One notable feature of depression is the tendency to view sensory inputs and daily experiences in a particularly negative light. However, the underlying processes of this “negativity bias,” which can lead to the onset of depressive symptoms, have been mostly unexplored. To better understand this phenomenon, researchers investigated the amygdala and its activity during depressive episodes. The results indicate that being in a depressive state modifies certain neural circuits, decreasing the response of neurons that process positive stimuli while increasing the response of those that handle negative ones.
One notable feature of depression is the tendency to view sensory inputs and daily experiences in a particularly negative light. However, the underlying processes of this “negativity bias,” which can lead to the onset of depressive symptoms, have been mostly unexplored. To better understand this phenomenon, researchers from the Institut Pasteur and the CNRS, along with psychiatrists from Paris Psychiatry and Neurosciences GHU, Inserm, and the CEA, studied the amygdala and its functioning during depressive episodes. Their results point to changes in specific neural circuits during depression, which decrease the activity of neurons linked to positive perception and increase the activation of those linked to negative perception. These findings could lead to the creation of new medications for patients who do not respond to traditional therapies, and were published in the journal Translational Psychiatry in September 2024.
Between 15% and 20% of individuals encounter a depressive episode, described as “a state of deep, lasting distress,” at some point in their lives. However, around 30% of people with depression do not respond to standard treatments like antidepressants. To create new therapies, it’s crucial to enhance our understanding of the mechanisms behind depression, especially those contributing to the “negativity bias.” Depression skews a person’s perception of the world and sensory inputs negatively—making positive experiences seem less appealing and negative ones seem worse—contributing to the persistence of depressive symptoms.
“We now understand that the amygdala is not only involved in emotional responses to stimuli, driving feelings of attraction or aversion, but it also plays a significant role in depression,” notes Mariana Alonso, co-lead author of the study and leader of the Emotional Circuits group at the Institut Pasteur’s Perception & Action laboratory. “Recent studies have highlighted the specific neural circuits in the amygdala responsible for processing environmental stimuli positively or negatively, but the impact of depression on these circuits had not been observed until now.”
In order to investigate how these circuits contribute to the negativity bias, researchers from the Institut Pasteur and the CNRS worked alongside psychiatrists from Paris Psychiatry and Neurosciences GHU, Inserm, and the CEA to examine the amygdala’s activity in a mouse model of depression. These mice, similar to depressed bipolar patients, displayed anxiety and stress indicators (they stopped grooming, remained close to walls, and preferred dark environments) and reacted negatively to olfactory signals (showing minimal interest in female urine odor, which typically attracts male mice and strong aversion to predator scents).
“To assess the amygdala’s functionality during depression, we observed the activity of neuronal networks that influence the positive or negative interpretation of smells,” Mariana Alonso explains. The research demonstrated that, during depressive states, neurons that usually respond to positive stimuli become less active, while those that process negative stimuli become more engaged. Essentially, depression appears to disrupt the amygdala’s circuits involved in processing environmental signals, which intensifies the negative bias associated with depression.
This information holds great promise for developing new treatments for those dealing with depression and individuals with bipolar disorder, who suffer from prolonged and intense mood fluctuations. “We managed to partially counteract the negative emotional bias and related depressive behavior in mice by stimulating the neurons that respond to positive environmental cues. This presents an intriguing pathway for creating new therapies,” Mariana Alonso emphasizes. “We are currently investigating whether effectively treating a depressive episode in humans relies on reactivating these neural networks,” adds Chantal Henry, a Professor of Psychiatry at Université de Paris, psychiatrist at Centre hospitalier Sainte-Anne, and researcher at the Institut Pasteur’s Perception & Action Unit.
