Guest Post: Can we engineer resilience to depression?

Welcome back to a new year of neuroscience blogging! This week, we have a guest contribution by Camilla d’Angelo on the molecular basis of psychological resilience. Camilla is a PhD student in Experimental Psychology, studying the brain basis of compulsivity. Thanks, Camilla!

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Whilst most of us are able to recover from difficult experiences, some people never do. A single molecule in the brain that promotes resilience might help to explain the difference.

From unemployment and financial hardship to the death of a loved one, many of us have had to deal with difficult experiences at some point in our lives. For most of us this just means going through a rough patch – eventually we bounce back and move on with our lives. For others, stress and trauma are important triggers for mental health problems such as depression and post-traumatic stress disorder (PTSD).

The ability to bounce back from difficult life experiences is known as resilience. Resilience was first documented in the 1970s, when a group of psychologists noticed that some children growing up in poverty or with alcoholic or mentally ill parents failed to exhibit destructive behaviours later in life. These findings prompted researchers to try to better understand why some people are affected by stress and others are not.

It is now known that people who recover from adversity are often optimistic, altruistic and tend to use more active coping strategies, such as adopting a problem-solving approach in the face of stress. It is only in recent years, however, that research has uncovered a variety of biological markers that underpin resilience, with genetic influences and several key neurochemicals playing a role.

For instance, neuropeptide Y (NPY), a hormone that is released in the brain during stress and acts to dampen down the stress response, has been established as a key resilience marker. This was demonstrated in a seminal study, which found that NPY levels went up in soldiers participating in high intensity military training. Moreover, Special Forces soldiers, who are trained to be more stress hardy, had higher levels of NPY than typical soldiers. The discovery of NPY and other molecules that are active in resilient people has inspired the development of drugs to promote resilience in those prone to stress-induced disorders such as PTSD and depression. For instance, researchers are now investigating the possibility of developing an NPY drug to help prevent PTSD.

Understanding resilience has never been more important: depression is now the leading cause of disability worldwide, with an estimated 350 million people affected. What’s more, typical antidepressants such as Prozac are only effective in about two thirds of patients and take several weeks to have an effect. The discovery of these drugs, which increase levels of the neurochemical serotonin in the brain, led to the serotonin hypothesis of depression. But we now know that serotonin is only part of the story.

It turns out that Prozac and related antidepressants activate many molecules inside cells, which in turn activate slow processes, including gene expression. This helps to explain why these drugs take so long to show therapeutic effects. Already, efforts to develop faster and more effective antidepressants have been met with some success. For instance, the hallucinogenic drug ketamine shows antidepressant effects in treatment-resistant patients within two hours. Importantly, ketamine targets a different brain system to Prozac.

The discovery of the rapid antidepressant effects of ketamine has shifted the focus away from serotonin. Another molecule that has received some attention lately is beta-catenin. Beta-catenin is a protein that is present throughout the brain and previous research suggests that malfunction of beta-catenin can lead to psychiatric disorders, including PTSD and depression. This is why Dias and colleagues set out to investigate whether beta-catenin might also be involved in resilience to depression.

The researchers first induced behaviour resembling depression in a group of mice by stressing them out over a long period of time. They then tried to see if they could prevent or enhance the depressive behaviour by manipulating levels of beta-catenin in a part of the brain called the nucleus accumbens. The nucleus accumbens is involved in rewarding experiences such as food, sex and drugs and is also thought to be dysfunctional in depression. Artificially increasing beta-catenin in the nucleus accumbens prevented the effects of stress. Conversely, blocking beta-catenin led to depressive behaviour, even after a small stress dose that normally does not cause depression.

The key finding of the study was that beta-catenin mediated resilience to stress by controlling the production of resilience proteins. Specifically, beta-catenin regulates the expression of an enzyme called Dicer1, which controls the production of small regulatory RNAs. These molecules, the best studied of which are microRNAs (miRNAs), are a type of RNA molecule that control gene expression. MiRNAs are involved in a wide range of biological processes and are proving to be very important in health and disease. The researchers demonstrated that genetically removing the Dicer1 gene prevented the resilient effects of beta-catenin. Therefore, through regulating the production of miRNAs, which themselves regulate many proteins, beta-catenin might control the expression of many resilience proteins.

The findings by Dias and colleagues suggest that differences in the functioning of a single molecule, beta-catenin, might explain why some of us find it harder to cope with stress. Importantly, the results of the study shift the spotlight away from serotonin, the main target of traditional antidepressants like Prozac. The discovery that miRNAs boost resilience could pave the way for novel ways to treat depression and others stress-related disorders. In the future, we could engineer resilience in people prone to depression by boosting the expression of miRNAs in the brain. Rather than focusing on reversing the negative effects of stress, clinicians might one day be able to prescribe resilience.

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