Toward Whole-Body Connectomics

Abstract

Recent advances in neuro-technologies have revolutionized knowledge of brain structure and functions. Governments and private organizations worldwide have initiated several large-scale brain connectome projects, to further understand how the brain works at the systems levels. Most recent projects focus on only brain neurons, with the exception of an early effort to reconstruct the 302 neurons that comprise the whole body of the small worm, Caenorhabditis elegans However, to fully elucidate the neural circuitry of complex behavior, it is crucial to understand brain interactions with the whole body, which can be achieved only by mapping the whole-body connectome. In this article, we discuss the current state of connectomics study, focusing on novel optical approaches and related imaging technologies. We also discuss the challenges encountered by scientists who endeavor to map these whole-body connectomes in large animals.

Figure 1.

Diverse neurons forming mushroom bodies in the Drosophila brain. The mushroom body is comprised of three major types of intrinsic Kenyon cells (light blue), with dendrites forming calyx and axons forming γ, α′/β′, and α/β lobes. Two large modulatory neurons (yellow), anterior paired lateral and dorsal paired medial, innervate all mushroom body lobes. Each lobe is subdivided into consecutive domains, which are innervated by dopaminergic input neurons (magenta) output neurons (green), and some neurons with both axons and dendrites connecting between two mushroom body domains (dark blue). Assembling the intersections between Kenyon cells and other cells reveals an intricate mushroom body circuit (top). All neuron images were derived from FlyCircuit database.

Figure 2.

Optogenetic mapping of whole-body neural-behavioral circuits in Drosophila. A, Laser (593.5 nm) activation of a small group of brain neurons initiates backward walking behavior in a VT50660-Gal4>UAS-ReaChR fly fed with 100 μm all-trans-retinal. B, The whole-body anatomy (250 μm thick) reveals several brain neurons (green) extending axons to the thoracic muscles in the VT50660-Gal4>UAS-mko;z-disc::GFP fly. Red represents muscle. Gray represents body and tracheal cuticle stained by Congo red dye. Scale bar, 500 μm.

Figure 3.

Steps toward brain simulation. Raw images first undergo complex image processing, followed by tracing and segmentation of single neurons. The data are then analyzed and stored in a database, which contains information at the neuronal, circuitry, and system levels. The data can then be used for network analyses, as well as model construction, which form the foundation for large-scale brain simulations. These computer simulations and network analyses may inspire novel technologies in neuromorphic computing and provide insight into neural circuit mechanisms of brain functions and associated disorders.