For some people, stress is a motivator to focus, work harder, and endure difficult circumstances until the stress ends. For others, stress quickly becomes overwhelming and spirals into paralyzing anxiety and depression.

A team of scientists at Cold Spring Harbor Laboratory have pinpointed a region of the brain that seems to control who will sink and who will swim. It’s called the medial prefrontal cortex (mPFC), and it has been previously associated with depression. The region is part of the default mode network, the circuitry responsible for self-awareness and introspection.

“Brain scans of depressed people have revealed significant hyperactivation of the mPFC,” said associate professor Bo Li, a principal investigator of this research, in an interview with Healthline. “The region is required for effective coping with stress, and its function has been implicated in a wide variety of mood and anxiety disorders. But we have never been able to move beyond correlation in humans.”

When mPFC-fueled introspection gets too strong and reward gets too weak, the result is two hallmark symptoms of depression: a tendency to get lost in thought and an inability to enjoy things.

Engineering Helplessness

To model the effects of stress, Li’s team employed a well-known theory called learned helplessness. They subjected mice to a series of uncontrollable, inescapable, randomly timed electric shocks over the course of an hour. The mice quickly learned that there was nothing they could do to make the pain stop.

The researchers then tested the mice to see how they responded to this stress. They placed the mice into a box, half of which was lined with an electric grid. Then they shone a light to signal to the mice that they were about to send an electric shock into the grid. If the mice fled to the other half of the box when they saw the light, or left quickly once the shock started, they were considered to be resilient. Despite their stressful conditioning, these mice still took action to protect themselves against further injury.

“Resilience is defined as ‘an ability to come back quickly after difficulty,’” said Li. “The majority will quickly avoid [the shocks]. But a subset of the mice, about 20 percent, will passively endure the shock. This helpless behavior is quite similar to what clinicians see in depressed individuals: an inability to take action to avoid or correct a difficult situation.”

Li examined the mice’s brains and found the expected: their mPFCs were more active if they were "depressed," and less active if they were resilient. But this correlation wasn’t enough to prove cause and effect on its own.

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Li’s team took the next step. Using a technique called chemical genetics, they took resilient mice and engineered them to have an overactive mPFC.

“We find that hyperactivation of the neurons in this region actually causes helplessness,” said Li. “We were able to convert once resilient mice into helpless ones. That makes these neurons an excellent target for treatment [of depression].”

Rebalancing the Brain

So why does hyperactivity of the mPFC cause depression?

When the default mode network is active, it decreases activity in its opposite half: the task-positive network, which is responsible for interacting with (and enjoying) the outside world. Normally, switching between the two networks allows people to shift between introspecting and paying attention to what’s around them. But when mPFC-fueled introspection gets too strong and reward gets too weak, the result is two hallmark symptoms of depression: rumination (the tendency to get lost in thought) and anhedonia (the inability to enjoy things).

Li’s research will add to knowledge available to scientists who are targeting the mPFC to treat depression. A few experimental techniques currently exist, including using electricity to stimulate the brain through the scalp, and implanting nets of electrodes deep into the brain to stimulate it directly.

The latter is more effective but also dangerous, since it requires brain surgery. “We have very little understanding about why it works,” said Li. “Our study sheds some light on one path that it might use to treat depression—it may be weakening neurons in the mPFC.”

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Li plans to take future research in this direction. “Beyond looking at how neurons in the mPFC become hyperactive, we are interested in trying to find ways to control the activity of the mPFC,” he said. “Our research may help to find less invasive treatments for depression.”

He added, “Complex neural mechanisms underlie the development of resilience or depression in the face of stress. With the advent of new techniques, scientists in the field are starting to unveil these mechanisms, which ultimately will lead to a better understanding of depression and better treatments.”