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Connecting the dots

Building brains from the bottom up

The human brain, with over 100 billion connections, is a truly remarkable organ that has piqued the interest of researchers worldwide. Huge amounts of funding and resources go into studying the brain. Projects such as the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative in the U.S., and McGill’s Big Brain project are aimed at developing further understanding of the underlying structure and function of the brain.

The scientists in the Neural Circuit Formation Lab at McGill are among those studying the mysteries of the brain. Brian Chen and his lab work to decipher the ‘instructions’ underlying the formation of neural circuits by uncovering different molecules and strategies used by the brain to build neural connections. Through developing an understanding of how these elements work, these researchers hope to offer insights into how genes can malfunction and disrupt the brain’s wiring – with the ultimate goal of ‘building a brain.’

The lab uses the fruit fly as the model of choice due to the fact that many of its behaviours have been hard-wired through years of evolution. Research is done under the assumption that a hard-wired behaviour is likely to be ‘predestined,’ meaning that it has been written into the genome. By manipulating genetics and observing subsequent changes in behaviours, researchers can map out the underlying circuitry of the brain. Fruit flies are easy models to manipulate, but the lab also studies mammalian nervous systems, such as mice and rats, to see how well these discoveries translate to humans.

Both Down syndrome and Fragile X syndrome – two common genetic conditions that often result in developmental delay and impaired cognitive functioning – are associated with excess protein production. A recent finding in the lab, published in Nature Neuroscience this May, points to a potential link between the two disorders. The Fragile X mental retardation protein (FMRP), which is depleted in Fragile X syndrome, was found to bind to a molecule implicated in Down syndrome (Down syndrome cell adhesion molecule, or Dscam). The depletion of FMRP causes elevated levels of Dscam, which have been associated with the altered neural wiring that causes impaired cognitive functioning in both Down syndrome and Fragile X syndrome. The lab is currently investigating these mechanisms further to find out how the changes in protein levels may give rise to these abnormalities.

By manipulating genetics and observing subsequent changes in behaviours, researchers can map out the underlying circuitry of the brain. Chen and the researchers in his lab are working on developing new technologies to improve the ease of research. One of the major projects, a new protein quantification technique, was born out of frustrations that existing techniques were time-consuming and unreliable.

“Our ability to quantitate protein amounts is still in the Dark Ages,” Chen told The Daily. Traditional forms of protein quantification include techniques like Western blotting that require collecting tissue levels from multiple animals, grinding them up, adding a fluorescent molecule that binds to proteins, and observing these using microscopy.

The new model developed by the Chen lab is a much simpler alternative that will hopefully allow researchers to quantify protein levels in live animals. Chen described this technique as a “protein translation reporter.” In simple terms, this technique is uses a fluorescent label that will express itself anytime a protein is produced. By observing the quantities of fluorescence in live cells, scientists would be able to observe a real-time picture of the amount of protein being produced in live animals. The hope for this technique is that it will provide a simpler means of protein quantification that will overcome the shortcomings of current techniques. “I’ve been told that it seems like a lot of my research is formed out of frustration,” admitted Chen.

So how far are scientists from successfully building a self-assembling brain? According to Chen, this is notoriously difficult to predict. With current technologies, we may be an estimated 50 to 60 years away. However, as scientific techniques develop and accelerate progress, that number grows smaller and smaller. It may be closer than we think.