  Mammalian whole-brain connectomes are a crucial ingredient for holistic
understanding of brain function. Imaging these connectomes at sufficient
resolution to densely reconstruct cellular morphology and synapses represents a
longstanding goal in neuroscience. Although the technologies needed to
reconstruct whole-brain connectomes have not yet reached full maturity, they
are advancing rapidly enough that the mouse brain might be within reach in the
near future. Human connectomes remain a more distant goal. Here, we
quantitatively compare existing and emerging imaging technologies that have
potential to enable whole-brain mammalian connectomics. We perform calculations
on electron microscopy (EM) techniques and expansion microscopy coupled with
light-sheet fluorescence microscopy (ExLSFM) methods. We consider techniques
from the literature that have sufficiently high resolution to identify all
synapses and sufficiently high speed to be relevant for whole mammalian brains.
Each imaging modality comes with benefits and drawbacks, so we suggest that
attacking the problem through multiple approaches could yield the best
outcomes. We offer this analysis as a resource for those considering how to
organize efforts towards imaging whole-brain mammalian connectomes.
