Connection has been made!

In his book “The Collapse of the Chaos: Discovering Simplicity in a Complex World” Ian Steward says that “If our brains were simple enough for us to understand them, we'd be so simple that we couldn't.” Even if the British mathematician is right, we might have just got one step closer to unravelling the importance of single junctions between neurons. A team led by William Schafer at the MRC Laboratory of Molecular Biology in Cambridge, UK, has just achieved what can be called a first worm neuron hack.

Nervous system of both nematode Caenorhabditis elegans which was used as a model organism and man consists of a network of interconnected neurons. The junctions between neurons, called synapses, can be divided into two types - electrical and chemical - based on the way they transmit the signal. While chemical synapses are composed of hundreds of different types of proteins, electrical ones are relatively simple – they are formed by channels linking adjacent cells, made by just one kind of protein. Neural network is a highly organized structure and which neurons form synapses is crucially important for appropriate signal propagation within the body.

Doctor Schafer’s team has found the way to introduce controlled changes into this complicated system. The scientists decided to target electrical synapses of C. elegans because of their less complicated nature. They managed to make a contact between two neurons engaged in the worm’s response to increased salt concentration which normally are not connected with each other. In a natural situation, presence of salt increases electrical activity in one of the neurons and decreases it in the other. When a junction between them was made, their responses became synchronised instead and this led to the worm being less sensitive to changes in salt concentration. The new synapse was created as a result of genetic modifications – DNA encoding the protein that builds the electrical junctions subunits was injected into the gonads of the worms. As a consequence, the protein has been expressed in some of the worms from the next generation. To control the specificity of synapse formation scientists used a mouse version of the channel protein. The gap junctions in invertebrates are composed of a different type of proteins than in vertebrates and nonmatching subunits can never form a functional channel. Thus, injecting of mammal connexin 63 under control of promoter specific for the targeted neurons ensured that no other than intended connections were made. The same system can also be used to replace already existing synapse with a different one. The team was able to introduce an electrical junction between two neurons that normally communicate by a chemical link. This time they targeted the cells responsible for the worm being able to detect chemical compounds and move in response to them. When the contact was modified, nature of the transmitted signal changed and the animals were no longer able to respond to benzaldehyde gradient.

The method published in the journal Nature Communications offers new insights into the nervous system functioning. It might answer the questions about what happens when particular synapses are damaged and how wiring patterns shape the activity of the brain. It also opens a possibility of creating of new signal paths by introducing artificially created circuits into the neural network. Modifications described by the team from Cambridge are similar to plugging and unplugging of cables in order to check their importance. The scientists believe that detailed mapping of neural connections is the first step towards new therapies. If we could redirect the signal between human brain cells, we would be able to help people whose neurons got damaged as a result of injury.

So far, experiments of Schafer’s team were focused on C. elegans, which only possess few hundreds of neurons without a centralised brain. In theory however, similar approach could be applied in higher organisms. At present, our understanding of brain is still very limited and we can learn a lot by observing even the simplest model systems. Human brain, of course, is also intensively studied. In 2009, National Institutes of Health launched the Human Connectome Project, aiming to provide a full map of anatomical and functional connections within healthy human brain. Such a detailed dataset will be an excellent baseline for studying the mechanisms of multiple dysfunctions like autism, Alzheimer’s disease and schizophrenia. The project is primarily conducted by two consortia. The first one, led by Washington University in Saint Louis and the University of Minnesota, applies imaging technologies to study human brain in parallel to conducting behavioural studies. The consortium will examine the networks of neural junctions, named connectomes, in brains of 1200 healthy volunteers, including twins and their siblings from 300 families. Data collected from 500 individuals was released in June 2014. The second consortium is led by Harvard University, Massachusetts General Hospital and University of California Los Angeles. Their studies base on the MRI imaging technology and aim to improve the resolution, quality and speed of currently available technology. Both consortia are in close collaboration and share collected data.

Undoubtedly, human brain is the most fascinating and mysterious part of our body. It is also extremely complex and as such, we might never fully understand the connection between its anatomy and function, at least not at a single synapse level. However, since neurons often work as groups, even less accurate knowledge might prove sufficient to solve some of the brains mysteries and give hope for advances in brain damage treatments.

Anna Oszmiana
 

Resources:

1. Rabinowitch et al., Nature Communications 2014, 5, Article number: 4442, available at: http://www.nature.com/ncomms/2014/140716/ncomms5442/full/ncomms5442.html#compounds
2. New Scientist: http://www.newscientist.com/article/mg22329792.300-worm-neuron-hack-to-probe-the-mysteries-of-our-brains.html#.U9kRyfldWRc
3. http://www.humanconnectomeproject.org/
4. http://www.humanconnectome.org/