Amygdala Neural Dysfunction May Underpin Depressive Negativity Bias

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.

Depression is characterized by, among other things, a tendency to perceive sensory stimuli and everyday situations in an overly negative manner. However, the mechanisms underlying this “negativity bias,” which might exacerbate the development of depression symptoms, were previously unclear.

To shed light on the issue, scientists from the Institut Pasteur and the CNRS, in partnership with psychiatrists from Paris Psychiatry and Neurosciences GHU, Inserm, and the CEA, chose to investigate the amygdala and how it functions during depressed episodes. Their findings¹ imply that a depressive state affects certain brain circuits, resulting in reduced activity of neurons involved in pleasant perceptions of positive stimuli and overactivation of those responsible for negative stimuli perception.

These results could pave the way for the development of new drugs for people resistant to conventional therapies.

Negative Bias

In depression, patients tend to perceive the world and all sensory stimuli in an excessively negative way. Pleasant stimuli become less attractive, and unpleasant stimuli become more undesirable. This contributes to the development and maintenance of depressive symptoms. This negative bias can be difficult to break without intervention.

“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. 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,”

said Mariana Alonso, co-last study author and head of the Emotional circuits group in the Perception & Action laboratory at the Institut Pasteur.

Depressive state in both BD patients and CORT-induced model for depression induce a negative olfactory bias (right) respect to healthy state (left). Patients present decreased number of odors rated as pleasant associated with increased number of rated unpleasant odors respect to control subject, while CORT-treated mice exhibit decreased approach behavior towards appetitive odors and increased avoidance behaviour towards aversive odors respect to control group. The chronic CORT administration elevates the activity of BLA projecting neurons to the CeA, which preferentially encode negative valence, and reduces the activity of BLA projecting neurons to the NAc, preferentially encoding positive valence.
Credit: Transl Psychiatry 14, 382 (2024). Doi: 10.1038/s41398-024-03085-6

To better understand how these circuits contribute to the negativity bias, researchers from the CNRS and Institut Pasteur, along with psychiatrists from the Paris Psychiatry and Neurosciences University Hospital Group (GHU), Inserm, and the CEA, chose to examine the amygdala’s activity in a mouse model of depression.

Encoding Environmental Inputs

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). 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).

The team measured the activity of some networks of neurons involved in the more or less negative interpretation of olfactory stimuli.

The researchers discovered that in a depressive state, neurons preferentially involved in encoding positive stimuli are less active than usual, but neurons preferentially involved in encoding negative stimuli are significantly more activated. In other words, depression appears to cause a malfunction in the amygdala circuits responsible for encoding environmental inputs, which promotes the negative valence bias characteristic of depression.

The resulting 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,”

explained Mariana Alonso.

“We are now exploring in humans whether successfully treating a depressive episode depends on reactivating these neural networks,”

concluded 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.

Bigot, M., De Badts, CH., Benchetrit, A. et al. Disrupted basolateral amygdala circuits supports negative valence bias in depressive states. Transl Psychiatry 14, 382 (2024). Doi: 10.1038/s41398-024-03085-6