High-throughput mapping of mesoscale connectomes in individual mice

Brain function is determined by connectivity among brain areas, and disruption of this connectivity leads to neuropsychiatric disorders. Understanding connectivity is essential to modern neuroscience, but mesoscale connectivity atlases are currently slow and expensive to generate, exist for few model systems, and require pooling across many brains. Here we present a method, muMAPseq (multisource Multiplexed Analysis of Projections by sequencing), which leverages barcoding and high-throughput sequencing to generate atlases from single animals rapidly and at low cost. We apply muMAPseq to tracing the neocortical connectome of individual mice, and demonstrate high reproducibility, and accuracy. Applying muMAPseq to the mutant BTBR mouse strain, which lacks a corpus callosum, we recapitulate its known connectopathies, and also uncover novel deficits. muMAPseq allows individual laboratories to generate atlases tailored to individuals, disease models, and new model species, and will facilitate quantitative comparative connectomics, permitting examination of how age, sex, environment, genetics and species affect neuronal wiring