To lay down the memory of a dangerous experience, the DNA of neurons and other brain cells is broken in numerous locations—more than previously realized, according to a new study.
The extent of DNA double-strand breaks (DSBs) in multiple key brain regions is surprising and concerning, said study senior author Li-Huei Tsai, director of The Picower Institute for Learning and Memory at MIT, because while the breaks are routinely repaired, that process may become more flawed and fragile with age. Tsai’s lab has shown that lingering DSBs are associated with neurodegeneration and cognitive decline and that repair mechanisms can falter.
In a study published July 1 in PLOS ONE, lead author Ryan Stott, co-author Oleg Kritsky, and their colleagues, report on DSB activity in learning and memory.
“We wanted to understand exactly how widespread and extensive this natural activity is in the brain upon memory formation because that can give us insight into how genomic instability could undermine brain health down the road,” said Tsai, who is also a leader of MIT’s Aging Brain Initiative. “Clearly memory formation is an urgent priority for healthy brain function but these new results showing that several types of brain cells break their DNA in so many places to quickly express genes is still striking.”
In 2015, Tsai’s lab provided the first demonstration that neuronal activity caused DSBs and that they induced rapid gene expression. In that research, they gave mice little electrical zaps to the feet when they entered a box, to condition a fear memory of that context. The creation of a fear memory doubled the number of DSBs among neurons in the hippocampus and the prefrontal cortex, affecting more than 300 genes in each region.
“Many genes essential for neuronal function and memory formation, and significantly more of them than expected based on previous observations in cultured neurons…are potentially hotspots of DSB formation,” the authors wrote in the study.
In another analysis, the researchers confirmed through measurements of RNA that the increase in DSBs indeed correlated closely with increased transcription and expression of affected genes, including ones affecting synapse function, as quickly as 10-30 minutes after the foot shock exposure.
“Overall, we find transcriptional changes are more strongly associated with [DSBs] in the brain than anticipated,” they wrote. “Previously we observed 20 gene-associated [DSB] loci following stimulation of cultured neurons, while in the hippocampus and prefrontal cortex we see more than 100-150 gene associated [DSB] loci that are transcriptionally induced.”
In the analysis of gene expression, the neuroscientists looked at not only neurons but also non-neuronal brain cells, or glia, and found that they also showed changes in expression of hundreds of genes after fear conditioning.
That study data also showed that in glia, many of the DSBs that occurred following fear conditioning occurred at genomic sites related to glutocortocoid receptors. Further tests revealed that directly stimulating those hormone receptors could trigger the same DSBs that fear conditioning did and that blocking the receptors could prevent transcription of key genes after fear conditioning.
Tsai said the finding that glia are so deeply involved in establishing memories from fear conditioning is an important surprise of the new study.
“The ability of glia to mount a robust transcriptional response to glutocorticoids suggest that glia may have a much larger role to play in the response to stress and its impact on the brain during learning than previously appreciated,” she and her co-authors wrote.
“Overall we have identified sites of DSBs at genes important for neuronal and glial functions, suggesting that impaired DNA repair of these recurrent DNA breaks which are generated as part of brain activity could result in genomic instability that contribute to aging and disease in the brain,” the researchers wrote.