Hyeon Son et al., PNAS (2012)

Neuron boost. Stressed, depressed rats show reduced neuron activity without treatment (left), but are restored to normal activity by the protein neuritin (right).

Why Stress Makes You Miserable

Stress really does mess with your mind. A new study has found that chronic stress can create many of the brain changes associated with mood disorders by blocking a gene called neuritin—and that boosting the gene's activity can protect the brain from those disorders. The results provide new insight into the mechanisms behind depression, anxiety, and bipolar disorder, and could offer researchers a novel target for drugs to treat those conditions.

Research has shown that mood disorders take a toll on patients' brains as well as on their lives. Postmortem studies and brain scans have revealed that the hippocampus (the brain's memory center) can shrink and atrophy in people with a history of depression and other mood disorders. People who live with mood disorders are also known to have low levels of brain-derived neurotrophic factor (BDNF), a growth factor that keeps neurons healthy. They also have low activity in the neuritin gene, which codes for a protein of the same name that may protect the brain's plasticity: its ability to reorganize and change in response to new experiences.

Ronald Duman, a neurobiologist at Yale University, and colleagues wondered if the poorly understood neuritin might play an important—and heretofore overlooked—role in depression and other mood disorders. They induced depression in a group of rats by subjecting them to chronic, unpredictable stress. Depriving them of food and play, isolating them, and switching around their day/night cycles for about 3 weeks left the rats with little interest in feeding or enjoying a sweetened drink. The rats also gave up and became immobile instead of swimming when placed in a tub of water—another measure of rodent depression.

All of the depressed rats showed low levels of neuritin gene activity, and all improved when treated with antidepressants. But boosting their neuritin protein levels helped just as much, the researchers report online today in the Proceedings of the National Academy of Sciences. The team found that increasing production of neuritin by injecting the rats with a virus that triggered the gene's expression protected the rats from brain cell atrophy and other structural brain changes seen in mood disorders, even when the rats were exposed to chronic stress.

"Neuritin produced a response that looked exactly like an antidepressant," says Duman. "I was surprised to find this molecule was sufficient, by itself, to block the effects of stress and depression."

To further confirm neuritin's role, the researchers blocked the activity of the gene in another group of rats without stressing them out. The rodents exhibited the same symptoms of depression as stressed rats.

The results add to a growing body of evidence that implicates stress in the development and progression of mood disorders, and it suggests that compounds mimicking neuritin's action are another way to treat them, says John Neumaier, a psychiatrist and neuroscientist at the University of Washington, Seattle, who was not involved in the work. "This is a great study, one that uncovers another layer in the biology of depression and antidepressants," he says. "It opens up a new therapeutic target."

That target is much-needed, adds neurobiologist Scott Russo of the Mount Sinai School of Medicine in New York City. Only about 30% of people with mood disorders achieve full remission on existing antidepressants, Russo says, "and there's been a fundamental failure to turn new discoveries into new drugs we can use in clinical practice … if someone is willing to take the risk and the financial responsibility, neuritin could be a good approach."

Posted in Biology, Brain & Behavior