Connectivity between neurons is central to nervous system function; on a more personal level, the unique connections within our brains may be what contribute to our individuality. The emerging field of connectomics seeks to gather and analyze information about neural connectivity so as to improve our understanding of the brain [1]. The initial goals of connectomics are similar to those of Google Earth: if you think of each neuron as an address, the goal of connectomics is to first understand the various routes between addresses, and then how they all come together to form one large map [2]. This three-dimensional “map” at the heart of connectomics is the “connectome,” a complete description of the connections between neurons in an organism’s nervous system. Neuroscientists hope that obtaining detailed information about how neurons are wired will give us a clearer picture of the functioning of the healthy brain, a complex organ that some liken to a bowl of spaghetti [3, 4]. With this information, we may someday be able to treat diseases that arise from misconnections in the brain.
Of worms and fruit flies
The neuron is the basic functional unit of the nervous system. This cell has three major parts that make up its beautiful, branched structure: the cell body, or soma, where metabolic activity occurs; branched extensions called dendrites, which receive information from other neurons; and a long extension called the axon, which transmits information to other neurons (see Figure 1 for a diagram; Figure 2 for an image of actual neurons). The small gap through which information flows from the axon of one neuron to a dendrite or cell body of another neuron is called the synapse. Since each human neuron can form multiple “connections,” you can imagine how complex a connectome can be — and how challenging it is to assemble one!
Figure 1. The basic structure of a neuron, with its dendrites and axon indicated (click image to expand). Information flows from one neuron to another at the synapse. From National Institute on Aging / National Institutes of Health (http://www.nia.nih.gov/Alzheimers/Publications/LaEnfermedaddeAlzheimer/Parte1/neuronas.htm).
Figure 2. Two actual neurons from the thalamus that have been filled with a fluorescent dye. The axon has been drawn in for clarity. From National Institute on Drug Abuse / National Institutes of Health (http://www.nida.nih.gov/pubs/teaching/teaching2/Teaching2.html).
So far, the only organism with a completely mapped connectome is the nematode worm Caenorhabditis elegans. This worm is tiny — an adult is about 1 mm long, roughly the size of a pinhead — but its nervous system is complex enough that its connectome took a team of neuroscientists, led by Nobel laureate Dr. Sydney Brenner, over a decade to compile [1, 5]. Using images obtained from an electron microscope, they reconstructed, by hand, a wiring diagram of the worm’s 302 neurons (all C. elegans worms always have the same number).
Building on that experience, neuroscientists are currently using more advanced methods to generate the connectomes of more complex model organisms. Just last month, a group in Taiwan released a brain atlas of the fruit fly (Drosophila melanogaster), which was obtained by imaging 16,000 randomly labeled neurons [6, 7]. After assembling these into 3-D images on a computer, they identified 41 distinct brain regions, called local processing units (LPUs), that connect to each other via long-range projection neurons. Though this brain atlas covers just a fraction of a fruit fly’s 100,000 neurons, and the LPU data produce only a crude wiring diagram, it is a very encouraging step in elucidating the complete fruit fly connectome. Because many parallels exist between fruit fly and mammalian brains, building connectomes of these model organisms helps scientists better understand how our own brains are assembled and function.
How do you build a mammalian connectome?
Naturally, we are most curious about the connectome of the human brain. So how do we build one? A complete connectome requires information at different resolutions, including the local synapses within a brain region, as well as long-range connections between different brain regions [8].
Cataloging individual neurons and their synapses is tricky, and current methods only allow information to be gathered from non-living tissues. Since the human brain contains at least 100 billion neurons, researchers are first tackling the mouse brain, which is comparatively less daunting with “only” 100 million neurons [3] (still a monumental task!). To build the mouse connectome, Jeff Lichtman and his colleagues at Harvard have begun to cut mouse brains into thin slices, acquire a 2-D image of each slice using an electron microscope, and put these images back together on a computer to create a 3-D model of the mouse brain. Although automating this method can speed up the process, handling the data they gather will be a huge challenge — scientists will require millions of terabytes of computer memory to process, analyze, and store their images [4].
Meanwhile, the National Institutes of Health (NIH) recently awarded $40 million over the next 5 years to fund the Human Connectome Project (HCP) [9]. The HCP is primarily interested in the long-range connections between different brain regions, which provide a more global view of brain connectivity. Researchers at Harvard/Massachusetts General Hospital and UCLA are making improvements to current magnetic resonance imaging (MRI) techniques, and are working together with collaborators from Washington University in St. Louis and the University of Minnesota to trace bundles of axons within hundreds of live, healthy adult human brains. While the resolution of these images will not be detailed enough to view individual synapses, these data will ultimately provide a valuable foundation for future efforts to map the human connectome at the synaptic level.
Criticisms and implications
As with any large-scale undertaking, connectomics has drawn its share of criticisms — much like the Human Genome Project did in its infancy. One common objection is that with current methods, the connectome only captures a static snapshot of a dynamic brain. How can we understand the relationships between individual neurons if we cannot observe the changes taking place at their synapses? Though this is a valid point, the current understanding among neuroscientists is that the size and shape of a synapse can reflect the strength of the connection between two neurons, so the microscale connectome could be used to predict whether or not a synapse within a neural circuit is active [1]. Furthermore, computational neuroscientists could use the connectome as a template to model brains more realistically and study their function on computers [8]. Throughout the reconstruction of the connectome, however, researchers will indeed have to find some way to account for variations in connectivity, not only between two different individuals, but also within the same individual during various stages of brain development [8].
While the reconstruction of a complete mouse connectome remains years away, and that of a human connectome many more still, the connectome can ultimately help us understand how cognitive function arises from neuronal structure [1]. The connectome could also benefit medicine: scientists suspect that some disorders such as schizophrenia and autism trace back to faulty connections of neurons, rather than their degeneration [1, 4, 8]. By comparing the connectomes of healthy brains and those of patients, we could determine whether these disorders are indeed “connectopathies”, and a better understanding could one day lead to development of more effective treatments. While assembling the connectome certainly requires an enormous amount of effort, untangling this “bowl of spaghetti” may well be a fruitful endeavor.
Emi Ling is a graduate student at Harvard Medical School.
References
[1] Lichtman, J.W., and Sanes, J.R. (2008). Ome sweet ome: what can the genome tell us about the connectome? Current Opinion in Neurobiology, 18 (3), 346-353
[2] Mapping Brain Circuits: The Connectome http://www.sfn.org/index.aspx?pagename=brainBriefings_09_mapping
[3] Seeking the Connectome, a Mental Map, Slice by Slice (New York Times) http://www.nytimes.com/2010/12/28/science/28brain.html
[4] Connectomics: Tracing the Wires of the Brain (Dana Foundation) http://www.dana.org/news/cerebrum/detail.aspx?id=13758
[5] White, J., Southgate, E., Thomson, J., & Brenner, S. (1986). The Structure of the Nervous System of the Nematode Caenorhabditis elegans. Philosophical Transactions of the Royal Society B: Biological Sciences, 314 (1165), 1-340
[6] Decoding the Human Brain, with Help from a Fruit Fly (New York Times) http://www.nytimes.com/2010/12/14/science/14neuron.html
[7] Chiang, A.-S., et al. (2010). Three-Dimensional Reconstruction of Brain-wide Wiring Networks in Drosophila at Single-Cell Resolution. Current Biology, 21 (1), 1-11
[8] Sporns, O., Tononi, G., Kötter, R. (2005) The Human Connectome: A Structural Description of the Human Brain. PLoS Comput Biol 1(4): e42. (Open Access)
[9] Human Connectome Project http://www.humanconnectomeproject.org
Further Reading
Schoonover, Carl. Portraits of the Mind: Visualizing the Brain from Antiquity to the 21st Century. New York: Abrams, 2010.
Sebastian Seung: I Am My Connectome (TED.com) http://www.ted.com/talks/sebastian_seung.html