DNA manipulation entails widespread DNA fracturing

In a groundbreaking study published in PLOS One (DOI: 10.1371/journal.pone.0249691), researchers have discovered that the brain produces more DNA double-strand breaks (DSBs) than previously understood during the process of memory storage, particularly in neurons and other brain cells.

The study, led by Li-Huei Tsai, involved giving mice electrical zaps to the feet to condition a fear memory and assessing DSBs and gene expression in the brains of the mice. Among the most significant findings was the discovery that glia, non-neuronal brain cells, showed changes in expression of hundreds of genes after fear conditioning.

One of the key functions of genes associated with fear conditioning-related DSBs in glia was the response to hormones, particularly glutocortocoids, which are secreted in response to stress. Directly stimulating glutocortocoid receptors could trigger the same DSBs that fear conditioning did, and blocking the receptors could prevent transcription of key genes after fear conditioning.

The increase in DSBs 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. Among the affected genes, many were associated with the function of synapses, which are crucial for learning and memory formation.

The transcriptional response of glia to glutocorticoids suggests a larger role of glia in the response to stress and its impact on the brain during learning than previously appreciated. Glia are deeply involved in establishing memories from fear conditioning, as a surprising finding of the new study.

The research identified sites of DSBs at genes important for neuronal and glial functions, suggesting impaired DNA repair could result in genomic instability contributing to aging and disease in the brain. The extent of these DSBs in multiple key brain regions is surprising and concerning, as while they are routinely repaired, the process may become more flawed and fragile with age.

The National Institutes of Health, The Glenn Foundation for Medical Research, and the JPB Foundation provided funding for the research. Ryan Stott, a researcher and author involved in the study project, is likely specializing in sociology or a related academic field.

The new study adds to evidence that the DSBs required for forming and storing fear memories may be a threat to later brain health. As our understanding of the brain's complex processes continues to grow, this research provides valuable insights into the potential risks and rewards of memory formation.