TIRANT: A novel transsynaptic labeling approach to map neuronal circuits

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The brain is more than the sum of its parts. Truly understanding the brain's most intricate properties requires both a census of the types of neurons it contains and a map of how these parts are interconnected to form functional circuits. It is estimated that several hundred types of neurons compose the mammalian brain, each embedded within complex circuits. The challenge of our generation consists of mapping the connection between these neuronal populations. Current approaches to map circuits have limitations that prevent their widespread adoption and their use in high-throughput experiments. We propose a novel transsynaptic labelling approach that will enable the mapping of interconnected neuronal populations through the binding of a genetically-encoded ligand to a synthetic receptor across the synaptic cleft. This method will allow genetic targeting of the pre- and post-synaptic components of neuronal circuits, and thus facilitates the investigation of circuit function. We will demonstrate the usefulness of our approach by mapping the transsynaptic connections of two distinct neuronal populations projecting to the nucleus accumbens, a structure critical to reward processing. The impact of this proposal extends beyond the understanding of the reward circuitry and provide a new toolset to accomplish the daunting task of mapping the brain's neuronal circuits.