Stress and the susceptible brain

We all respond to stress in different ways. Some of us work harder. Others drink more or eat our feelings. Sometimes we experience sleep loss, heart palpitations or sweats. When the stress dissipates, many of us go back to our daily lives, none the worse for wear. We are resilient. But some people find that stress is a first step on the way to a major depressive episode.

It’s not quite clear what’s different between people who go back to normal after stress, and those who descend into depression. “One of the most important questions is, how do the brains of resilient animals (or humans) differ from those that are vulnerable to depression following stress?” asks John Morrison, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York. A new study from Minghui Wang and colleagues at Cold Spring Harbor Laboratory in New York provides a new hint. Mice with a depressive-like response to stress have stronger connections between neurons in the medial prefrontal cortex of the brain following the stress. Resilient mice show weaker connections. The mechanism could help scientists understand why some people respond to stress with depression, while others are able to shake it off.

The prefrontal cortex is best known for its role in executive function — thought, memory, prediction and other tasks. But dysfunction in some areas of the cortex, particularly one called Brodmann area 25, has been linked with recurring major depressive disorder. Scientists have been electrically stimulating this area to relieve depression in patients. But researchers still don’t understand what makes this brain area important in depression, and how dysfunctions might occur.

“I’ve had a long interest in the mechanism of human diseases like depression,” says study coauthor Bo Li, a cellular and behavioral neuroscientist at Cold Spring Harbor. “The idea has been to identify an area that is responsible, to link a mechanism in the brain to a behavior.” Wang, Li and their colleagues were especially interested in changes to the mouse prefrontal cortex following stress.

They used a technique known as learned helplessness. Mice are placed in a small chamber with a metal grid floor. In the chamber, they receive an hour of randomly presented painful, but harmless, foot shocks through the floor. After two days of training, the mice get an opportunity to escape the shocks. When a light comes on, the mice can head to another chamber. If they are fast, they will never feel another shock again.

After training, about 80 percent of the mice learn to head for the door when they see the light. They are resilient, and can still change their behaviors in response to stress. But 20 percent of the mice react differently: They display what is called learned helplessness, and instead of making their escape, hunker down and take the punishment. These mice are “susceptible,” and are a model of depression. They display other symptoms such as weight loss and anhedonia, the inability to experience pleasure.

The scientists looked at the medial prefrontal cortices of these resilient and susceptible mice, an area that corresponds to Brodmann area 25 in humans. They were looking for c-Fos, a gene that’s turned on in the first 15 minutes after a brain cell is activated. The authors then looked at the synapses, or connections, between those activated neurons.

In results published in the May 27 Journal of Neuroscience, Wang and Li showed that activated brain cells fell into two different patterns in susceptible and resilient mice. Susceptible mice had stronger neuronal connections in the stress-activated cells following learned helplessness than control animals. Resilient mice showed the opposite effect — weaker connections in the stress-activated cells.

But the presence of weak connections in resilient mice doesn’t mean that learned helplessness directly caused those connections to change. So the authors took resilient mice, and artificially increased the cell activity in the prefrontal cortex. With increased activity, the resilient mice became susceptible.

The results show that different patterns in synapse strength can be linked to susceptible or resilient behaviors in mice. It’s an “important neurophysiological basis for the different behavioral responses,” Morrison says. The results also mirror findings showing increased activity in Brodmann area 25 in depressed patients. “It’s quite exciting,” Li says, “because we saw changes in mice that could be used to analyze the changes in brain activity in depression.”

But of course, the study tested one stressor and one brain area. Learned helplessness is not the only model to produce depressive-like behaviors in animals and is a relatively short-term stressor. Li hopes to look at other behavioral models to see how the brain adapts long-term.  Morrison notes that it is also important to look at other factors, such as age and sex.

And while the prefrontal cortex is clearly an important area for depressive behaviors, it is certainly not the only one involved. “The devil is in the details,” explains Helen Mayberg, a neurologist at Emory University in Atlanta. “It’s not any one region. Any lab may pursue this pathway or that pathway, but no one should expect that any one place, any one cell is explaining depression.” But she notes that this study helps to show how important the prefrontal cortex is. This study is another step, she says, in “piecing the circuits together.”