Hitting Molecular Targets in the Brain to Develop Better Treatments for Depression: Dr. Mary Kay Lobo
In her first year of One Mind research support, 2016 One Mind / Janssen Rising Star Translational Research Award winner, Mary Kay Lobo, has made significant advancements toward the identification of molecular targets and effective medications for major depressive disorder (MDD). MDD affects more than 200 million people worldwide. While FDA-approved medications and other treatments are available for MDD, they often have unwanted side effects or limited benefits. New treatments that target specific molecular pathways that cause MDD are urgently needed to improve the short- and long-term effectiveness of these treatments.
Dr. Lobo uses a mouse model of depression to investigate how various drug treatments alter behavior and brain function, specifically focusing on a brain region called the nucleus accumbens. The nucleus accumbens is commonly referred to as the brain’s “reward center” and is known to play an important role in depression and other mood disorders. In her previous research, Dr. Lobo observed that chronic stress in susceptible mice decreases the size of nerve cells (neurons) and the number of branches (dendrites) and connections they form with other cells. She also discovered alterations in RhoA, a small protein involved in the growth and maintenance of dendritic shape and size. Her publication “Molecular basis of dendritic atrophy and activity in stress susceptibility” reported on these findings in the journal of Molecular Psychiatry in 2017 (Francis et al.). Dr. Lobo and Dr. Megan Fox, her team’s Postdoctoral Fellow, also presented results from this study at the Society for Neuroscience’s 2017 conference. Additionally, this work was presented by Dr. Fox at the recent Basal Ganglia Gordon Research Conference and by Dr. Lobo at a symposium on “The Emotional Brain” at Concordia University’s Center for Studies in Behavioral Neurobiology. In addition, Dr. Lobo and her team’s publication “Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior” was published in Molecular Psychiatry in August 2018.
These discoveries led Dr. Lobo to hypothesize that RhoA and its downstream molecular target, ROCK, could be key targets for restoring brain function and behavior in MDD. During the past year, Dr. Lobo’s team evaluated several drugs. Importantly, they demonstrated that Rhosin and CT04 (both RhoA inhibitors) can produce resilient, antidepressant-like responses to stress. Furthermore, Rhosin enhanced dendritic spine formation and partially prevented the loss and shrinkage of dendrites in subpopulations of nerve cells in the nucleus accumbens. Her team also demonstrated that the Y-27632 ROCK inhibitor when given after stress in susceptible mice resulted in improved social interaction, restored the dendritic size, and decreased ROCK activity in the nucleus accumbens. Following up on this discovery, Dr. Lobo’s team is now examining the effects of the Y-27632 ROCK inhibitor on cell signaling within these neuronal subtypes. Dr. Lobo’s team has recently submitted a manuscript on these studies.
We congratulate and thank Dr. Lobo and her team for their productivity towards the goal of uncovering new and improved treatment strategies for MDD. We also thank Janssen Research and Development and our donors for enabling us to provide this Rising Star Award to this remarkable scientist.
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