Scientists have discovered a gene in the brain that drives anxiety. Modifying it can reduce anxiety levels, offering a potential drug target for anxiety disorders. Anxiety disorders affect 1 in 4 people, and trauma can trigger genetic changes in the amygdala, leading to anxiety disorders. Currently, available anti-anxiety drugs have limited efficacy. Developing potent drugs has been challenging due to a poor understanding of the neural circuits underlying anxiety. The study was led by researchers at the Universities of Bristol and Exeter and published in Nature Communications.
Anxiety disorders affect 25% of the population and are difficult to treat with available medications. The amygdala region of the brain is critical for the development of stress-induced anxiety, and various types of neurons contribute to anxiety-like states. MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression, and the role of miRNAs in anxiety is not well understood.
The study identified miR-483-5p as a critical regulator of stress-related dendritic arbor and dendritic spine plasticity in the amygdala. The upregulation of miR-483-5p reduced anxiety-like behavior. The miR-483-5p-mediated repression of Pgap2 was identified as a critical molecular event that facilitated the consequences of psychological Stress.
Dr. Valentina Mosienko, one of the study’s lead authors and an MRC Fellow and Lecturer in Neuroscience at Bristol’s School of Physiology, Pharmacology, and Neuroscience, said: “Stress can trigger the onset of a number of neuropsychiatric conditions that have their roots in an adverse combination of genetic and environmental factors. While low-stress levels are counterbalanced by the natural capacity of the brain to adjust, severe or prolonged traumatic experiences can overcome the protective mechanisms of stress resilience, leading to pathological conditions such as depression or anxiety.
Furthermore, researchers found that upregulation of miR-483-5p in the basolateral amygdala is sufficient to produce an anxiolytic effect, meaning it reduces anxiety. This effect can be mimicked by either lentiviral overexpression of the miR-483-5p or shRNA-mediated suppression of the Pgap2 gene. Overexpression of both miR-483-5p and miR-483-5p-resistant Pgap2 prevents the effects of miR-483-5p on stress-induced changes to spine morphology and behavior.
Scientists have discovered a group of molecules in the brain, known as miRNAs, that can regulate multiple target proteins and control cellular processes in the amygdala, which is responsible for processing emotions such as anxiety. The researchers found that after acute Stress, there was an increased amount of one type of molecule called miR483-5p in a mouse amygdala. This increased miR483-5p suppressed the expression of another gene, Pgap2, which drives changes to neuronal morphology in the brain and behavior associated with anxiety.
The team showed that miR-483-5p acts as a molecular brake that offsets stress-induced amygdala changes to promote anxiety relief. This discovery offers the potential for developing anti-anxiety therapies for complex psychiatric conditions in humans. Several organizations, including the Medical Research Council and the Leverhulme Trust, funded the study.
In this experiment, male mice were used to investigate the molecular events in the brain that underpin anxiety. The researchers focused on a group of molecules called miRNAs, which regulate multiple target proteins controlling the cellular processes in the amygdala. The mice were exposed to acute Stress to induce anxiety-like behavior. The team then measured the amount of miR483-5p in the amygdala. It examined the effect on the expression of another gene, Pgap2, involved in anxiety-related behavior.
The researchers used a range of behavioral tests to investigate the effects of miR-483-5p on behavior. They also used in vitro electrophysiology to examine the effects on synaptic transmission in the amygdala. Overall, the study used a combination of molecular biology techniques and behavioral assays to investigate the role of miR-483-5p in regulating anxiety-related behavior in male mice.
The study found that an increase in miR-483-5p levels in the basolateral amygdala of male mice after acute Stress suppressed the expression of a gene called Pgap2, which led to changes in neuronal morphology and behavior associated with anxiety. This suggests that miR-483-5p acts as a molecular brake to offset stress-induced amygdala changes and relieve anxiety. The discovery of this pathway provides a potential target for developing novel anti-anxiety therapies.
These findings are significant as anxiety disorders are the most common psychiatric conditions currently diagnosed, affecting approximately 25% of the population at least once in their lifetime. However, the low efficiency of available anxiolytic therapies means that up to 50% of patients do not achieve complete remission despite multiple medication attempts. This limited success in developing effective anxiolytic drugs stems from insufficient knowledge of the neural circuits of anxiety and molecular events underpinning stress-related neuropsychiatric states.
The researchers hope that their findings will contribute to the development of more effective treatments for anxiety disorders and deepen our understanding of the neural circuits and molecular mechanisms underlying these conditions.
- Mucha, M., Skrzypiec, A. E., Kolenchery, etal. MiR-483-5p offsets functional and behavioral effects of Stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala. Nature Communications. DOI: 10.1038/s41467-023-37688-2