By Daan Viering
“We are our brains.” If Dick Swaab is right, we can only discover who we are if we learn more about the complexities of our brain. From macroanatomy to microanatomy and back, scientists continuously invent new techniques to investigate how individual neurons work together to achieve the incredible performances of our brains. Recent advances in this field include methods to activate single neurons with ultrafast and extremely precise lasers (optogenetics) and mapping neuronal projections with help of RNA-sequencing (MAPseq).
From the Renaissance onwards, researchers have discovered much about the macroanatomy of the brain. Anatomical studies combined with functional research in patients with localized brain-damage have revealed the specific function of many different brain areas. Studies on microscopical level, to elucidate the structure and function of individual neurons, started in the very late 19th century. A century thereafter, studies on the function of specific brain areas or specific neurons took a flight with the development of (f)MRI and molecular imaging. However, it is only very recently that we have started to develop methods to study the level between gross brain areas and individual neurons: how small groups of neurons cooperate to fulfil a specific task. What happens at that level?
From neurobiologists to computer scientists, many have expressed their interest towards understanding the mechanisms by which neurons collaborate to produce memory and perform other functions. Large steps in this area were the coming of genetical engineering and protein labelling. With these techniques, a mouse could be genetically altered so it would automatically label one type of protein in one specific cell type of its brain with a fluorescent marker. By clever microscopical detection ex vivo as well as in vivo, scientists could subsequently observe the location and extensiveness of specific types of neurons. Suddenly, if you wanted to know where the neurons reside that secrete the neurotransmitter noradrenalin, it was not so hard to find out anymore.
However, with this last technique, it is not possible to see where the axons of one single neuron lead to. To be able to do this, scientists created a mixture of viruses, in which each virus carried a different piece of RNA. When these viruses were injected into a mouse brain, neurons were infected by the viruses, started to replicate the viral RNA, and thus acquired a unique RNA profile. By dissecting the brain and sequencing each piece, the research group was able to find out where the axons of each infected neuron led to. In this way, they found out that some of the neurons that secrete noradrenalin projected their axons very broadly, while other neurons projected to very specific places in the cortex. They combine known techniques for novel applications to provide another piece of the map that leads us past the complexities of that interesting organ up in our heads.
- Kebschull JM, Garcia da Silva P, Reid AP, Peikon ID, Albeanu DF, Zador AM. High-Throughput Mapping of Single-Neuron Projections by Sequencing of Barcoded RNA. 2016 Aug 17. pii: S0896-6273(16)30421-4. doi:10.1016/j.neuron.2016.07.036. [Epub ahead of print] PubMed PMID: 27545715.