Gene discovery may pave the way for precision medicine approaches to treat depression

A team of scientists at the Medical University of South Carolina (MUSC) has identified a stress-regulatory gene that plays a role in the association between long-term stress and common types of depressive behavior in mice. Specifically, this gene was necessary for long-term stress to cause loss of interest in activities that were once rewarding or enjoyable. However, this gene was not involved in other common depression-like symptoms, such as increased social avoidance and anxiety-like behavior. Did.

The study was led by neuroscientists Dr. Makoto Taniguchi, Dr. Christopher Cowan, and Dr. Brandon Hughes, a neuroscience graduate student at MUSC at the time of the study. Currently, Mount He is a postdoctoral fellow at the Icahn School of Medicine in Sinai.

The finding that a gene pathway affected only one type of depressive behavior could have implications for how depression is treated, Taniguchi said.

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

Makoto Taniguchi, Ph.D., Neuroscientist, MUSC

Not everyone with long-term stress develops depression, says Taniguchi, chair of MUSC’s Neuroscience Division, member of the Brain & Behavior Research Foundation’s Scientific Council, and a close collaborator. explained Cowan, the author.

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

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

Effects of stress on the brain

Taniguchi leads a laboratory in the Department of Neuroscience investigating the relationship between stress and depression in the brain. In mice, long-term stress reduces function in the front of the brain, he said. Scientists have long believed that this loss of brain activity in the frontal lobe of the brain contributes to the symptoms of depression.

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

They knew that the gene NPAS4 was involved in the functioning of a part of the brain called the prefrontal cortex. They also knew it would act as a “master regulator”. That means it can change the way many genes are expressed based on brain activity.

Exposure of mice to stress induces NPAS4 in the prefrontal cortex. NPAS4, in turn, alters gene expression and impairs the function of this key brain region associated with reward. This gene expression change is also found in the brains of people with psychiatric disorders such as depression.

The researchers speculated that NPAS4 may play an important role in linking long-term stress and depression-like behavior.

To test this hypothesis, the research team manipulated NPAS4 in stressed mice and observed how the mice behaved. Surprisingly, NPAS4 did not affect all depressive behaviors, only loss of interest in pleasurable activities. NPAS4 was not involved in either social avoidance or anxiety-like behavior.

One size does not fit all

The team’s findings suggest that there is not one central mechanism by which stress drives various symptoms of depression. Instead, multiple pathways may link stress to different types of symptoms. there is.

The diagnostic manual lists a variety of depressive symptoms, including energy loss, sleep disturbances, and difficulty concentrating. However, most people with major depressive disorder develop only some of the common symptoms. In other words, depression is not “one size fits all”.

The results of this study, which identifies novel brain mechanisms associated with a single depression-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 about the idea 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 disorders, such as anxiety disorders, substance use disorders, and schizophrenia.

Targeting specific symptoms can be a way to provide more effective and personalized treatment. For example, transcranial magnetic stimulation (TMS) is a non-invasive treatment for depressed patients and is typically used when other treatments are ineffective. In TMS, an electronic magnetic coil is placed near an individual’s forehead and a magnetic field stimulates nerve cells in the brain. The findings of this study help us know how to more effectively target the parts of the brain most relevant to the symptoms patients are experiencing.

“Depression is complex and presents with different symptoms for each individual,” Cowan said. “Understanding the brain mechanisms underlying various symptoms, and recognizing that they may differ, will lead to precision medicine approaches to treat specific symptoms in individuals suffering from mental disorders. It may open the way.”