Parts of the genome that do not code for proteins may nonetheless play a significant role in how emotional experiences can lead to drug and mental health issues, preclinical research suggests.
The study, in mice, found that long, non-coding (lnc)RNAs played a critical role in controlling the expression of a behavioral gene linked with substance misuse and stress.
The findings, in the journal Science, offer a possible mechanism into how emotional experiences can impact the brain and lead to maladaptive behaviors.
They could also lead to new RNA therapies for psychiatric disorders, such as addiction and depression.
“By understanding this process, we hope to get better insights into how changes in the brain can lead to maladaptive changes in behavior,” said researcher Christopher Cowan, PhD, chair of the department of neuroscience at the Medical University of South Carolina.
“We could also improve our fundamental understanding of how the brain works and how emotions and emotionally relevant experiences help to shape brain circuits.”
Gene regulation is essential to both how the brain functions and neurons communicate.
Neuronal activity after emotional experiences may trigger the expression of immediate-early response genes (IEGs), which can be crucial for adapting to the surrounding environment.
But they can also lead to maladaptive behaviors associated with neuropsychiatric disorders.
To investigate further, the researchers examined the role of lncRNAs that interact with chromatin and protein-coding genes in multiple ways, including those involved in mental illness.
Specifically, they looked at long non-coding enhancer RNA (Inc-eRNA), which affects the expression of genes by binding to regulatory regions and forming what is known as R-loop structures.
The team examined the impact of blocking the creation of R loops relating to an IEG that encodes the transcription factor neuronal PAS domain protein 4 (NPAS4), which drives cellular programs that support behavioral adaptations.
NPAS4 has been linked with stress-induced anhedonia, where there is a lack of joy in activities that were once pleasurable, and also drug relapse.
The investigators found that blocking R loops in front of the NPAS4 gene in the nucleus accumbens region of the brain in mice led to them not showing a preference for cocaine.
When blocking was performed in the prefrontal cortex, the animals did not develop behaviors akin to stress-induced anhedonia.
The R loop appeared to help turn a gene on by bringing together a promotor region, which allows it to be turned on, with an enhancer region, which includes instructions for turning it on.
The findings offer the first evidence for behavioral changes induced by emotional experiences managed by R-loops.
In an accompanying Perspective article, Kyle S. Czarnecki and Elizabeth A. Heller from the University of Pennsylvania in Philadelphia caution that the immediate relevance of the findings “opaque.”
Nonetheless, they add that “such detailed mechanistic knowledge of gene regulation could guide the development of therapies for complex diseases, including intractable psychiatric disorders.”
