Redesigning brain circuits in development

ongoing

In the pre-optogenetics era, molecular genetics defined the concepts of neural circuit development providing mechanistic insights into axon guidance and synapse assembly. However, this approach often revealed limited insights into the function of the circuits studied. Since 2005, optogenetics has revolutionized our approach to functionally dissect brain circuits and has tremendously increased our understanding of how they contribute to specific behaviours. However, how these circuits assemble during development remains mostly unknown. Here, I propose to combine these two approaches: to genetically redesign specific circuits during mouse development in a predictable fashion, and to test the consequences for innate and learned behaviour. This novel line of research follows concepts of synthetic biology, which aims at reconstructing cellular systems, with the intention of redesigning brain circuits to reroute information processing for new behavioural purposes. We aim to demonstrate that targeted mis-expression of connectivity signals can alter specific neural circuits and communications between circuit components along measurable hypotheses. Activation of such an artificial circuit, by either natural stimuli or optogenetics, is likely to produce a set of behavioural outcomes that will reveal general connectivity rules, the capacity for behavioural plasticity, and possible functional redundancies between circuits. Anatomical and physiological dissection of the redesigned circuit will reveal to what extent the incoming afferents instruct the target cells to produce their output responses. Our focus will be on the amygdala, a forebrain structure necessary for processing aversive and rewarding stimuli and orchestrating behavioural responses, and a brain circuit characterized by a high degree of cellular heterogeneity and interconnectivity. Overall, this work will provide important insights into the principles of developmental circuit wiring in the mammalian brain.