Rapid and automatic serial reconstruction of large tissue volumes, enabled by the recent development of automated electron microscopy techniques, is the method of choice in defining the synaptome. Nevertheless, even using this technology, full reconstruction of whole brains is possible only for relatively simple nervous systems. Indeed, even for a small mammal like the mouse, it is impossible to reconstruct the brain completely at the ultrastructural level, because the magnification needed to visualize synapses yields relatively small images.
For example, it has been estimated that if we were to use sections of about 35 square micrometers (millionths of a meter) at a thickness of 20 nanometers, we would need more than 1.4 billion sections to reconstruct fully just 1mm3 of tissue.
So, while complete reconstructions of a small region of the mammalian brain are feasible, structures like the cerebral cortex — with a surface area of 2.2m2 and a thickness of between 1.5mm and 4.5mm — cannot be fully reconstructed.
Nonetheless, despite the technical difficulties, it should be possible to make spectacular advances in unraveling brain organization, even in humans, by adopting appropriate strategies with the tools now available.
For example, although the synaptic density within a given area and layer may vary, this variability remains within a relatively narrow window, so the statistical distribution of the variation can be modeled. That means that we do not need to reconstruct the entire layer within a given area to determine the absolute number and types of synapses; instead, the range of variability can be determined by multiple sampling of relatively small regions within that area.
By combining these detailed structural data with the incomplete light and electron microscopy wiring diagrams, it could be possible to generate a realistic statistical model, rather than attempting to reconstruct the brain in its entirety.
Computational models of neuronal networks based on real circuits already have become useful tools to study aspects of the functional organization of the brain.
Thus, although a true synaptome of the mammalian brain is a chimerical quest, it is possible that in the near future we will be able to construct a “silicon cortex,” a computerized machine based on a realistic model of the complete anatomical, physiological and molecular design of the cortical circuit.
If we succeed, we will finally be able to see the forest — without having to look for every tree.
Javier DeFelipe is a professor and director of the Laboratorio Cajal de Circuitos Corticales at the Polytechnic University of Madrid and of the Laboratorio de Microorganizacion de la Corteza Cerebral Normal y Alteraciones de los Circuitos at Instituto Cajal in Madrid.
Copyright: Project Syndicate