题-刺激单个兴奋性突触如何影响神经元的活动，以及当邻近或远处的抑制性突触也活跃时，这种变化如何？这些研究将为神经元和回路如何发育以及兴奋性和抑制性信号如何整合到健康大脑中提供重要的见解。反过来，这将为在神经系统疾病模型中研究这些过程奠定基础。

A single neuron in the brain can receive signals from thousands of other neurons. Each signal arrives at specialised sites, known as synapses that are distributed across a tree-like structure known as the dendrite. Every neuron must then decide, based on these incoming signals, whether or not to generate an output signal of its own. The integration of input signals by a neuron is therefore crucial for determining how information flows through the brain. Recent evidence has shown than not all synapses are alike however. The strength of a synapse, i.e. its ability to influence the generation of an output signal, can vary according to position on the dendrite. What's more remarkable though is that neurons receive two types of input: excitatory signals that promote output, and inhibitory signals that prevent it. The behaviour of a neuron is therefore precisely regulated by how these two opposing forces interact with one another in space and time. The importance of developing and maintaining a correct balance between excitation and inhibition is underscored by the fact that an incorrect balance may underlie many neurological disorders such as epilepsy, autism and schizophrenia. However, we know very little about precisely how excitatory and inhibitory synapses are distributed across neurons in the mature brain or how the interaction between them influences neuronal output. We know even less about how the spatial relationship of excitatory and inhibitory synapses is established as the neurons in the brain wire up during development nor how they are adjusted the sensory experience the animal is subjected to as they grow. This is particularly important given that many neurological disorders arise as a consequence of abnormal brain development. In this proposal we will engineer neurons in the mouse brain to express fluorescent markers of different colours to label excitatory and inhibitory synapses. This will allow us to visualize, in a single neuron, how both types of synapse are distributed and how this distribution develops during the wiring of the brain. We will also examine how the distribution of excitatory and inhibitory inputs changes in response to chronic changes in experience (in this case visual input) that results in changes in the activity of neurons. These fluorescent markers will also serve as a guide that will allow us to selectively activate identified synapses and ask specific questions - how does stimulation of single excitatory synapse influence the activity of a neuron and how does this change when neighbouring or distant inhibitory synapses are also active? These studies will provide important insight into how neurons and circuits develop and how excitatory and inhibitory signals are integrated in the healthy brain. This, in-turn, will lay the foundations for studying these processes in models of neurological disorders.