The development of methods enabling the mapping of all synaptic connections between all neurons comprising an individual mammalian brain would lead to brain-wide circuit reconstructions that precisely define the neuronal networks underlying and responsible for generating the diverse behavioural repertoire for that individual. Recent advances in mouse whole-brain electron microscopic (EM) sample preparation (Mikula & Denk, 2015), multi-beam scanning electron microscopy (mSEM, Kemen et al., 2015), ultramicrotomy and synchrotron X-ray nanoCT (Dyer et al, 2017) have brought us closer to a complete mouse whole-brain cellular connectome.
Several obstacles remain, however. Here, I report on three different approaches using serial section scanning electron microscopy (ssSEM), serial block-face electron microscopy (SBEM) and synchrotron X-ray nano-computed-tomography (nanoCT).
Both ssSEM and SBEM from whole mouse brains indicate that sample membrane contrast and section thickness are sufficient for identifying matching neurites across adjacent slices. Synapses can be readily identified. Quantitative assessments of neurite traceabilty and synapse detection across whole-brain samples indicate that both ssSEM and SBEM are suitable for reconstructing brain-wide circuits.
In contrast to ssSEM and SBEM, both of which require ultramicrotomy to serially-section the sample, synchrotron X-ray nanoCT allows for non-invasively imaging whole brains at the nano-scale. Current resolutions with this method allow for brain-wide cell body detection and the tracing of large myelinated axons, though further improvements in resolution will be required for complete neuronal circuit reconstructions, possibly through the use of brighter light sources and improved iterative back-projection algorithms.

References:
Dyer, E. L., Gray Roncal, W., Prasad, J. A., Fernandes, H. L., Gürsoy, D., De Andrade, V., … Kasthuri, N. (2017). Quantifying Mesoscale Neuroanatomy Using X-Ray Microtomography. ENeuro, 4(5).

 Kemen, T., Malloy, M., Thiel, B., Mikula, S., Denk, W., Dellemann, G., & Zeidler, D. (2015). Further advancing the throughput of a multibeam SEM (Vol. 9424, p. 94241U–94241U–6).

SPIE Advanced Lithography, 2015, San Jose, California, United States
https://doi.org/10.1117/12.2188560

 Mikula, S., & Denk, W. (2015). High-resolution whole-brain staining for electron microscopic circuit reconstruction. Nature Methods, 12(6), 541–546.
https://doi.org/10.1038/nmeth.3361