The molecular path of best resilience

We all experience stress, but some handle it better than others. A lot of research has focused on what makes animals and people susceptible to stress and how that, in turn, can trigger depression. It makes sense to study the condition, not the people that don’t experience it. Depression and susceptibility are the broken state. Resilience seems normal by comparison.

But resilience is not just the absence of susceptibility. It turns out that a protein called beta-catenin plays an active role in resilience. A new study, from Eric Nestler’s laboratory at the Mount Sinai School of Medicine in New York City, also identifies a large number of new targets that could help scientists understand why some people are susceptible to stress — and how they might be made more resilient.

“When people study stress responses, we often just assume that in an animal that’s stressed, there’s an active process that creates these depression-like behaviors,” says Andre Der-Avakian, a neuroscientist at the University of California, San Diego. “But this study and studies from others have shown that resilience is also an active process.”

The nucleus accumbens is an area of the brain most often linked with reward and pleasure from items we enjoy, such as food or drugs. But the area also shows changes in people with depression. “It makes sense — here’s a region important in responding to rewards,” Nestler explains. “One of the symptoms of people with depression is that they don’t derive pleasure from things in life.”

In studies seeking molecular targets for depression and stress in the nucleus accumbens, different pathways tend to pop up. Several of these pathways, Nestler’s lab noticed, lead to a protein called beta-catenin. Beta-catenin is found throughout the body, where it plays important roles in how genes become translated into proteins. But in the brain, it does double duty, also regulating the connections between brain cells that help our neurons communicate.

The many functions of beta-catenin make it a difficult target to study. It’s hard to, say, increase levels of beta-catenin all over the brain and determine whether any changes resulted from effects on brain cell connections or the effects on DNA within the brain cell nucleus.

Nestler’s lab was working with a virus that inserts genes into the genomes of mice and increases levels of beta-catenin. But by a stroke of luck, the technique only boosted beta-catenin in cell nuclei, not in the connections between cells. So the lab could narrow down the DNA functions of beta-catenin in the brain.

The scientists inserted the virus into cells in the nucleus accumbens of mice, and then exposed the mice to social defeat stress. “It’s a very relevant and useful model,” says Olivier Berton, a neurobiologist at the University of Pennsylvania Perlman School of Medicine in Philadelphia. “A dominant mouse is used as a bully to inflict defeat on experimental animal. So a subset of the animals are exposed to repeated bullying, and develop behavioral changes resembling depression. It’s stress from social interactions, which is the more common type of human stress.” Mice susceptible to social defeat become antisocial, avoiding other new mice even though those new mice have never been aggressive.

Whereas control mice showed symptoms of social defeat, mice with boosted beta-catenin levels in the nucleus accumbens showed resilience. Blocking beta-catenin, conversely, made mice more susceptible to social defeat stress.

Nestler’s lab also studied human cadaver brains and found that people diagnosed with depression when they died had lower beta-catenin levels in the nucleus accumbens than those who did not have depression.

There are several cell types in this brain area, but two of the most studied are cells that express dopamine D1 receptors and those that express dopamine D2 receptors. The D1 and D2 receptors are both proteins that are specific for the chemical messenger dopamine. Dopamine binds to the receptors, causing signal changes. But cells with D1 receptors and cell with D2 receptors have very different functions.  “D1 is the direct pathway to the substantia nigra, while D2 is indirect,” explains Der-Avakian. “Other labs have shown that D1 is involved in rewarding behaviors, while the D2 pathway is important in aversive and flexible behaviors.”

It turns out that the effects of beta-catenin were restricted to only the neurons that had D2 receptors, suggesting that beta-catenin was especially crucial to behavioral flexibility. Within these cells, beta-catenin recruits the protein Dicer. Dicer is an enzyme that trims RNA down into tiny fragments, called microRNAs.

These microRNAs attach on to messenger RNAs, the code required to make proteins, and cut off their activity. In this way, beta-catenin has the power to recruit a host of molecules that change the proteins the cell makes, contributing to a pathway that makes a mouse more flexible in the face of defeat.

So resilience to stress involves increases in beta-catenin in the nucleus accumbens, initiating a cascade of other effects via microRNA regulation of how proteins are made. The results show that resilience requires changes in signaling. It is not just the absence of a stress reaction. Instead, resilience, like susceptibility, requires change.

Berton says the finding opens up a “library of possible pathways that could be used by others as a starting point for more experiments.”

The work may have shown scientists a large number of targets for future investigation — but no immediate new ideas for treatment. “It’s difficult to translate this right away to clinical treatment because of the various roles of beta-catenin in other cell types,” Der-Avakian says. “But it identifies new molecular targets for susceptibility and resilience to stress.”

Nestler hopes the new molecular details in this study could help reveal new drug targets for depression. “Today’s antidepressants have the same mechanism as drugs developed several generations ago,” he says. “We need new approaches to find better treatments, and this study gives us a fundamental neurobiology with which to find such improvements.”

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