Analysis of neuronal wiring diagrams

Abstract

To understand how the brain works, one must know its neurons and their connections. Maps of synaptic connections between neurons can be created by acquiring and analyzing electron microscopic (EM) brain images, but until recently, even the largest datasets were insufficient to map full neuronal circuits in most organisms or even small brains. Advances in automated EM image acquisition and analysis have now given rise to neuronal reconstructions of mammalian brain circuits and entire insect brains. Errors in these automated reconstructions must still be corrected through proofreading. This thesis introduces new methods to bridge the gap between automated neuron reconstructions and the analysis of neuronal wiring diagrams. First, it presents a proofreading infrastructure that facilitates correction of whole neurons in up to petascale (∼1mm^3 brain tissue) datasets by communities of scientists and proofreaders. Second, it embeds this proofreading system into an analysis infrastructure to enable queries of the connectome data while it is actively being edited. Third, it presents a self-supervised learning technique for efficient inference of semantic information which is crucial for circuit analyses. These methods have already been used by hundreds of users and enabled numerous neuroscientific analyses. Additionally, this thesis presents the analysis of the largest connectivity map to date between cortical neurons of a defined type (L2/3 pyramidal neurons in mouse visual cortex) which identified constraints on the learning algorithms employed by the cortex. Finally, this thesis reports on the completion of the wiring diagram of the Drosophila melanogaster brain containing ∼130,000 neurons and describes how this work enabled it. The Drosophila connectome was created through a years-long community-based effort and is an incredible resource for the science community and a milestone for connectomics on the way to large mammalian brains. The methods presented in this thesis will be useful for the analysis of larger brain samples as we aim for connectomes of whole mammalian brains.