As should be said repeatedly, we don’t know how the brain works. Not yet. Neuroscience is just starting on the vastly complex study of the brain at the molecular level, perhaps the lowest common denominator and the most important. A new study, published April 15 in Nature, by a team of researchers from Harvard Medical School and Boston Children’s Hospital (USA) is a good case in point.
It’s been known for some time that brain cells, neurons, react to external stimulus (for example, sensory input) at the genetic level. It’s part of the way the brain continues to develop throughout the lifetime of an individual. Learning creates changes in existing neurons, but it also creates new neurons and new connections between neurons. These latter changes are directed by genetics. If a baby gets a finger stuck in the railings of a crib, the sensations not only register in the brain but also start a cascade of effects that ends in a complex learning experience. That experience is recorded in memory, in part, by stimulation of the neuronic genome, which in turn directs the creation of new connections. How this happens has been unknown.
When a stimulus occurs, say by putting your finger in a flame, the neurons involved in sensory interpretation register the effect (‘pain’) by releasing a chemical called a neurotransmitter. The neurotransmitters set in motion a chain reaction in neighboring neurons, part of which affects the genetic activity of the cells. The question is how is this activity affected?
The researchers applied some very recent gene-sequencing technology (ChIP-seq and RNA-seq) to look into mouse brain cells as they register a stimulus. Using RNA-sequencing, they were able to isolate RNA sequences that are created when a neuron is stimulated by a neurotransmitter (or a mimic). Then the RNA sequences were analyzed by ChIP-sequencing (Chromatin ImmunoPrecipitation) to find the genetic location of protein factors that control the expression of genes involved in reacting to the stimulus.
They discovered that there are segments of neuronic DNA that amplify or enhance the genes that produce RNA and protein production needed for making new neurons and neuron connections. These segments, called “enhancer regions” were found to affect genes far away (on the chromosome), much like a broadcast. It was discovered these regions manufactured their own RNA molecules – enhancer RNA, or eRNA – that intensified the ability of neurons to produce protein. The widespread effect was something new.
“Biologists have known about enhancers since 1980, and there has even been a paper or two describing RNA produced at enhancer regions, but it was largely considered an isolated curiosity,” says Greenberg. “What we’ve discovered here is how widespread this phenomenon is. We’ve found that there are thousands of these enhancers, that they’re spread throughout the genome, and that they are essential to the process in which experience results in new synaptic connections. What’s more, we suspect that they’re active in many other mammalian cell types, not just neurons.”
This study started with the existence of regions of DNA that created RNA that could enhance the production of protein – facilitating rapid genetic response to stimulus. It showed that this type of RNA, eRNA, has a much wider effect than was previously suspected. In fact, eRNA may be one of the more important mechanisms for directing cell growth – although that is an area for new research. This is part of what seems to be an ever widening pattern discovered by molecular biology – it includes the active areas in what used to be considered ‘junk’ DNA, the role of proteins in epigenetics, and newly discovered forms of RNA involved in the complex feedback system that is a living cell.