Some say it’s the most complex object in the universe, but just how difficult is it going to be to finally understand how the human brain works?

If we take a purely anatomical view, the numbers become a little daunting. The brain is made up of maybe a hundred billion neurons, 100 trillion connections (synapses), and a 100 billion non-neuronal cells (glia). Our knowledge of the human brain is so sparse that even these numbers have to be taken with a pinch of salt. This is without mention of what’s going on inside the cells with its different neurotransmitters, synaptic vesicles, transport proteins and the unbelievable number of other proteins that allow neurons to function normally.

This complexity is what drives neuroscience research and hints at why treatments for neurological disorders such as Alzheimer’s or schizophrenia lag so far behind that of other conditions: Without understanding how the normal brain is wired we can never know how it can go wrong. The sheer scale, intricacy and complexity of the brain is one of the main reasons why large initiatives like the White House’s BRAIN Initiative are so important – but the magnitude of the task at hand can be daunting.

A recent study from researchers at Harvard University demonstrates just how complicated, densely packed and intricate mammalian brains are, but provides hope that these problems one day may become tractable. The Lichtman lab took an area of the mouse neocortex, the most recently evolved and arguably most complex part of the brain, measuring just 1500 cubic microns and set out to reconstruct every 3-dimensional object in this area.

To do this, the piece of tissue was cut into impossibly thin sections measuring of 29 nanometres. To put this into context, a standard piece of paper of paper is around 100 microns (or 0.1 millimeters) thick, you would have to slice that piece of paper into about 3,448 sections to get slices of the same thickness. Each of these brain sections was then imaged with a scanning electron microscope, which blasts a beam of electrons at the sections measuring how they are scattered when they come into contact with the sample.

2,250 sections later, the tiny piece of mouse brain was digitally reconstructed. For this reconstruction the authors had to design new ways to analyze the imaging data, and they have made these techniques freely available to other researchers. This means other groups will now be able to tackle similar problems on a larger scale.

This is not to say that this was a mere proof of principle study, even understanding tiny area can give us important information about how the brain works. Just by looking at the roughly 1,600 fragments of neurons and 1,700 connections, they were able to solve a fundamental problem in neuroanatomy. They showed that when neurons form connections with each other, they do not just make contact with whoever happens to be their neighbor, they can ignore those cells closest to them and seek out a more appropriate wiring partner somewhere else.

What about mapping the whole brain though, is all lost, is it just too large and complicated to tackle? Indeed, it would take an incredible amount of time to reconstruct an entire mouse brain – it took six years for this tiny fragment, and the mouse brain is obviously much smaller than that of a human. But there are several reasons for hope.

First, the technology used in this study is advancing all the time, meaning that future investigations can advance more quickly. Second, and perhaps more importantly, it’s likely not necessary to reconstruct the entire brain in such exquisite detail. The principles of connectivity and structural features that this study unveiled will likely be applicable to many other parts of the brain – meaning that future studies can take a broader look at neuroanatomy.

It may have only been 1,500 cubic microns, but it represents a great chunk of progress in understanding brain connections.

References

Abbott, A. (2015). Crumb of mouse brain reconstructed in full detail Nature, 524 (7563), 17-17 DOI: 10.1038/nature.2015.18105

Kasthuri, N., Hayworth, K., Berger, D., Schalek, R., Conchello, J., Knowles-Barley, S., Lee, D., Vázquez-Reina, A., Kaynig, V., Jones, T., Roberts, M., Morgan, J., Tapia, J., Seung, H., Roncal, W., Vogelstein, J., Burns, R., Sussman, D., Priebe, C., Pfister, H., & Lichtman, J. (2015). Saturated Reconstruction of a Volume of Neocortex Cell, 162 (3), 648-661 DOI: 10.1016/j.cell.2015.06.054

Ostroff, L., & Zeng, H. (2015). Electron Microscopy at Scale Cell, 162 (3), 474-475 DOI: 10.1016/j.cell.2015.07.031

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