Key Mediator of Anhedonia-Like Behavior Identified

An MUSC team of researchers uncovered a stress-regulated gene that is important in the relationship between chronic stress and typical depressed behavior in mice. This gene was found to be required for persistent stress to cause anhedonia or a loss of interest in formerly rewarding or pleasurable activities.

Other typical depressive-like symptoms, like social withdrawal and an increase in anxiety-like behavior, were not affected by the gene, though. The team just published its findings in eLife.

Brandon Hughes, PhD, who was a Graduate Student in neuroscience at MUSC and is now a Postdoctoral Fellow at the Icahn School of Medicine at Mount Sinai, as well as neuroscientists Makoto Taniguchi, PhD, and Christopher Cowan, PhD, served as the study’s principal investigators.

According to Taniguchi, the discovery that the genetic pathway only affected one form of depressive behavior may have an impact on how scientists approach treating depression.

If we can find the individual mechanisms for the different symptoms, we can target these symptoms specifically in future therapeutic strategies.”

Makoto Taniguchi, Medical University of South Carolina

According to Cowan, chair of the MUSC Department of Neuroscience, member of the Brain & Behavior Research Foundation’s scientific council, and close associate of Taniguchi, not everyone who experiences prolonged stress goes on to develop depression.

“Many individuals can rebound from chronic stress,” Taniguchi notes.

Some people, however, acquire depressive symptoms as a result of prolonged stress. Recognizing how stress and depression are linked in the brain can help find better treatments for those suffering from mental disorders.

How Stress Affects the Brain

Taniguchi directs a lab in the Department of Neuroscience that studies the brain's link between stress and depression. Long-term stress reduces functionality in the front region of the brain in mice, he claims. People suffering from serious depression frequently show lower brain activity in the same area of the brain. Scientists have long suspected that this decrease in frontal brain activity relates to depression symptoms.

Taniguchi and Cowan investigated if there was a vital link between long-term stress and the development of depressed behavior.

Researchers discovered the gene NPAS4 was involved in the function of the prefrontal cortex of the brain. They also knew it functioned as a “master regulator,” which means it could alter the expression of multiple genes based on brain activity.

Stress activates NPAS4 in the prefrontal cortex of mice. As a result, NPAS4 alters gene expression and impairs the function of this key reward-related brain area. This alteration in gene expression is also evident in the brains of patients suffering from mental disorders such as depression.

The researchers hypothesized that NPAS4 would be important in linking long-term stress to depression-like behaviors.

To test this theory, researchers altered NPAS4 in stressed mice and observed their behavior. Interestingly, NPAS4 did not alter all depressive behaviors; rather, it primarily affected the lack of interest in enjoyable activities. NPAS4 was not found to be implicated with social avoidance or anxiety-like behaviors.

One Size Does Not Fit All

The findings of the team indicate that there is no single central mechanism through which stress generates the various symptoms of depression. Instead, several mechanisms could link stress to various sorts of symptoms like tiredness, difficulty sleeping, and difficulty concentrating, according to diagnostic manuals.

However, the majority of patients with severe depressive disorder experience only a subset of the prevalent symptoms. To put it another way, depression is not a “one-size-fits-all” condition.

The outcomes of the research, which discover a new brain mechanism associated with a single depressive-like symptom, support the concept of treating mental health disorders at the symptom level rather than the diagnosis level. They also imply that effective treatments may require targeting different brain mechanisms.

“I'm excited about the idea that we can start to focus in on individual symptoms,” said Cowan.

Cowan explained that individuals with other mental health conditions, like anxiety disorders, substance use disorders, and schizophrenia, can also suffer some depressive symptoms.

Specific symptom targeting could be a means to provide more effective, individualized treatments. Transcranial magnetic stimulation (TMS), for instance, is a non-invasive treatment for depression that is often employed when other treatments have failed.

TMS involves the placement of an electronic magnetic coil near the individual’s forehead, and the magnetic fields stimulate nerve cells in the brain. The findings of this study can help to inform how to more effectively target the portions of the brain that are most relevant to the symptoms that someone is experiencing.

Depression is a mixed thing—different symptoms emerge in different individuals. Understanding the brain mechanisms underlying the varied symptoms, and recognizing that they are potentially distinct, is likely to pave the way for precision medicine approaches to treat specific symptoms in individuals struggling with mental health disorders.”

Christopher Cowan, Medical University of South Carolina