April 28, 2023
Author: Manish Verma
Editor: Dr. Jitendra Kumar Sinha
Summary: New research reveals that small RNA fragments called miRNAs (miR-483-5p) can help counteract the genetic, biochemical, and morphological changes associated with anxiety disorders.
Anxiety disorders are highly prevalent, with approximately one in four people experiencing such a disorder at least once in their lifetime. Severe psychological trauma can elicit genetic, biochemical, and morphological changes in neurons within the amygdala, a region of the brain that is involved in stress-induced anxiety. These changes may contribute to the onset of anxiety disorders, such as panic attacks and post-traumatic stress disorder.
While some people can manage stress better than others, severe psychological trauma can lead to high levels of anxiety and other behavioral abnormalities. Unfortunately, current therapeutic approaches are often ineffective, with more than half of patients failing to achieve remission following treatment. The limited success in developing potent anxiolytic drugs is likely due, at least in part, to our incomplete understanding of the neural circuits underlying anxiety and the molecular events that underlie stress-related neuropsychiatric states.
Recent research has shown that miRNAs, small RNA fragments that regulate gene expression, can play a crucial role in mitigating the effects of stress.
In a recent study published in Nature Communications, researchers aimed to elucidate the molecular mechanisms underlying anxiety. Their findings demonstrated that miR-483-5p, a type of miRNA present in the amygdala of male mice, could counteract the genetic, biochemical, and morphological changes associated with anxiety. MicroRNAs (miRNAs) are a type of small, non-coding RNA molecules that are essential in the regulation of gene expression, influencing various biological processes such as development, differentiation, and disease development. On the other hand, the amygdala is a brain region responsible for emotional and memory processing and is often implicated in fear and anxiety-related behaviors.
The study found that miR-483-5p is upregulated in the synaptic compartment of amygdala neurons in response to stress. This upregulation leads to the direct repression of three stress-associated genes: Pgap2, Gpx3, and Macf1. Pgap2 plays a critical role in the stress response, and miR-483-5p’s repression of this gene is a critical cellular event that offsets the functional and behavioral consequences of psychological stress.
Interestingly, the upregulation of miR-483-5p leads to the selective contraction of the distal parts of the dendritic arbour and the conversion of immature filopodia into mature, mushroom-like dendritic spines. These changes in neuronal morphology are consistent with the reduction in anxiety-like behavior observed in the mice.
The researchers showed that the stress-induced neuromorphological and behavioral effects of miR-483-5p could be recapitulated by suppressing Pgap2 with shRNA. Furthermore, these effects could be prevented by simultaneously overexpressing miR-483-5p-resistant Pgap2. These results demonstrate that miR-483-5p is sufficient to confer a reduction in anxiety-like behavior and point to miR-483-5p-mediated repression of Pgap2 as a critical event in mitigating the effects of stress.
This study highlights the importance of miRNAs in regulating gene expression and their potential as therapeutic targets for stress-related disorders. While this research was conducted in male mice, further studies are needed to determine if miR-483-5p plays a similar role in females and in humans. Nevertheless, this research provides valuable insight into the biological mechanisms underlying stress-induced anxiety and potential avenues for future treatments.
Reference:
- Mucha, M., Skrzypiec, A.E., Kolenchery, J.B. et al. miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala. Nat Commun 14, 2134 (2023). https://doi.org/10.1038/s41467-023-37688-2
- Remes, O., Brayne, C., van der Linde, R., & Lafortune, L. (2016). A systematic review of reviews on the prevalence of anxiety disorders in adult populations. Brain and behavior, 6(7), e00497. https://doi.org/10.1002/brb3.497
- Hollins, S. L., & Cairns, M. J. (2016). MicroRNA: Small RNA mediators of the brains genomic response to environmental stress. Progress in neurobiology, 143, 61–81. https://doi.org/10.1016/j.pneurobio.2016.06.005
- Issler, O., & Chen, A. (2015). Determining the role of microRNAs in psychiatric disorders. Nature reviews. Neuroscience, 16(4), 201–212. https://doi.org/10.1038/nrn3879