Fear Memory-making Involves Extensive DNA Breakage that Leads to Neurodegeneration

Fear Memory-making Involves Extensive DNA Breakage that Leads to Neurodegeneration

Double-strand DNA breaks, which occur when the phosphate backbones of both DNA strands are hydrolyzed, are considered the most significant DNA damage and have been shown to increase the risk of cancer and other deadly diseases.

So, it’s surprising enough that previous research has shown the brain actually causes double-strand breaks (DSBs) when it is trying to create a fear-based memory. What’s even more shocking—and concerning—is the extent of these DSBs in multiple key brain regions, according to a new study by Li-Huei Tsai, professor of neuroscience at MIT and director of The Picower Institute for Learning and Memory.

In a new paper published in PLOS One , Tsai and colleagues show that while the breaks are routinely repaired, the process may become more flawed and fragile with age.

“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. “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 striking.”

In the most recent study, researchers in Tsai’s lab gave mice low-power electrical zaps to the feet when they entered a box to condition a fear memory. Then, the team used several methods to assess DSBs and gene expression in the brains of said mice.

Compared with control mice, the creation of a fear memory in those who were zapped doubled the number of DSBs among neurons in the hippocampus and the prefrontal cortex, affecting more than 300 genes in each region—two brain regions known to form and store fear memories. Among the 206 affected genes common to both regions, many of the genes were associated with synapses.

“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 explain in the study.

Through RNA measurements, the researchers also demonstrated that an increase in DSBs correlated with increased transcription and expression of affected genes—including ones affecting synapse function—as quickly as 10 to 30 minutes after the foot shock exposure.

Surprisingly, the researchers also recorded gene expression changes in glia, or non-neuronal brain cells in the central nervous system. In glia, many of the DSBs that occurred following fear conditioning occurred at genomic sites related to the specific stress hormone glutocortocoid. Further tests revealed that directly stimulating glutocortocoid receptors could trigger the same DSBs that fear conditioning did. Moreover, blocking the receptors could prevent transcription of key genes after fear conditioning.

“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,” writes Tsai and her co-authors.

The scientists say more research will have to be done to prove that the DSBs required for forming and storing fear memories are a threat to later brain health, but their new study certainly adds evidence linking lingering DSBs with neurodegeneration and cognitive decline.

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