The finding reported in the journal Science takes the research team a step closer to unravelling the mystery as to what controls the birth of new cells in the brain's hippocampus.
"How is it that when you see someone you met ten years ago, you still recognize them? How do these transient events become long lasting in the brain, and what potential role does the birth of new neurons play in making these memories?" says Hongjun Song, Ph.D., an associate professor of neurology and member of the Johns Hopkins Institute of Cell Engineering's NeuroICE.
"We really want to understand how daily life experiences trigger the birth and growth of new neurons, and make long-lasting changes in the brain," the researcher added.
According to the researchers, making long-term memories might require long-term changes in brain cells, and one type of cellular change that has long-lasting effects is so-called epigenetic change that can alter a cell's DNA without changing its sequence, but does change how and which genes are turned on or off.
Considering this reasoning, the researchers decided to look at the 40 to 50 genes known to be involved in epigenetics, and see whether any of them were turned on in mouse brain cells that had been stimulated with electroconvulsive therapy-shock treatment.
"It's long been known that ECT induces neurogenesis in rodents and humans, so we used it as our test case to find what is triggered downstream to cause new cells to grow," says Song.
The researcher revealed that one gene turned on in response to ECT was Gadd45b, a gene previously implicated in immune system function and misregulated in brain conditions like autism.
With a view to determining that Gadd45b was turned up in response to brain activity, the team further examined mice experiencing a different activity. They found exposure to new surroundings also turned on Gadd45b in brain cells.
The researchers then tested mice engineered to lack the Gadd45b gene for their ability to generate new brain cells after ECT, in order to find out whether this gene is required for new brain-cell growth.
They injected the mice with a dye that marks new cells, and three days after ECT, examined the number of new cells containing that dye in brains from mice with and without the Gdd45b gene.
It was observed that while normal brains showed a 140 percent increase in cell number after ECT, brains lacking Gadd45b only showed a 40 percent increase.
"The question then was, How does Gadd45b do this? It's been controversial that Gadd45b can promote epigenetic changes like global DNA demethylation, but we show that it can promote demethylation of certain genes," says Song.
When the researchers dissected mature neurons from normal mouse brains and looked for the presence of methyl groups at certain genes known to promote cell growth, they found that the genes had become demethylated after ECT.
However, doing the same thing with mice lacking Gadd45b did not result in demethylation, suggesting that the gene was indeed required for demethylation.
"We're really excited about this-it's the first time we've seen dynamic epigenetic DNA changes in response to brain activity," says Song.
"Now that we have the mice lacking Gadd45b, our next goal is to see if these mice have problems with learning and memory and how Gadd45b specifically promotes the demethylation to lead to these long-term changes in the brain." (ANI)