title: Pervasive and opposing effects of Unpredictable Chronic Mild Stress (UCMS) on hippocampal gene expression in BALB/cJ and C57BL/6J mouse strains.
abstract: BACKGROUND
  BALB/cJ is a strain susceptible to stress and extremely susceptible to a defective hedonic impact in response to chronic stressors. The strain offers much promise as an animal model for the study of stress related disorders. We present a comparative hippocampal gene expression study on the effects of unpredictable chronic mild stress on BALB/cJ and C57BL/6J mice. Affymetrix MOE 430 was used to measure hippocampal gene expression from 16 animals of two different strains (BALB/cJ and C57BL/6J) of both sexes and subjected to either unpredictable chronic mild stress (UCMS) or no stress. Differences were statistically evaluated through supervised and unsupervised linear modelling and using Weighted Gene Coexpression Network Analysis (WGCNA). In order to gain further understanding into mechanisms related to stress response, we cross-validated our results with a parallel study from the GENDEP project using WGCNA in a meta-analysis design.
  
  
  RESULTS
  The effects of UCMS are visible through Principal Component Analysis which highlights the stress sensitivity of the BALB/cJ strain. A number of genes and gene networks related to stress response were uncovered including the Creb1 gene. WGCNA and pathway analysis revealed a gene network centered on Nfkb1. Results from the meta-analysis revealed a highly significant gene pathway centred on the Ubiquitin C (Ubc) gene. All pathways uncovered are associated with inflammation and immune response.
  
  
  CONCLUSIONS
  The study investigated the molecular mechanisms underlying the response to adverse environment in an animal model using a GxE design. Stress-related differences were visible at the genomic level through PCA analysis highlighting the high sensitivity of BALB/cJ animals to environmental stressors. Several candidate genes and gene networks reported are associated with inflammation and neurogenesis and could serve to inform candidate gene selection in human studies and provide additional insight into the pathology of Major Depressive Disorder.
authors: MRC SGDP Centre, King's College London at the Institute of Psychiatry, PO80, DeCrespigny Park, London, UK. karim.malki@kcl.ac.uk.
authors: Karim
authors: K
authors: Malki
authors: Present address: Department of Psychiatry, Yale School of Medicine, New Haven, USA. yann.mineur@yale.edu.|Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA, USA. yann.mineur@yale.edu.
authors: Yann S
authors: YS
authors: Mineur
authors: MRC SGDP Centre, King's College London at the Institute of Psychiatry, PO80, DeCrespigny Park, London, UK. maria.tosto@kcl.ac.uk.|Department of Psychology, Tomsk State University, Tomsk, Russia. maria.tosto@kcl.ac.uk.
authors: Maria Grazia
authors: MG
authors: Tosto
authors: The Institute of Cancer Research, London, UK. james.campbell@icr.ac.uk.
authors: James
authors: J
authors: Campbell
authors: MRC SGDP Centre, King's College London at the Institute of Psychiatry, PO80, DeCrespigny Park, London, UK. karia.priya@kcl.ac.uk.
authors: Priya
authors: P
authors: Karia
authors: MRC SGDP Centre, King's College London at the Institute of Psychiatry, PO80, DeCrespigny Park, London, UK. irfan.bin_anwar_ali@kcl.ac.uk.
authors: Irfan
authors: I
authors: Jumabhoy
authors: MRC SGDP Centre, King's College London at the Institute of Psychiatry, PO80, DeCrespigny Park, London, UK. frans.sluyter@googlemail.com.
authors: Frans
authors: F
authors: Sluyter
authors: Present address: University of Bordeaux, Institute for Cognitive and Integrative Neuroscience (INCIA), Bordeaux, France. wim_crusio@yahoo.com.|Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA, USA. wim_crusio@yahoo.com.
authors: Wim E
authors: WE
authors: Crusio
authors: School of Biological Sciences, University of Essex, Colchester, UK. lschal@essex.ac.uk.
authors: Leonard C
authors: LC
authors: Schalkwyk
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D013045:Species Specificity; D013315:Stress, Psychological / Q000235:genetics*