Downstream signals found in brain circuits regulating depression

Understanding and treating depression, a potentially debilitating mental condition that affects millions of people around the world, remains a priority among neuroscience researchers. For example, major depressive disorder (MDD) affects approximately 33 million people, approximately 5% of the world's adult population.

Emotion regulation is an important brain function that allows the suppression of emotions and depressive states, and is considered one of the protective mechanisms in MDD. However, the neurobiological mechanisms underlying how the brain regulates depressive states are still unclear.

To explore this issue, a recent study conducted by Satoko Amemori and Ken-ichi Amemori and published in Nature Communications examined how specific brain circuits regulate emotional responses by providing new evidence on the neural basis of depression.

In this study, the researchers focused on the dorsolateral prefrontal cortex (dlPFC), which has long been known for its role in emotion regulation. The researchers examined how dlPFC signal changes in depression and identified the mechanism by which dlPFC regulates the cingulostriatal network.

Unraveling the neural mechanisms underlying depressive behavior in primates may lay the groundwork for the development of new therapeutic approaches targeting specific brain circuits.

The study examined the so-called “top-down influence” of the dlPFC on the depression-related cingulostriatal network in the context of emotional regulation. Scientists have also examined how these circuits influence decision making and emotional reactions.

Using microstimulation techniques, researchers modified the neural activity of the subgenual anterior cingulate cortex (sgACC) in rhesus monkeys (Macaca mulatta) and were able to experimentally induce pessimistic decision-making and depressive states.

During these stimulation experiments, the researchers also recorded local field potentials (LFPs) to analyze the top-down influence of the dlPFC on the cingulostriatal network.

They found that experimentally induced pessimistic decision making was accompanied by a decrease in the top-down influence of the dlPFC on the cingulostriatal regions.

This finding suggests that disruption of the top-down signal from cognition to emotion may lead to pessimistic decision making, which is a characteristic feature of MDD.

One of the key findings of the study was the role of beta oscillations in frontostriatal circuits. Beta oscillations have long been associated with motor control and attention, and more recently they have also been linked to cognitive functions such as working memory.

In this new study, effective depressive microstimulation of the sgACC decreased the magnitude of beta oscillations encoding positive variables associated with decision making.

Stim: microstimulation, dlPFC: dorsolateral prefrontal cortex, pACC: pregenual anterior cingulate cortex, sgACC: subgenual anterior cingulate cortex.
Source: Nature Communications (2024). DOI: 10.1038/s41467-024-48375-1

This decrease in beta oscillations is important because it indicates a link between sgACC activity and negativity bias in decision making, providing a potential mechanism for how the brain processes positive and negative values.

The study also examined interactions between regions within the frontocingulo-striatal network. By examining factors such as coherence and Granger causality (a statistical test to determine whether a variable can be meaningfully described as a dependent variable), the researchers found that effective sgACC microstimulation changed these interactions, reflecting network involvement in the decision-making process.

They found that the “top-down influence” of the dlPFC on the cingulostriatal network was encoded by LFP beta oscillation, and a decrease in top-down influence was associated with experimentally induced depressive state.

These results highlight the important role of this network in emotion regulation and decision making, and how its dysfunction can lead to depressive behavior.

This study provides valuable insight into the neural basis of depression, highlighting the role of specific brain circuits in regulating emotional responses. Importantly, the study established a primate model of depression and showed that frontocingulo-striatal circuits are involved in regulating the limbic system through beta oscillations.

Importantly, the researchers were able to demonstrate that monkeys exhibit depressive behavior in the absence of this regulation. By revealing the mechanisms underlying depressive behavior in primates, this research opens new avenues for developing more effective treatments for MDD.