Brain cells snap open DNA to create memory – the degree of DNA double-strand breaks is “surprising and concerned”

To provide access to the genes needed to encode and store memory, brain cells snap open DNA and cut both strands. New studies have shown that this occurs more extensively than previously recognized and occurs not only in neurons but also in other supporting cell types.

In order to rapidly express learning and memory genes, brain cells snap both strands of DNA in far more locations and cell types than previously realized.

Since it is urgent to remember dangerous experiences, the brain needs to make a series of potentially dangerous movements. Neurons and other brain cells snap open DNA in different places. Previously realized, According to a new study, to provide rapid access to genetic instructions regarding the mechanism of memory and memory.

The extent of these DNA double-strand breaks (DSBs) in multiple major brain regions is staggering and of concern, as MIT’s professor of neuroscience and director of the Picower Institute for Learning and Memory. Author Li-Huei Tsai states. Breaks are repaired on a regular basis and the process can become more flawed and fragile with age. Tsai’s lab shows that prolonged DSB is associated with neurodegeneration and cognitive decline. The repair mechanism may stop working..

“We wanted to understand exactly how widespread and widespread this natural activity is in the brain during memory formation. It is how genomic instability impairs future brain health. It gives us insight into what’s possible, “says Tsai, a professor at the department. He holds a degree in brain and cognitive science and is a leader in MIT’s Aging Brain Initiative. “Obviously, memory formation is an urgent priority for healthy brain function, but these new results show that some types of brain cells disrupt DNA in so many places and express genes rapidly. It shows that. “

Break tracking

In 2015, Tsai’s lab provided the first demonstration that neuronal activity triggered DSBs, which induced rapid gene expression. However, these discoveries were made primarily in the laboratory preparation of neurons and did not capture the full extent of activity in the context of memory formation in behavioral animals, asking what happened in cells other than neurons. I wasn’t investigating.

In a new study published on July 1, 2021, PLOS ONE, Lead author and former graduate student Ryan Stott, and co-author and former research engineer Oleg Klitsky sought to explore the overall picture of DSB activity in learning and memory. To do so, they gave the mice a small electrical zap on their paws when they entered the box, adjusting their fear memory in that context. Next, several methods were used to assess DSB and gene expression in the mouse brain for the next 30 minutes. In particular, between the various cell types of the prefrontal cortex and hippocampus, there are two areas essential for the formation and preservation of conditioned fear memory. .. They also made measurements in the brains of mice that did not experience foot shock to establish a baseline of activity for comparison.

The creation of fear memory doubled the number of DSBs between neurons in the hippocampus and prefrontal cortex, affecting more than 300 genes in each region. Next, among the 206 affected genes common to both regions, researchers looked at what those genes do. Many were related to the function of connections that neurons make with each other, called synapses. This makes sense because learning occurs when neurons change connections (a phenomenon called “synaptic plasticity”), and memories are formed when groups of neurons connect to an ensemble called an ensemble.

“Many genes essential for neuronal function and memory formation, and far more genes than expected based on previous observations in cultured neurons … are potential hotspots for DSB formation.” The authors wrote in a study.

In another analysis, researchers conducted RNA measurements with transcription of affected genes, including genes that affect synaptic function, with increased DSB 10-30 minutes after exposure to foot shock. We have confirmed that it is actually closely correlated with increased expression.

“Overall, we see that transcriptional changes are more strongly related. [DSBs] It’s in my brain more than I expected, “they wrote. “I have previously observed 20 gene associations. [DSB] Over 100-150 genes are associated in the hippocampus and prefrontal cortex, whereas loci after stimulation of cultured neurons [DSB] Transcriptionally induced locus. “

Snap with stress

In gene expression analysis, neuroscientists examined non-neuronal brain cells, or glia, as well as neurons, and found changes in the expression of hundreds of genes after fear conditioning. Glia, called astrocytes, are known to be involved in fear learning, for example, and have shown significant changes in DSB and gene expression after fear conditioning.

Among the most important functions of genes associated with fear conditioning-related DSBs in glial cells was the response to hormones. Therefore, researchers investigated which hormones were particularly involved and found that it was glutcorticoid that was secreted in response to stress. Indeed, research data showed that in glia, many of the DSBs that occurred after fear conditioning occurred at genomic sites associated with the glutcorticoid receptor. Further testing shows that direct stimulation of these hormone receptors can trigger the same DSBs as fear conditioning, and blocking the receptors can interfere with transcription of important genes after fear conditioning. It became clear.

Tsai says the discovery that glia are very deeply involved in establishing memory from fear conditioning is an important surprise in new research.

“The ability of glia to initiate a strong transcriptional response to glutcorticoids may play a far greater role than previously recognized in glia’s response to stress and its effects on the learning brain. It suggests that there is, “she and her co-authors write.

Damage and danger?

Further research is needed to prove that the DSB required for the formation and preservation of fear memory is a threat to later brain health, but new research provides evidence that it may be the case. Just add it, the author says.

“Overall, we have identified DSB sites with genes that are important for neural and glial function. This is because DNA repair disorders of these recurrent DNA breaks that are produced as part of brain activity are associated with brain aging. It suggests that it can lead to genomic instability that contributes to the disease. “They wrote.

See: “Profiling DNA cleavage sites and transcriptional changes in response to contextual fear learning,” Ryan T. Stott, Oleg Kritsky, Li-Huei Tsai, July 1, 2021. PLOS ONE..
DOI: 10.1371 / journal.pone.0249691

The research was funded by the National Institutes of Health, the Glenn Medical Research Foundation, and the JPB Foundation. Brain cells snap open DNA to create memory – the degree of DNA double-strand breaks is “surprising and concerned”

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