Gene discovery could pave way for precision medicine approaches to treat depression

A team of scientists from the Medical University of South Carolina (MUSC) have identified a stress-regulated gene that plays a role in linking long-term stress to a common type of depressive behavior in mice. Specifically, this gene was required for long-term stress to produce a loss of interest in once rewarding or enjoyable activities – often referred to as anhedonia. However, the gene did not play a role in other common depression-like symptoms, such as social avoidance and increased anxiety behaviors. The team reported their findings recently in eLife.

The study was led by neuroscientists Makoto Taniguchi, Ph.D., and Christopher Cowan, Ph.D., as well as Brandon Hughes, Ph.D., who at the time of the study was a graduate neuroscience student at MUSC and is now a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai.

The finding that the genetic pathway only affected one type of depressive behavior could have implications for how we treat depression, Taniguchi said.

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

Makoto Taniguchi, Ph.D., neuroscientist, MUSC

Not everyone who suffers from long-term stress develops depression, explained Cowan, chair of MUSC’s department of neuroscience, a member of the scientific advisory board of the Brain & Behavior Research Foundation and a close collaborator of Taniguchi.

“Many people can bounce back from chronic stress,” he said.

However, some people who experience repeated stress develop depressive symptoms. Understanding how stress and depression are linked in the brain can help us develop better treatments for people with mental disorders.

How stress affects the brain

Taniguchi directs a lab in the Department of Neuroscience that examines the relationship between stress and depression in the brain. In mice, long-term stress decreases the functioning of the front part of the brain, he said. People with major depressive disorder often have reduced brain activity in the same part of the brain. Scientists have long thought that this loss of brain activity in the front part of the brain contributes to symptoms of depression.

Taniguchi and Cowan wondered if there might be an important intermediary linking long-term stress to the development of depressive behavior.

They knew that the NPAS4 gene was involved in the functioning of a part of the brain called the prefrontal cortex. They also knew it acted as a “master regulator”, meaning it could alter how many genes are expressed based on brain activity.

Exposure of mice to stress triggers NPAS4 in the prefrontal cortex. In turn, NPAS4 alters gene expression and reduces the functioning of this important reward-related region of the brain. This change in gene expression is also seen in the brains of people with mental disorders, such as depression.

The research team hypothesized that NPAS4 may play a crucial role in linking long-term stress to depression-like behaviors.

To test this hypothesis, the team manipulated NPAS4 in stressed mice and observed their behavior. Surprisingly, NPAS4 did not affect all depressive behaviors – only loss of interest in pleasurable activities. NPAS4 was not implicated in social avoidance or anxiety behaviors.

One size does not fit all

The team’s findings suggest that there is no central mechanism by which stress causes the various symptoms of depression. Instead, multiple pathways could link stress to different types of symptoms.

Diagnostic manuals list a variety of different depressive symptoms, including loss of energy, sleep problems, and difficulty concentrating. However, most patients with major depressive disorder develop only some of the common symptoms. In other words, depression is not “one size fits all”.

The study findings, which identify a new brain mechanism associated with a single depressive-like symptom, support the idea of ​​treating mental health disorders at the symptom level rather than the diagnostic level. They also suggest that effective treatments may need to target distinct brain mechanisms.

“I’m excited that we can start focusing on individual symptoms,” Cowan said.

Cowan explained that some depressive symptoms can also be experienced by people with other mental health conditions, such as anxiety disorders, substance use disorders and schizophrenia.

Targeting specific symptoms could be a way to offer more effective and personalized treatments. For example, transcranial magnetic stimulation (TMS) is a non-invasive treatment for people with depression that is usually used when other treatments have not been effective. During TMS, an electronic magnetic coil is placed near an individual’s forehead and the magnetic fields stimulate nerve cells in the brain. The results of this study may help shed light on how to more effectively target the parts of the brain that are most relevant to the symptoms someone is experiencing.

“Depression is a mixed thing — different symptoms show up in different individuals,” Cowan said. “Understanding the brain mechanisms underlying various symptoms and recognizing that they are potentially distinct will likely pave the way for precision medicine approaches to address specific symptoms in people with mental health disorders.”