title: Molecular Signatures of Psychosocial Stress and Cognition Are Modulated by Chronic Lithium Treatment.
abstract: Chronic psychosocial stress is an important environmental risk factor of psychiatric diseases such as schizophrenia. Social defeat in rodents has been shown to be associated with maladaptive cellular and behavioral consequences including cognitive impairments. Although gene expression changes upon psychosocial stress have been described, a comprehensive transcriptome profiling study at the global level in precisely defined hippocampal subregions which are associated with learning has been lacking. In this study, we exposed adult C57Bl/6N mice for 3 weeks to "resident-intruder" paradigm and combined laser capture microdissection with microarray analyses to identify transcriptomic signatures of chronic psychosocial stress in dentate gyrus and CA3 subregion of the dorsal hippocampus. At the individual transcript level, we detected subregion specific stress responses whereas gene set enrichment analyses (GSEA) identified several common pathways upregulated upon chronic psychosocial stress related to proteasomal function and energy supply. Behavioral profiling revealed stress-associated impairments most prominent in fear memory formation which was prevented by chronic lithium treatment. Thus, we again microdissected the CA3 region and performed global transcriptome analysis to search for molecular signatures altered by lithium treatment in stressed animals. By combining GSEA with unsupervised clustering, we detected pathways that are regulated by stress and lithium in the CA3 region of the hippocampus including proteasomal components, oxidative phosphorylation, and anti-oxidative mechanisms. Our study thus provides insight into hidden molecular phenotypes of chronic psychosocial stress and lithium treatment and proves a beneficial role for lithium treatment as an agent attenuating negative effects of psychosocial stress on cognition.
authors.affiliation: Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig-Maximillians-University, Munich, Germany; magdalena.brzozka@med.uni-muenchen.de.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Brzózka
authors.affiliation: Department of Psychiatry and CNMPB-DFG Research Center, Georg-August-University, Goettingen, Germany;
authors.forename: Ursula
authors.initials: U
authors.lastname: Havemann-Reinecke
authors.affiliation: Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig-Maximillians-University, Munich, Germany;
authors.forename: Sven P
authors.initials: SP
authors.lastname: Wichert
authors.affiliation: Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig-Maximillians-University, Munich, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.affiliation: Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig-Maximillians-University, Munich, Germany; Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Goettingen, Germany.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000517:prevention & control*; D003213:Conditioning, Psychological / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods*; D061346:Laser Capture Microdissection; D018020:Lithium Compounds / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds
keywords: chronic psychosocial stress; cognition; fear memory; gene expression; hippocampus; laser capture microdissection; lithium; resident-intruder paradigm; social defeat