Researchers at the Medical University of South Carolina (MUSC) have identified a crucial genetic mechanism that aids the brain in adapting to emotional experiences, potentially paving the way for RNA-based therapies for psychiatric disorders. This discovery, published in Ciencia, sheds light on the genetic processes influencing how emotional experiences can lead to lasting behavioral changes, which may become problematic in conditions such as depression or substance abuse.
The team, led by Dr. Makoto Taniguchi, Dr. Christopher Cowan, and Rose-Marie Akiki, focused on understanding how emotional experiences like chronic stress and drug use induce behavioral changes over time. Their findings suggest that a specific genetic structure, an 'RNA:DNA sandwich', plays a fundamental role in these adaptations.
“We hope to gain better insights into how changes in the brain can lead to maladaptive changes in behavior,” stated Cowan. “We could also enhance our fundamental understanding of how the brain works and how emotions and emotionally relevant experiences help shape brain circuits.”
At the core of their discovery is a type of long non-coding RNA (lncRNA), referred to as long non-coding enhancer RNA (Inc-eRNA), which interacts with the regulatory region of genes to form structures called R-loops. These R-loops help control gene activation by bringing together key regions of a gene (the enhancer and the promoter), allowing it to respond to external emotional stimuli.
The team investigated the NPAS4 gene, which plays a role in stress-induced anhedonia (the inability to experience pleasure) and drug-induced relapse. Their study reveals the first evidence that R-loops are essential for regulating genes like NPAS4 in response to emotional experiences, providing new insights into how these experiences influence behavior.
“By bringing the enhancer and promoter together in space and time, R-loops seem to facilitate their interaction and drive the response to activate a gene,” explained Cowan.
The researchers utilized a preclinical mouse model to test their hypothesis. They found that blocking R-loop formation in the NPAS4 gene significantly reduced cocaine-seeking behavior in the nucleus accumbens of the brain and prevented stress-induced anhedonia when manipulated in the prefrontal cortex. These results suggest that R-loops in the NPAS4 gene are crucial for the brain's adaptation to emotional experiences, influencing substance use behaviors and mood disorders. “A change in the genetic basis of how everything works, what gets transcribed, what forms in the cell to create stronger neural circuits that underlie behavior is needed,” said Akiki.
The researchers also noted that these R-loops are highly conserved across species, indicating their evolutionary significance. Their work suggests that R-loops may play a broader role in how neural circuits adapt to stimuli, similar to their function in the immune system, where they help develop immunity. “We found that neurons, like immune cells, can respond to a stimulus by forming an R-loop,” Akiki elaborated.
The team's ultimate goal is to explore how widespread this genetic mechanism is across different brain regions and whether its alterations could contribute to psychiatric disorders. “This is a new way of thinking about how genes can be activated,” said Cowan.
This discovery not only enhances our understanding of the brain's response to emotional experiences but also has the potential to inform the development of RNA-based therapies that could treat psychiatric disorders, offering hope for more targeted treatments in the future.