Anxiety: a new mechanism deciphered by researchers from the Côte d'Azur

Fight or flight. The anxious response to danger is essential for survival. Rooted in fear, it pushes us to be cautious and avoid risky situations. But for some, this natural response becomes excessive, causing hypervigilance and inhibition that disrupt daily life. "Anxiety disorders are among the most common mental illnesses. They often occur early in life and tend to persist or recur over time," explains Sebastian Fernandez, a researcher at the Institute of Molecular and Cellular Pharmacology (IPMC) in Sophia Antipolis.

Where does this pathological anxiety originate? And how can it be better treated, given that available treatments are poorly targeted and often associated with significant side effects? These are the questions that guided the research undertaken 5 years ago by his team, which led to the discovery of a previously unknown mechanism (1).

Amygdala hyperactivity

The research began with a clinical observation: "In patients suffering from pathological anxiety, excessive activity is detected in a small area of ​​the brain, the amygdala (in yellow in the photo). Under normal conditions, the activity of the amygdala is well regulated, allowing the individual to assess whether a situation is threatening or not and to adopt appropriate responses. However, when there is an imbalance, it can go into overdrive, leading to excessive anxious reactions," explains the researcher.

Another well-established fact: intense or prolonged stress can modify the very structure of the amygdala, making its neurons more reactive.

Two brain areas

To decipher the mechanisms at play in these processes, Sebastian Fernandez, part of the team led by ^Professor Jacques Barik (UCA), will use an animal model exposed to repeated social stress (see box). "Using cutting-edge techniques, we have uncovered specific connections between the amygdala and another brain region involved in emotions, the ventral tegmental area (VTA). And we have observed that chronic stress strengthens these connections: the influence of the VTA on the amygdala becomes more significant, which increases anxiety in mice."

Ultimate proof of the key role of these connections in regulating anxiety : "By artificially activating this circuit for five days, without exposing them to any stress, we induce an anxious state in mice. Conversely, by blocking this connection during a stressful situation, we prevent the onset of anxiety. It is therefore a bidirectional circuit that we can manipulate to increase or decrease anxiety."

Another part of the study focused on the underlying molecular mechanisms. "At the synapses specifically connecting the VTA to the amygdala, chronic stress causes changes in the composition of proteins that play a major role in excitatory neurotransmission. By preventing this change, we block the effect of stress on the amygdala and reduce anxiety. We have thus identified two levels of therapeutic intervention: acting directly on the neuronal circuits or targeting the molecular changes induced by stress." This is a great hope against a disease whose incidence continues to increase.

Hostile environment

The model used by the researchers is based on moderate social stress: mice are regularly confronted with other, larger, aggressive mice. "Social interaction, normally perceived as positive, gradually becomes aversive. After several exposures, the mice develop a form of generalized anxiety; they show signs of avoidance not only towards other mice, but also in new environments. This model is particularly relevant because it is based on a well-known risk factor for the development of anxiety disorders in humans: repeated negative social experiences."

1- This research was published in the journal Biological Psychiatry, thanks to the support of the ANR and the FRM.