Summary: An international team of scientists has identified a gene in the brain responsible for anxiety symptoms and found that modifying the gene can reduce anxiety levels, providing a new drug target for anxiety disorders. The finding highlights a novel miR483-5p/Pgap2 amygdala pathway that regulates the brain’s stress response and provides a potential therapeutic approach for anxiety disorders.
Source: University of Bristol
A gene in the brain responsible for anxiety symptoms has been identified by an international team of scientists. Critically, modifying the gene has been shown to reduce anxiety levels, providing an exciting new drug target for anxiety disorders.
The discovery, led by researchers from the universities of Bristol and Exeter, is published online today (April 25) in Nature Communication.
Anxiety disorders are common with one in four people diagnosed with a disorder at least once in their lifetime. Severe psychological trauma can trigger genetic, biochemical, and morphological changes in neurons in the brain’s amygdala, the region of the brain implicated in stress-induced anxiety, leading to the onset of anxiety disorders, including panic attacks and post-traumatic stress disorder.
However, the efficacy of currently available anxiolytics is low, with more than half of patients not achieving remission after treatment. The limited success in developing potent anxiolytics (anti-anxiety) is the result of our poor understanding of the neural circuitry underlying anxiety and the molecular events leading to stress-related neuropsychiatric states.
In this study, scientists sought to identify the molecular events in the brain that underlie anxiety. They focused on a group of molecules, known as miRNAs in animal models. This important group of molecules, also present in the human brain, regulates multiple target proteins controlling cellular processes in the amygdala.
Following acute stress, the team discovered an increased amount of a type of molecule called miR483-5p in a mouse amygdala. Importantly, the team showed that increasing miR483-5p suppressed the expression of another gene, Pgap2, which in turn leads to changes in neuronal morphology in the brain and behavior associated with anxiety.
Together, the researchers showed that miR-483-5p acts as a molecular brake that compensates for stress-induced changes in the amygdala to promote anxiety relief.
The discovery of a new miR483-5p/Pgap2 amygdala pathway by which the brain regulates its stress response is the first step towards finding new, more potent and much-needed treatments for anxiety disorders that will ameliorate this pathway.
Dr Valentina Mosienko, one of the study’s lead authors and MRC Fellow and Senior Lecturer in Neuroscience at Bristol’s School of Physiology, Pharmacology and Neuroscience, said: “Stress can trigger the occurrence of a number of neuropsychiatric disorders that have their roots in an adverse reaction. combination of genetic and environmental factors.
“While low levels of stress are counterbalanced by the brain’s natural ability to adapt, severe or prolonged traumatic experiences can overcome the protective mechanisms of stress resilience, leading to the development of pathological conditions such as depression or anxiety.
“miRNAs are strategically positioned to control complex neuropsychiatric conditions such as anxiety. But the molecular and cellular mechanisms they use to regulate resilience and susceptibility to stress were until now largely unknown.
“The miR483-5p/Pgap2 pathway we identified in this study, whose activation exerts anxiolytic effects, offers enormous potential for the development of anti-anxiety therapies for complex psychiatric disorders in humans.
About this genetics and anxiety research news
Author: Press office
Source: University of Bristol
Contact: Press Office – University of Bristol
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Original research: Free access.
“miR-483-5p mediates the functional and behavioral effects of stress in male mice through targeted repression at Pgap2 synapses in the basolateral amygdala” by Mariusz Mucha et al. Nature Communication
miR-483-5p mediates functional and behavioral effects of stress in male mice through targeted repression at Pgap2 synapses in the basolateral amygdala
Severe psychological trauma triggers genetic, biochemical, and morphological changes in amygdala neurons, which underlie the development of stress-induced behavioral abnormalities, such as high levels of anxiety. miRNAs are small non-coding RNA fragments that orchestrate complex neuronal responses through simultaneous transcriptional/translational repression of multiple target genes.
Here, we show that miR-483-5p in the amygdala of male mice counteracts the structural, functional, and behavioral consequences of stress to promote a reduction in anxious behaviors.
During stress, miR-483-5p is upregulated in the synaptic compartment of amygdala neurons and directly represses three stress-associated genes: Pgap2, Gpx3 And Macf1. Upregulation of miR-483-5p results in selective contraction of distal parts of the dendritic arbor and conversion of immature filopodia into mature mushroom-like dendritic spines.
Consistent with its role in reducing the stress response, upregulation of miR-483-5p in the basolateral amygdala produces a reduction in anxious behavior. The 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.
Our results demonstrate that miR-483-5p is sufficient to confer a reduction in anxiety-like behavior and indicate miR-483-5p-mediated repression of Pgap2 as a critical cellular event compensating for the functional and behavioral consequences of psychological stress.