Depression: Dysfunction of neurons in the amygdala may be behind negative perceptions of the environment

One of the characteristics of depression is a tendency to perceive sensory stimuli and everyday situations in an excessively negative way. But the mechanisms underpinning this "negativity bias," which can fuel the development of depressive symptoms, had previously remained largely unknown. To shed light on the question, scientists from the Institut Pasteur and the CNRS, in collaboration with psychiatrists from Paris Psychiatry and Neurosciences GHU, Inserm and the CEA, decided to explore the amygdala and observe how it functions during depressive episodes. Their findings suggest that a depressive state alters certain specific neural circuits, leading to a reduction in the activity of neurons involved in pleasant perceptions of positive stimuli and an overactivation of those responsible for the perception of negative stimuli. These results, which could pave the way for the development of new drugs for people resistant to conventional therapy, were published in the journal Translational Psychiatry in September 2024.

Between 15 and 20% of people experience a depressive episode – "a state of deep, lasting distress" – at some point in their lives. But 30% of patients with depression are resistant to conventional medical treatment with antidepressants. To develop novel therapies, we need to improve our understanding of the mechanisms underlying depression, especially those that induce a "negativity bias." Depression causes patients to perceive the world and all sensory stimuli in an excessively negative way – pleasant stimuli become less attractive and unpleasant stimuli become more undesirable –, and this contributes to the development and maintenance of depressive symptoms.

"We now know that the amygdala is not only involved in our emotional response to environmental stimuli, fostering attraction or repulsion, but that it also plays a role in depression," explains Mariana Alonso, co-last author of the study and head of the Emotional circuits group in the Perception & Action laboratory at the Institut Pasteur. "Recent research has demonstrated the role of certain specific neural circuits in the amygdala in the positive or negative perception of environmental stimuli, but the alteration of these circuits during a depressive episode had not previously been observed."

To shed light on the involvement of these circuits in the negativity bias, scientists from the Institut Pasteur and the CNRS, in collaboration with psychiatrists from Paris Psychiatry and Neurosciences University Hospital Group (GHU), Inserm and the CEA, decided to study the activity of the amygdala in a mouse model for depression. Like depressed bipolar patients, these mouse models exhibited behavior characterized by anxiety and stress (they stopped self-grooming, stayed close to walls and preferred to be in the dark) and they responded to olfactory stimuli with a negative valence bias (they were barely attracted by the smell of female urine, which would normally be attractive for male mice, and were strongly repulsed by predator odors).

"To analyze how the amygdala functions during depression, we measured the activity of some networks of neurons involved in the more or less negative interpretation of olfactory stimuli," says Mariana Alonso. The scientists revealed that in a depressive state, the neurons preferentially involved in encoding positive stimuli are less active than normal, while the neurons preferentially involved in encoding negative stimuli are much more recruited. In other words, depression seems to induce a dysfunction of the amygdala circuits involved in encoding environmental stimuli, and this in turn further encourages the negative valence bias typical of depression.

These data are extremely valuable for the development of novel treatments for people with depression and also for those with bipolar disorder, who experience disproportionately lengthy and severe mood swings. "We were able to at least partly reverse the negative emotional bias induced in mice, and the related depressive behavior, by overactivating the neurons involved in the positive encoding of environmental stimuli. This is an interesting avenue to explore for the development of novel therapies," stresses Mariana Alonso. "We are now exploring in humans whether successfully treating a depressive episode depends on reactivating these neural networks," concludes Chantal Henry, a Professor of Psychiatry at Université de Paris, psychiatrist at the Centre hospitalier Sainte-Anne and scientist in the Institut Pasteur's Perception & Action Unit.