Elevated levels of a class of hormones called glucocorticoids have long been linked to anxiety disorders and depression. It is known that the presence of too much of these hormones mediates what we call ‘stress’ and that resulting damage can happen in the brain creating various brain and behavior disorders. But glucocorticoids also play essential roles in the body’s equilibrium by fine tuning immune responses and the systems through which cells manufacture and adjust their energy levels. An appropriate level of these hormones is essential—it is not possible to simply try to ‘turn them off’ or reduce their level to treat stress-related disorders.

This is often the conundrum of medical research: it is not enough to identify what has gone ‘wrong’ to cause an illness, but it is necessary to identify and understand the complex biological underpinnings of what has gone wrong to be able to effectively treat the illness. Both parts of this process are complex in the human body, and remain particularly unknown in the realm of brain and behavior disorders.

So while it might seem logical to simply find a way of blocking the action of glucocorticoids to prevent stress and the resulting damage, doing so globally may actually cause more harm than it prevents by stopping other essential functions of these hormones. Olivier Berton, Ph.D., a two-time NARSAD Young Investigator Grantee and Assistant Professor of Psychiatry at the University of Pennsylvania, has recently published discoveries that point to a potentially powerful strategy to overcome this obstacle and achieve blockade of the intracellular action of glucocorticoids more precisely in certain brain circuits critical for depression and anxiety. His new research findings were published on March 28, 2012 in The Journal of Neuroscience.

With the support of his NARSAD Grants, Dr. Berton and his team studied mice exposed to the mouse-equivalent of bullying. Many of the mice developed behavioral problems, notably ‘social defeat,’ which takes the form of self-defeating social avoidance. These mice can be successfully treated with antidepressants. But Berton’s team also noticed that a certain number of bullied mice were naturally resilient—the bullying did not cause them to withdraw socially; indeed, these mice behaved as if they were already taking antidepressants.

Subsequent studies have identified one molecular ‘signature' that confers this self-protective effect of resiliency: the action of a class of enzymes called histone deacetylases, or HDACs. But as with the stress hormones whose impact they help to regulate, no one has been able to figure out how to target them specifically. Berton’s new research marks major progress in that search.

The research team discovered that the natural reduction in the expression of HDAC6—one member of the HDAC family—was a hallmark of resilience in the animals that did not succumb to bullying. They went on to figure out a way to manipulate HDAC6 levels in neurons that mediate the neurotransmitter serotonin. Deleting HDAC6 in serotonin neurons in the mouse brain dramatically reduced social and anxiety symptoms in mice that were not naturally resilient.

HDAC6 thus becomes a possible biomarker for, or predictor of, stress vulnerability. It also points toward the development of medications that can specifically inhibit the enzyme, thus minimizing the harmful impact of glucocorticoid signaling in serotonin neurons that results in symptoms of anxiety.