Circuit and stage specific rules for activity in neuronal wiring

大脑在发育过程中是如何连接的，大脑中的活动是如何控制这一过程的？尽管这个基本问题多年来吸引了大量的调查，但它仍然存在争议，许多数据似乎相互矛盾。然而，即使在给定的大脑区域内，不同和独特的神经元也会建立不同和独特的联系。在这项提议中，我们认为，不同类型的活动将在发育过程中以特定的电路方式在特定的时期或“时间窗”运行，而不是一套“一刀切”的连接规则。我们将专注于大脑中被称为海马体的部分，它长期以来一直吸引着研究人员，因为它在学习、记忆和空间导航中发挥着关键作用。在早期发育过程中，在感觉体验开始之前，大脑会产生自己的“活动”。神经元甚至在突触(神经元之间的连接)形成之前就会释放神经递质，如兴奋性递质谷氨酸。它们还表现出自发放电或电压变化，通常是成组同步的。我们的目标是确定哪些类型的活动对于突触连接的形成和神经元细小分支过程的形成是重要的，这些活动在哪些发育阶段运行，并看看这如何依赖于海马体中的特定连接或电路。我们将能够使用转基因小鼠和病毒靶向来精确控制不同类型活动阻断在海马区发育过程中的时间和位置。然后，我们将能够在3D中对神经元进行成像，以评估这些操作对其形状和形成的突触密度的影响，并记录这些突触的电信号。了解管理特定电路形成的特定规则将有助于我们了解这些电路在成年时是如何发挥作用的，这对于改进我们研究和开发治疗大脑发育障碍的新方法至关重要。

How does the brain wire up during development, and how does activity in the brain govern this process? Although this fundamental question has attracted a huge amount of investigation over many years, it remains controversial, with much data that appears conflicting. However, even within a given brain region, different and distinctive neurons make different and distinctive connections. In this proposal, we suggest that rather than a 'one size fits all' set of rules for wiring, different types of activity will operate at particular periods or 'time windows' during development in a circuit-specific way.We will focus on a part of the brain called the hippocampus, which has long fascinated researchers due to its critical role in learning, memory and spatial navigation. During early development, before the onset of sensory experience, the brain generates its own 'activity'. Neurons release neurotransmitters, such as the excitatory transmitter glutamate, even before synapses (the connections between neurons) are formed. They also exhibit spontaneous firing, or voltage changes, often synchronised in groups. We will aim to identify which types of activity are important for the formation of synaptic connections and the shaping of the finely branched processes of the neuron, operating during which development stages, and see how this depends on the specific connection or circuit in the hippocampus. We will be able to use transgenic mouse lines and viral targeting to precisely control the timing and location of different types of activity blockade in developing hippocampal circuits. We will then be able to image neurons in 3D to assess the impact of these manipulations on their shape and the density of synapses formed onto them, as well as recording the electrical signals of these synapses.Elucidating the specific rules that govern the formation of specific circuits will help us to understand how these circuits function in adulthood, and will be critical for improving how we investigate and develop new treatments for disorders of brain development.