Dynamic of prefrontal-cortex transcriptome profiles in mice exposed to social defeat stress
N.P. Bondar1,3*, L.O. Bryzgalov1, N.E. Ershov1, 3, F.E. Gusev3,5, V.V. Reshetnikov1, D.F. Avgustinovich2, M.V. Tenditnik4, E.I. Rogaev3,5*, T.I. Merkulova1
1 Laboratory of Gene Expression Regulation, Institute Cytology and Genetics, SD RAS, Russia;2Laboratory of Molecular Mechanisms of Pathological Processes, Institute Cytology and Genetics, SD RAS, Russia;3The Center of Brain Neurobiology and Neurogenetics, Institute Cytology and Genetics, SD RAS, Russia; 4Laboratory of Experimental Models of Emotional Pathologies, Institute of Physiology and Fundamental Medicine, SB RAMS, Russia;5University of Massachusetts Medical School, USA
Chronic social defeat stress is a well-validated murine model of depression. We aimed to study dynamic changes of genes expression during development of depression-like state in C57BL/6 mice. We analyzed the effects of social defeat stress of varying duration (10 and 30 days) on the behavioral patterns and prefrontal-cortex transcriptome in C57BL/6 mice. Commonly used 10-day exposure to defeat stress resulted only in a high level of social avoidance. Contrariwise, most mice exposed to 30-day stress demonstrated clear hallmarks of depression, including higher level of social avoidance, increased immobility in the forced swim test, and anhedonic behavior. Surprisingly, an analysis of RNA-seq data revealed massive changes on the 10th day, but a few ones on the 30th day of stress due to a reversal of most of the stress-induced changes to the initial state. We have found that glucocorticoid target genes stop responding to the elevated corticosterone level after 30-day stress. The majority of genes altered by 30-day stress were downregulated, with the most relevant ones being Robo3 participating in neurodevelopment and cell adhesion and some other cell adhesion molecules.Taken together, our data suggest that depression may be caused by weakening of the response to the stressful environmental factors in terms of both behavior and gene expression. Our results also support the hypothesis that major depressive disorder is associated with defective cell adhesion and impaired neuronal plasticity.
This work has been done by the finance support of the Government of the Russian Federation (Project №14.B25.31.0033, Resolution No.220 Federation of April 9, 2010).