Targeting a Newly Identified Gene in the Brain May Reduce Anxiety

Anxiety disorders—including generalized anxiety disorder, panic attacks, phobias, obsessive-compulsive disorder, and post-traumatic stress disorder—are the most diagnosed psychiatric conditions, affecting 1 in 4 people in their lifetime. Occasional stress is normal, and the brain has a capacity to adjust.

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Prolonged or severe stress combined with other genetic and environmental factors can overwhelm the brain’s adaptability and lead to psychotic states, anxiety, and/or depression. Anxiety disorders create social and economic burdens as the availability of effective anxiolytic treatments are low, with 50% failing to reach remission despite numerous attempts.

Many studies in rodents have shown the amygdala as the brain region responsible for the development of stress-induced anxiety. The amygdala relays relevant signals to other areas of the brain, which trigger behaviors—such as risk avoidance, low food intake, social withdrawal, increase in blood pressure and heart rate—that depict anxiety conditions and interfere with activities of daily living.

A study published in April 2023 in Nature Communications aimed to identify the molecular actions in the brain that regulate anxiety. Scientists focused on a group of molecules known as miRNAs.

These molecules are found in both mice and human brains. They are involved in controlling multiple cellular processes in the amygdala, including the development of stress-associated neuropsychiatric states, such as anxiety, fear, and depression.

The mechanisms by which miRNAs regulate stress and the subsequent responses are unknown. This study’s objective was to identify the specific mouse amygdala miRNAs activated by acute psychological stress and evaluate the pathways involved in stress response regulation.

Upon stress, scientists found that miR-483-5p is upregulated in amygdala neurons, which inhibits the stress-related gene, Pgap2. Repression of the Pgap2 gene subsequently reduces the functional and behavioral effects of stress thereby producing an anxiolytic effect. Upregulation of miR-483-5p also promoted growth of mushroom-like dendritic spines important for emotional memory processing.

The results of this study identified miR-483-5p-mediated suppression of Pgap2 as a crucial molecular process in driving changes in stress-induced behavior associated with anxiety. A large pharmaceutical deficit exists for those suffering with anxiety disorders. These findings are promising first steps to developing new and necessary treatments for anxiety disorders in humans.

“Stress-induced neuromorphological and behavioral effects of miR-483-5p can be recapitulated by shRNA mediated suppression of Pgap2 and prevented by simultaneous overexpression of miR-483-5p-resistant Pgap2,” the study authors concluded. “Our 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 cellular event offsetting the functional and behavioral consequences of psychological stress.”

About the Author

Dr. Tolliday is an Outpatient Pharmacy Lead at Wentworth-Douglass Hospital in Dover, NH.

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. (2023)14:2134. https://doi.org/10.1038/s41467-023-37688-2