Circuit and stage specific rules for activity in neuronal wiring

在发育过程中，大脑是如何连接起来的？大脑的活动又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研究，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，不同且独特的神经元也会形成不同且独特的连接。在这个提案中，我们建议不同类型的活动将以特定的电路方式在开发过程中的特定时期或“时间窗口”运行，而不是“一刀切”的布线规则。我们将重点关注大脑中被称为海马体的部分，由于它在学习、记忆和空间导航方面的关键作用，长期以来一直吸引着研究人员。在早期发育阶段，在感官体验开始之前，大脑会产生自己的“活动”。甚至在突触（神经元之间的连接）形成之前，神经元就会释放神经递质，比如兴奋性递质谷氨酸。它们也表现出自发放电或电压变化，通常在群体中同步。我们的目标是确定哪些类型的活动对突触连接的形成和神经元精细分支过程的形成是重要的，在哪个发育阶段操作，并了解这如何取决于海马体中的特定连接或回路。我们将能够使用转基因小鼠系和病毒靶向来精确控制发育中的海马回路中不同类型活动阻断的时间和位置。然后，我们将能够对神经元进行3D成像，以评估这些操作对神经元形状和突触密度的影响，并记录这些突触的电信号。阐明控制特定回路形成的具体规则将有助于我们了解这些回路在成年期的功能，并将对我们如何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.