Summary: Researchers have identified a brain gene that drives anxiety symptoms and shown that altering its activity reduces anxiety in animal models. The work points to a new amygdala miR-483-5p/Pgap2 pathway that helps regulate the brain’s response to stress and suggests a promising target for future anxiety therapies.
Source: University of Bristol
Scientists from an international collaboration, led by teams at the Universities of Bristol and Exeter, have pinpointed a specific genetic mechanism in the amygdala that contributes to anxiety-related behaviour. Crucially, experimental modification of this mechanism reduces anxiety-like symptoms in animal models, revealing a potential new target for drug development.
The findings, published in Nature Communications, shed light on how stress alters the brain’s molecular and cellular architecture and identify a pathway that naturally acts to limit those stress effects.
Anxiety disorders are widespread: roughly one in four people will be diagnosed with an anxiety condition at some point in their lives. Severe psychological trauma can trigger changes in the amygdala—the brain area central to processing fear and stress—leading to alterations in gene expression, biochemistry and neuronal structure that underlie conditions such as panic disorder and post-traumatic stress disorder (PTSD).
Current medications for anxiety have limited effectiveness; more than half of patients do not achieve full remission with existing treatments. This shortfall reflects, in part, gaps in our understanding of the precise neural circuits and molecular events that convert stress into persistent anxiety. The new study addresses that gap by focusing on small regulatory molecules called microRNAs (miRNAs), which modulate multiple target proteins and finely tune cellular processes in the brain.
Using mouse models, the researchers observed that acute stress increases levels of miR-483-5p specifically in the amygdala. Laboratory experiments showed that miR-483-5p directly suppresses expression of the gene Pgap2. This suppression leads to measurable changes in neuronal shape—particularly in the structure of dendrites and synapses—and to reductions in anxiety-like behaviour. In effect, miR-483-5p functions as a molecular brake that counteracts stress-induced changes in the amygdala and promotes behavioral recovery.
The study highlights a previously unrecognized amygdala miR-483-5p/Pgap2 pathway by which the brain buffers the effects of stress. Modulating this pathway could form the basis of new, more effective treatments that enhance the brain’s natural resilience mechanisms to reduce pathological anxiety.
Dr. Valentina Mosienko, a lead author and MRC Fellow and Lecturer in Neuroscience at Bristol’s School of Physiology, Pharmacology and Neuroscience, explained that while the brain can adapt to everyday stress, severe or prolonged trauma can overwhelm protective mechanisms and trigger mental health disorders. She noted that miRNAs are well positioned to regulate complex neuropsychiatric states, but until now their precise roles in stress resilience and vulnerability were poorly understood. The miR-483-5p/Pgap2 pathway identified by the team appears to produce anxiety-reducing effects and therefore holds strong therapeutic promise.
About this genetics and anxiety research news
Author: Press Office
Source: University of Bristol
Contact: Press Office – University of Bristol
Image: The image is in the public domain
Original Research: Open access.
Title: “miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala” by Mariusz Mucha et al., Nature Communications
Abstract (summary)
miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala
Severe psychological trauma produces genetic, biochemical and structural alterations in amygdala neurons that contribute to high anxiety and other stress-induced behavioural changes. MicroRNAs (miRNAs) are short, non-coding RNA molecules that coordinate complex neuronal responses by repressing multiple target genes simultaneously. The study demonstrates that miR-483-5p in the amygdala of male mice mitigates the structural, functional and behavioural consequences of stress and promotes a reduction in anxiety-like behaviour.
After stress, miR-483-5p increases in the synaptic compartment of amygdala neurons and directly represses several stress-associated genes, including Pgap2, Gpx3 and Macf1. Elevation of miR-483-5p causes selective retraction of distal dendritic branches and a shift from immature filopodia toward mature, mushroom-shaped dendritic spines—changes consistent with refined synaptic connectivity.
Experimentally increasing miR-483-5p in the basolateral amygdala reduces anxiety-like behaviour, while suppressing Pgap2 through RNA interference reproduces the neuromorphological and behavioural effects of miR-483-5p. Conversely, restoring a form of Pgap2 that is resistant to miR-483-5p prevents those effects. Collectively, the results indicate that miR-483-5p is sufficient to lower anxiety-like behaviour and that repression of Pgap2 is a critical cellular event that offsets the functional and behavioural consequences of psychological stress.