Comparative prospects of imaging methods for whole-brain mammalian connectomics

Mammalian whole-brain connectomes are a foundational ingredient for a holistic understanding of brains. Indeed, imaging connectomes at sufficient resolution to densely reconstruct cellular morphology and synapses represents a long-standing goal in neuroscience. Mouse connectomes could soon come within reach, while human connectomes remain a more distant yet still worthy goal. Though the technologies needed to reconstruct whole-brain connectomes have not yet reached full maturity, they are advancing rapidly. Close examination of these technologies may help plan connectomics projects. Here, we quantitatively compare imaging technologies that have the potential to enable whole-brain mammalian connectomics. We perform calculations on electron microscopy (EM) techniques and expansion light-sheet fluorescence microscopy (ExLSFM) methods. We consider techniques that have sufficient resolution to identify all synapses and sufficient speed to be relevant for whole mammalian brains. We offer this analysis as a resource for those considering how to organize efforts toward imaging whole-brain mammalian connectomes.