New Study of Brain Circuits Finds Key Links to Symptoms of Depression

Depression affects millions of individuals worldwide, and while current treatments can be useful to control mood and behavioral symptoms, for many, they often paint too wide a stroke, providing counterproductive side effects. Unsuccessful or incomplete treatment of depression stems from our inadequate understanding of the neural pathways that mediate various mood disorders.

However now, scientists at the University of California, San Diego have just released their findings that link specific wiring in the brain to distinct behavioral symptoms of depression.  In a new study, researchers found brain circuits tied to feelings of despair and helplessness and were able to alleviate and even reverse such symptoms in mice studies. Two populations of neurons were identified in the brain’s ventral pallidum region (part of the basal ganglia) as key to underlying depressive behavior.

Results from the new study were published online in Cell in an article entitled “Distinct Ventral Pallidal Natural Pop Populations Mediate Separate Symptoms of Depression.”

“We took an approach of studying depression in the sense that different brain areas and circuits of the brain might mediate or contribute to very discrete aspects of depression,” explained lead study investigator Daniel Knowland, a graduate student at UC San Diego “For example, brain area A might contribute to loss of appetite, brain area B to social withdrawal, and so forth.”

Utilizing a mouse model of depression, the researchers employed several tools to track brain pathways and specific areas of neurons involved in specific behaviors, including imaging techniques and social strategy behavioral models. Two populations of neurons were identified in the brain’s ventral pallidum region (part of the basal ganglia) as key to underlying depressive behavior.

“We identify two discrete circuits of parvalbumin-positive (PV) neurons in the ventral pallidum (VP) projecting to either the lateral habenula or ventral tegmental area contributing to depression,” the authors wrote. “We find that these populations undergo different electrophysiological adaptations in response to social defeat stress, which are normalized by antidepressant treatment. Furthermore, manipulation of each population mediates either social withdrawal or behavioral despair, but not both.”

“This is one of the first studies providing clear evidence showing that different brain circuitry is involved in different types of depressive behavior with specific symptoms,” noted senior study investigator Byung Kook Lim, Ph.D., assistant professor of neurobiology at UC San Diego. “Each area of the brain is different, with distinct cell types and connectivity, so if we can confirm that one area of circuitry is more involved in a particular symptom than another, we may eventually be able to treat a depression patient more efficiently than treating everyone the same way.”

The investigators found that these distinct brain regions in mice that displayed depression led to improved behavioral changes similar to those of healthy mice. More importantly, this study provides strong insight into understanding the interaction between several brain areas in depression. Previous studies have mainly focused on the role of certain brain areas in isolation. Researchers in the new study were able to examine connections across multiple regions and how one impacted the other.

The authors concluded that “distinct components of the VP PV circuit can subserve related, yet separate depressive-like phenotypes in mice, which could ultimately provide a platform for symptom-specific treatments of depression.”