Mapping the Whole Mouse Brain with Electron Microscopy
Do we really need to map the entire brain with electron microscopy?
Yes. Given the dense inter-connectedness of the brain and the thinness of individual neural wires (which can be less than 50 nm in diameter), the importance of whole-brain electron microscopy mapping cannot be over-emphasized and is, in fact, necessary in order to make sense of behaviorally-relevant computations in even small sub-volumes (since neuromodulation, arising from distant sources, is a crucial determinant of network computations).
The Road to the Circuit Diagram of the Whole Brain
The path to mapping the complete circuit of the whole mouse brain is shown in the cartoon below.
We have developed the only known methods for preparing the whole mouse brain (and other small mammalian brains) for electron microscopy. Here is an example of what a stained whole mouse brain embedded in plastic looks like:
And here is what an X-ray microCT of that brain looks like:
We are currently working on imaging one of these brains in its entirety with high-throughput 91-beam scanning electron microscopy in order to determine the precise neural circuitry of a mammalian brain. We are working on whole-brain volume electron microscopy acquisition using Serial Blockface Electron Microscopy (SBEM) with a specially-designed whole-brain microtome (WBM).
Automated Circuit Reconstruction
The whole mouse brain will be mapped ultrastructurally at the single-synapse level in the near future. This will open the door to the unsolved problems of reliable automated segmentation and circuit reconstruction, which will require substantial advances in machine learning and computer vision.
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