Circuit and stage specific rules for activity in neuronal wiring

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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.