Depression: is the amygdala responsible for the negative perception of the environment? 🧠

Depression is characterized, among other things, by a tendency to excessively perceive sensory stimuli and life situations in a negative way. However, the mechanisms underlying this "negativity bias," which may fuel depressive disorder, have so far remained poorly understood.


To elucidate the issue, researchers from the Institut Pasteur and CNRS, in collaboration with psychiatrists from GHU Paris Psychiatry and Neuroscience, Inserm, and CEA, decided to explore the amygdala and observe its functioning during depressive episodes. They then highlighted that the depressive state induces an alteration of specific neuronal circuits, with a reduction in the activity of neurons involved in the pleasurable perception of positive stimuli, and conversely, an overactivation of neurons responsible for the perception of negative stimuli.

These results, which could help develop new medications for those resistant to conventional treatments, were published in the journal Translational Psychiatry in September 2024.

Between 15 and 20% of the population experiences a depressive episode¹ at some point in their lives, meaning "a state of deep distress that lasts." However, 30% of depressive patients are resistant to traditional drug treatments, such as antidepressants.

To develop new therapies, it is essential to better understand the mechanisms underlying the depressive state, particularly those inducing a "negativity bias." Indeed, depression leads patients to perceive the world and all sensory stimuli excessively negatively—pleasurable stimuli become less appealing, and unpleasant stimuli more aversive—fostering the development and maintenance of depressive symptoms.

It is now known that the amygdala is involved in assessing the emotional value of environmental stimuli, resulting in attraction or repulsion, and that it also plays a role in depression.


"More recently, the role of specific neuronal circuits in the amygdala in the positive or negative perception of environmental stimuli has been highlighted, but we had never before observed the alteration of these circuits during a depressive episode," says Mariana Alonso, co-lead author of this study and head of the Emotional Circuits group within the Perception and Action lab at the Institut Pasteur.

To learn more about the involvement of these circuits in the negativity bias, researchers from the Institut Pasteur and CNRS, in collaboration with psychiatrists from GHU Paris Psychiatry and Neuroscience, Inserm, and CEA, decided to study the activity of the amygdala in a mouse model of depression.

As with depressed bipolar patients, these mouse models exhibit so-called anxiety and stress behaviors (neglect their grooming, stick to the walls, seek refuge in the dark) and respond to olfactory stimuli with a negative valence bias (they are very little attracted to the smell of female urine, usually attractive to male mice, and strongly repelled by predator scents).

"To study the functioning of the amygdala during depression, we measured the activity of certain neuronal networks involved in the more or less negative interpretation of olfactory stimuli," explains Mariana Alonso. The scientists were then able to demonstrate that in a depressive state, neurons preferentially involved in coding positive stimuli are less active than usual, while neurons preferentially involved in coding negative stimuli are strongly solicited.

In other words, depression seems to induce a dysfunction in the amygdala circuits involved in coding environmental stimuli, which in turn fosters the negative valence bias characteristic of depression.


These data are extremely valuable for developing new treatments for people with depression but also for those with bipolar disorder, who experience mood swings that are disproportionate in both duration and intensity. "We were able to partially reverse the negative emotional bias induced in the mice, as well as the associated depressive behavior, by hyperactivating neurons involved in positive environmental stimuli coding. This is a promising avenue to explore for developing new treatments," emphasizes Mariana Alonso.

"We are now exploring in humans whether recovery from a depressive episode depends on the restoration of activation in these neuronal networks," concludes Chantal Henry, professor of psychiatry at the University of Paris, psychiatrist at Sainte-Anne Hospital, and researcher within the Perception and Action unit at the Institut Pasteur.