Brain Protein Influences How the Brain Manages Stress; Suggests New Model of Depression
Discovery of new molecular and behavioural connections may provide a foundation for the development of new treatments to combat some forms of depression
Whether or not a given individual’s brain can deal effectively with stress, and thus their susceptibility to depression, depends on a single protein type in each person’s brain, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published November 12 in the journal Nature.
The Mount Sinai study findings challenge the current thinking about depression and the drugs currently used to treat the disorder.
“Our findings are distinct from serotonin and other neurotransmitters previously implicated in depression or resilience against it,” says the study’s lead investigator, 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. “These data provide a new pathway to find novel and potentially more effective antidepressants.”
The protein involved in this new model of depression is beta-catenin (B-catenin), which is expressed throughout the brain and is known to have many biological roles. Using mouse models exposed to chronic social stress, Mount Sinai investigators discovered that it is the activity of the protein in the D2 neurons, a specific set of nerve cells (neurons) in the nucleus accumbens (NAc), the brain’s reward and motivation center, which drives resiliency.
Specifically, the research team found that animals whose brains activated B-catenin were protected against stress, while those with inactive B-catenin developed signs of depression in their behavior. The study also showed suppression of this protein in brain tissue of depressed patients examined post mortem.
“Our human data are notable in that we show decreased activation of B-catenin in depressed humans, regardless of whether these individuals were on or off antidepressants at the time of death,” says the study’s co-lead investigator, Caroline Dias, an MD-PhD student at the Icahn School of Medicine at Mount Sinai. “This implies that the antidepressants were not adequately targeting this brain system.”
In the study, researchers blocked B-catenin in the D2 brain cells in mice that had previously shown resilience to depression and found the animals became susceptible to stress. Conversely, activating B-catenin in stress mice bolstered their resilience to stress.
Nearly all nerve cells in the NAc brain region are called medium spiny neurons. These cells are divided into two types based on how they detect the neurotransmitter dopamine, which is important in regulating reward and motivation. One type of neuron detects dopamine with D1 receptors and the other with D2 receptors. The Mount Sinai data specifically implicate the D2 neurons in mediating deficits in reward and motivation that contribute to depression or enhancements that mediate resilience.
Examining the genes regulated by B-catenin, the team then traced the pathway that was engaged when B-catenin was activated in the D2 neurons and discovered a novel connection between the protein and Dicer1, an enzyme important in making microRNAs, small molecules which control gene expression.
“While we have identified some of the genes that are targeted, future studies will be key to see how these genes affect depression. Presumably, they are important in mediating the pro-resilient effects of the B-catenin-Dicer cascade,” says Dr. Dias.
While the molecular underpinnings of depression have remained elusive despite decades of research, the new Mount Sinai study breaks new ground in understanding depression in three important ways. It is the first report that B-catenin is deficient in nucleus accumbens in human depression and mouse depression models; it is the first study to show that higher activity of B-catenin drives resilience and the first report demonstrating a strong connection between B-catenin and control of microRNA synthesis.
The findings also suggest that future therapy for depression could be aimed at bolstering resilience against stress.
“While most prior efforts in antidepressant drug discovery have focused on ways to undo the bad effects of stress, our findings provide a pathway to generate novel antidepressants that instead activate mechanisms of natural resilience,” says Dr. Nestler.
This work was supported by grants from the National Institute of Mental Health and Hope for Depression Research Foundation.
Researchers from the University of Texas Southwestern, the Massachusetts Institute of Technology, Michigan State University, the UCLA College of Life Sciences, the University of Arizona College of Medicine and the Institut National de la Sante et de la Recherhe Medicale (INSERM) in Paris contributed to the study.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.