Synaptic-resolution connectomics: towards large brains and connectomic screening.

Neuronal circuits are the key target of both evolutionary and individual adaptation that enable organisms to successfully navigate, predict and shape their environment. Synaptic-resolution connectomics has the ambition to map neuronal circuits at scale to uncover the phylogenetic and ontogenetic implementations realized across the animal kingdom. The past 20 years have seen an ambitious methodological agenda using large-scale 3D electron microscopy and machine learning that have expanded, by a factor of 1,000, the connectomically accessible volumes at synaptic resolution from about 100 µm3 to about 1 mm3. This implies that the field can now move beyond specialized miniature circuits to a large range of local neuropil in mice, including areas of cortical grey matter. Resolving the local cortical circuits of larger brains, including human, and whole-brain synaptic connectomes of small reptiles, rodents, birds and non-human primates is the next major target. In this Review, the critical methodological innovations in brain tissue preparation, ablation or sectioning, imaging and artificial intelligence-based 3D image analysis are discussed alongside remaining challenges, in particular for connectomic mapping of centimetre-scale circuits such as a whole adult mouse brain. Importantly, these advances at the connectomic frontier are now enabling the multifold mapping of comparably smaller circuits. This will enable connectomic screening for the study of complex interactions between evolutionary determinism, individual experience and behavioural performance, as well as age-dependent and pathological alterations of connectomes.