Depression: Neuronal dysfunction in the amygdala may contribute to negative perceptions of the environment.
Depression is often marked by an excessive tendency to perceive sensory stimuli and everyday situations in a negative light. The mechanisms behind this "negativity bias," which can drive the development of depressive symptoms, had largely remained unclear. To investigate this, scientists from the Institut Pasteur and the CNRS, in collaboration with psychiatrists from Paris Psychiatry and Neurosciences GHU, Inserm, and the CEA, examined the amygdala’s function during depressive episodes. Their research indicates that depression alters specific neural circuits, reducing activity in neurons responsible for positive perceptions while overactivating those involved in negative perceptions. These findings, published in Translational Psychiatry in September 2024, may open new avenues for developing drugs to treat patients resistant to conventional therapies.
Between 15% and 20% of individuals experience a depressive episode, characterized by deep and lasting distress, at some point in their lives. However, about 30% of people with depression do not respond to standard antidepressant treatments. To develop new therapies, it is essential to understand the mechanisms behind depression, particularly the negativity bias. This bias causes patients to view the world and sensory stimuli overly negatively, making pleasant stimuli less appealing and unpleasant stimuli even more aversive, thus sustaining depressive symptoms.
"We now know that the amygdala is not only involved in emotional responses to environmental stimuli, influencing attraction or repulsion, but also plays a key role in depression," says Mariana Alonso, co-last author of the study and head of the Emotional Circuits group at the Institut Pasteur. "Recent studies have shown the role of specific neural circuits in the amygdala in perceiving positive or negative stimuli, but their alteration during depressive episodes had not been observed before."
To explore the role of these circuits in negativity bias, researchers used a mouse model for depression, in collaboration with psychiatrists from the Paris Psychiatry and Neurosciences University Hospital Group (GHU), Inserm, and the CEA. These mice, like depressed bipolar patients, exhibited anxiety and stress behaviors (e.g., lack of self-grooming, staying close to walls, and preferring darkness) and showed a negative valence bias to olfactory stimuli (e.g., little attraction to female urine and strong aversion to predator odors).
"We analyzed amygdala activity by measuring the neuronal networks involved in interpreting olfactory stimuli," explains Alonso. The findings revealed that, during depression, neurons encoding positive stimuli were less active than normal, while those encoding negative stimuli were more activated. In other words, depression appears to disrupt amygdala circuits responsible for processing environmental stimuli, further intensifying the negative bias typical of the condition.
These insights are crucial for developing new treatments for depression and bipolar disorder, where patients experience extreme mood swings. "We were able to partially reverse the negative emotional bias and related depressive behaviors in mice by overactivating neurons responsible for positive encoding of stimuli," says Alonso. "This offers a promising pathway for future therapies," she adds. "We are now exploring whether successfully treating a depressive episode in humans involves reactivating these neural networks," concludes Chantal Henry, Professor of Psychiatry at Université de Paris and psychiatrist at Centre hospitalier Sainte-Anne.