2023-04-27 18:25:09
As current anxiolytic treatments are often ineffective, research is focusing on identifying new therapeutic targets to combat anxiety disorders. An international team may have discovered one of them by identifying a new genetic mechanism that governs the symptoms of anxiety, thus filling important gaps in the understanding of its biomolecular mechanism.
Stress can trigger a wide range of neuropsychiatric disorders, resulting from genetic or environmental factors. Among these disorders, anxiety would affect one in four people at least once during their lifetime. It manifests in a complex series of symptoms, such as social behavior problems, cognitive deficits, depressive disorders, and recurrent and harmful behaviors. To some extent, brain plasticity allows affected individuals to adapt and recover from anxiety.
However, severe psychological trauma can lead to significant anxiety disorders that can cause genetic, biochemical and morphological changes in neurons. These changes show up in the amygdala, the region of the brain implicated in stress-induced anxiety, whose activity can trigger anxiety attacks and intense feelings of danger.
« 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 depression. ‘anxiety says Valentina Mosienko, co-lead author of the new study and senior lecturer in neuroscience at the University of Bristol’s Institute of Physiology, Pharmacology and Neuroscience, in a communiqué. The research was co-led by the University of Exeter.
From a physiological point of view, the symptoms of anxiety would result from an excessive reaction of the autonomic nervous system, caused by an overproduction of catecholamines and norepinephrine. Upstream, this reaction is caused by a decrease in the level of gamma-aminobutyric acid (or GABA, playing a crucial role in the control of stress and fear), leading to hyperactivity of the central nervous system. This process would lead to an increase in the level of dopamine and a decrease in serotonin, a combination that reduces the feeling of well-being.
Low serotonin levels have long been considered one of the main causes of anxiety disorders and depression. However, recent research has found evidence that seems to refute this theory. The biomolecular mechanisms governing these disorders are indeed complex and have many gaps in their understanding. This misunderstanding probably explains the lack of efficacy observed for the anxiolytics currently available in the clinic.
Trying to fill the gaps in understanding the neural mechanisms of anxiety, previous studies recently highlighted networks of genes called miRNAs (or microRNAs) involved in the symptoms of the disorder. ” miRNAs are strategically positioned to control complex neuropsychiatric conditions such as anxiety Mosienko points out. However, the molecular and cellular mechanisms implicating these miRNAs in the regulation of stress resilience remain largely unknown.
The new study, published in the journal Nature
Communications, complements this research by identifying a genetic mechanism involving a specific miRNA (miR483-5p) and gene (Pgap2) directly linked to anxiety symptoms. The research results suggest that the miR483-5p/Pgap2 pathway might be a promising target for novel therapies for anxiety and various complex psychiatric disorders.
A gene inhibiting anxiety symptoms
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miRNAs are small non-coding RNA molecules present in the brain and regulating a large number of pathophysiological processes of mental disorders. These RNA fragments can in particular bind to the 3′-UTR region of mRNA to inhibit gene expression at the post-transcriptional level. Their ability to simultaneously regulate hundreds of mRNAs and their presence in strategic brain regions give them significant potential for controlling the activation of entire cellular pathways involved in the regulation of complex processes such as behavior. Additionally, research has suggested that dysregulation of many miRNAs is involved in the pathophysiology of neuropsychiatric disorders.
In the new research, the Bristol and Exeter team found that acute stress led to overexpression of miR483-5p in the amygdala of mice. This overexpression inhibited that of Pgap2, Gpx3 and Macf, all three implicated in changes in the structure of neurons and in anxiety-related behaviors. The increase in miR-483-5 would lead to a selective contraction of the distal parts of the dendrites and the transformation of immature filopodia into mature dendritic spines.
The researchers then concluded that miR-483-5p acts as a molecular brake, attenuating stress-induced amygdala changes and thus may relieve anxiety. The changes in neuronal morphology observed in anxious people might be explained by the overexpression of Pgap2, “resistant” to miR-483-5p. Thus, stimulation of the miR483-5p/Pgap2 amygdala pathway might be a particularly promising strategy for the treatment of severe anxiety disorders, as well as other neuropsychiatric conditions.
Source : Nature Communications
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