Brain circuits tied to depression’s “negativity effect” uncovered

A recent study conducted by scientists in France and published in Translational Psychiatry offers new insights into how depression affects the brain’s processing of positive and negative experiences. The research found that during depressive episodes, specific brain circuits become hyperactive in response to negative stimuli, while those involved in perceiving positive stimuli are less active. This shift in brain activity may contribute to the pessimistic outlook commonly seen in individuals with depression.

Understanding how depression affects the brain’s interpretation of everyday experiences is important for developing more effective treatments. Depression is marked by a “negativity bias,” where people interpret situations and sensory experiences—such as sights, sounds, and smells—in an excessively negative way.

Scientists know this bias plays a significant role in reinforcing depressive symptoms, but they don’t fully understand the brain mechanisms behind it. The new study aimed to explore the brain circuits involved in this bias, focusing on the amygdala, a brain region known for its role in processing emotions.

“Negative emotional biases alter the perception of emotional stimuli in individuals with depression. As a result, pleasant stimuli lose their hedonic value, while negative stimuli become even more negative,” said study authors Chantal Henry (a professor of psychiatry at Paris Cité University) and Mariana Alonso (a research associate at Institut Pasteur), who are both affiliated with the Emotional Circuits research group.

“These biases lead to the development and maintenance of depressive symptoms and are assessed by various tests in humans. However, there are very few tests in animals to measure emotional bias in a translational way. Importantly, restoring these biases is essential for recovering from a depressive state, making it crucial to understand their mechanisms.”

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To investigate this, the researchers used both human participants and a mouse model of depression. In the human part of the study, the team recruited 48 adults with bipolar disorder, 23 of whom were currently experiencing a depressive episode. They also included 11 individuals without a history of mental illness as a control group. All participants completed an “odor test,” a test designed to assess how they rated different smells. Using this method, the researchers could determine whether the participants had a negativity bias in their perception of odors, especially for those in a depressive state.

“The olfactory preference test we developed is simple but allows us to study essential emotional processes involved in the onset and maintenance of depression,” Henry and Alonso explained.

In parallel, the scientists created a similar depressive state in mice by giving them a chemical (corticosterone) that induces depression-like behavior. They then used an odor preference test, where the mice were exposed to neutral, pleasant, and unpleasant odors, and their behaviors were observed. Researchers monitored the time the mice spent near each odor, assessing whether depressive mice displayed a similar negativity bias.

To further understand the brain mechanisms involved, the scientists used imaging techniques on the mice to examine changes in brain circuits, focusing on two specific pathways in the amygdala: the basolateral amygdala-to-nucleus accumbens pathway and the basolateral amygdala-to-central amygdala pathway. The first pathway is generally associated with positive experiences, while the second is associated with negative experiences.

The researchers found significant differences between the depressed and non-depressed groups, both in humans and in mice. Depressed individuals and depressive-like mice rated or responded more negatively to odors, even to neutral or positive ones. This negativity bias was associated with heightened activity in the brain circuits responsible for processing negative experiences. In the mice, researchers observed that the basolateral amygdala-to-central amygdala circuit was more active in those with depressive-like symptoms, while the pathway associated with positive experiences was less active.

The mice treated with the antidepressant fluoxetine showed a reduction in negativity bias, suggesting that these brain pathways are indeed tied to depressive symptoms. When specific neurons in the basolateral amygdala-to-nucleus accumbens pathway were activated in the depressive mice, their negativity bias diminished, and they responded more positively to neutral and pleasant smells. However, this manipulation did not change their negative response to unpleasant odors, suggesting that additional brain pathways might be required to fully address this bias in depressive states.

“Using an olfactory test, we demonstrated the presence of a negative emotional bias in mice with a depressive phenotype (which mimics some symptoms of human depression), closely resembling what is observed in depressed patients (pleasant odors are less pleasant, and unpleasant odors are more aversive),” Henry and Alonso told PsyPost. “We showed that this bias is linked to an imbalance in the activation of specific neurons within a small brain area, the amygdala, which generates emotions. By manipulating these neurons in mice, we were able to correct this bias by increasing attractiveness of positive odors, and induce recovery from the depressive phenotype, demonstrating that it represents a critical target for understanding the action of antidepressants.”

While the study sheds light on how certain brain circuits contribute to negativity bias, it has some limitations. The odor tests used in both humans and mice were a simple way to measure emotional responses but might not capture the full complexity of depressive symptoms. Also, while the mouse model of depression is helpful for studying some aspects of the illness, it cannot replicate the full experience of depression in humans, particularly in cases of bipolar disorder. Future studies could explore additional brain circuits that might contribute to depressive symptoms, as well as examine whether similar biases occur with visual or auditory stimuli.

Long-term, this research could help scientists develop more targeted therapies for depression. By focusing on the specific brain circuits associated with negative and positive perception, researchers hope to create treatments that reduce negativity bias in individuals with depression, offering new ways to alleviate symptoms for patients who do not respond to traditional antidepressants.

“Around 30% of patients with depression are resistant to conventional medical treatment with antidepressants,” Henry and Alonso said. “Our goal is to pursue this research to improve our understanding of the mechanisms at the cellular and molecular levels, in order to identify more precise molecular targets exhibiting antidepressant properties.”

The study, “Disrupted basolateral amygdala circuits supports negative valence bias in depressive states,” was authored by Mathilde Bigot, Claire-Hélène De Badts, Axel Benchetrit, Éléonore Vicq, Carine Moigneu, Manon Meyrel, Sébastien Wagner, Alexandru Adrian Hennrich, Josselin Houenou, Pierre-Marie Lledo, Chantal Henry, and Mariana Alonso.