New research at the Icahn School of Medicine at Mount Sinai sheds light for the first time on how depression and emotional resilience operate on a molecular level. The findings, published in the December 4, 2014, issue of Nature, bring fresh perspective to an area that has eluded researchers for decades by outlining the mechanisms within cells that activate depression and laying the groundwork for new treatments. Current drugs for depression focus on neurotransmitters, or communication between cells, but identification of this novel biochemical pathway could pave the way for more effective drugs with very different mechanisms.
The study’s first author, Caroline Dias, an MD/PhD candidate at the Icahn School of Medicine, launched the research as a PhD thesis project. She found that mice became depressed-like when activation levels of the signalling protein beta-catenin (b-Catenin)—located within neurons in the brain’s reward and motivation center—were lowered. Conversely, mice exhibited signs of resilience when b-Catenin levels were increased.
These results were corroborated through post-mortem studies of human brains. People who had been depressed exhibited lower b-Catenin activation compared to nondepressed individuals.
“Identifying this novel biochemical pathway has opened up a whole new avenue of depression-stress research,” says Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience, and Director of The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai. “Our molecular findings are very distinct from serotonin and other neurotransmitters previously implicated in depression or resilience against it.”
By using next-generation sequencing technology, the research team was able to trace the activation of b-Catenin to a gene called Dicer1, which plays an important role in making microRNAs, small molecules that control gene expression. In the final phase of research, Jian Feng, PhD, a postdoctoral fellow at the Icahn School of Medicine and the study’s co-lead investigator, identified a group of microRNAs that are regulated by b-Catenin. These microRNAs may prove to be critical in the pro-resilient effects of b-Catenin.
“The study provides a template for many years of research and potential new treatments,” says Dr. Nestler, who is also past President of the American College of Neuropsychopharmacology. “Next, we plan to pursue microRNAs and many of the other targets of b-Catenin. We picked one gene out of 100, and there are many others to study.”
“As in other tissues and organs, we can identify cells that are healthier or sicker,” says Ms. Dias. “It is obviously more complicated in the brain, but instead of focusing on trying to correct what goes wrong in depression, we can perhaps make neurons healthier by targeting the pathways within the cells that naturally mediate resilience.”
Funding for the research was provided by the National Institute of Mental Health and the Hope for Depression Research Foundation.