Large Scale Systematic Tract Tracing in the Rodent Brain

Tract tracing studies require a lot of expertise and are tedious to perform. Therefore they are usually hypothesis-driven experiments using the method that appears most suitable to address the specific question. This makes it difficult to compare tracing studies even within the same species. This limitation during could be overcome, however, if the studies could be automated both the experiments and the subsequent analyses. For a large-scale systematic tract tracing study of a substantial part of the brain a number of requirements must be met: 1) Since the transport of at most a few tracer deposits can be analyzed in the same brain there must be a large enough population of brains to study their circuitry including its possible variability. 2) The tracer injections should be made in unbiased locations so that an objective estimate of the circuitry is obtained. Ideally, the entire brain would be divided into voxels of an adequate size and an injection be made in every single one of them. 3) The further processing should be automated as much as possible such that the results can be compared across individual brains. This requires standardized protocols for tissue processing, label detection and 3D reconstruction.

Depending on the size of the injections and the size of the brain one would have to deal with about 100,000 locations even with white matter excluded. Given that each location would need to be studied about three times and that one would want to exclude any ambiguity from injecting several locations at once, this project would seem unlikely to be done in the near future even by large consortia, or by the Allen Brain Institute, which mapped the expression patterns of almost the entire genome in the mouse brain.

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