Major depressive disorder (MDD) is a devastating disease that afflicts about 5% of the population. Stress is known to play a large role in causing major depressive episodes in people who are biologically susceptible. What is it about the brains of those 5% of people that makes them susceptible to depressive episodes when they are under too much stress? What neurobiological property do the other stress-experienced people have that makes them resilient to depression? Ming-Hu Han, Ph.D., an assistant professor of Pharmacology and Systems Therapeutics at Icahn School of Medicine at Mount Sinai, and a 2011 Rising Star Awardee, is finding out what makes resilience work, and pursuing a medical means to strengthen it.
In 2011-12, Dr. Han and his team found in their work with mice that a single dose of the compound called flupirtine can remedy depressive episodes which are brought on by chronic, extreme social stress. By activating potassium channels to slow down the too-fast firing of dopamine neurons in the ventral tegmental area, the brain’s reward center, flupirtine actually makes these stress-susceptible mice’s symptoms disappear. The mice become more sociable, less apathetic, and more likely to seek out a sweet treat in the form of a sucrose solution. Essentially, they become more resilient. In 2012-13 Han’s team has demonstrated that the too-fast firing of these dopamine neurons is a direct cause of depressive symptoms (, 2013). His team has further found that certain similar potassium channel activators, such as the human-approved epilepsy drug retigabine, also slow down these neurons and restore resilience. These findings provide solid evidence that resilience can be enhanced by selective inhibition of this reward-related pathway in the brain, which mimics the natural resilience process.
In 2013-14, Han’s team has found out further how this mechanism works: the antidepressant effect of such firing rate inhibition occurs through its promotion in the nucleus accumbens of the neural growth factor called BDNF. And, more interestingly, Han’s team found that this BDNF promotion occurs only in mice which have experienced social stress, and not in stress-naÃƒÂ¯ve mice. They were even able to elucidate the mechanism behind this response: they discovered that the stress hormone corticotrophin-releasing factor (CRF) plays an important role in activating BDNF if, and only if, stress has been present. The team published these results in Nature Neuroscience in 2013.
Surprisingly, Han’s team has found this year that when they made stress-susceptible mice’s too-fast neural firing rate go even faster, this enhancement also worked to reduce depressive behaviors. Han says, “These results suggest that pathogenic mechanisms are not always bad; they may become therapeutically useful if they beneficially activate resilience mechanisms.” This discovery received widespread media attention after its publication in Science in 2014.
Altogether, Han’s lab has revealed that depression-related behaviors can be quickly adjusted by turning on or off specific dopamine circuits in the brain. Says Han, “This finding provides highly useful information for target-oriented therapeutics such as deep brain stimulation.”
Dr. Han speculates that fast-acting therapies like these could be potential lifesavers for people at risk for suicide, and could bring rapid relief to people with MDD.
IMHRO is thrilled to have been given the opportunity to fund Dr. Han’s research, and we are grateful to our donors for their enabling support. Would you like to support research like Dr. Han’s? Donate now.