title: Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder.
abstract: BACKGROUND
  Social-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD). The model involved exposure of an intruder (subject) mouse to a resident aggressor mouse followed by exposure to trauma reminders with rest periods. C57BL/6 mice exposed to SJL aggressor mice exhibited behaviors suggested as PTSD-in-mouse phenotypes: intermittent freezing, reduced locomotion, avoidance of the aggressor-associated cue and apparent startled jumping. Brain tissues (amygdala, hippocampus, medial prefrontal cortex, septal region, corpus striatum and ventral striatum) from subject (aggressor exposed: Agg-E) and control C57BL/6 mice were collected at one, 10 and 42 days post aggressor exposure sessions. Transcripts in these brain regions were assayed using Agilent's mouse genome-wide arrays.
  
  
  RESULTS
  Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited.
  
  
  CONCLUSIONS
  Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients.
authors.affiliation: Advanced Biomedical Computing Center, Frederick National Lab for Cancer Research, Fort Detrick, MD, 21702, USA. seid.muhie@nih.gov.|Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. seid.muhie@nih.gov.
authors.forename: Seid
authors.initials: S
authors.lastname: Muhie
authors.affiliation: Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. aarti.gautam.ctr@mail.mil.
authors.forename: Aarti
authors.initials: A
authors.lastname: Gautam
authors.affiliation: Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. james.meyerhoff@rcn.com.
authors.forename: James
authors.initials: J
authors.lastname: Meyerhoff
authors.affiliation: Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. nabarun.m.chakraborty.ctr@mail.mil.
authors.forename: Nabarun
authors.initials: N
authors.lastname: Chakraborty
authors.affiliation: Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. rasha.hammamieh1.civ@mail.mil.
authors.forename: Rasha
authors.initials: R
authors.lastname: Hammamieh
authors.affiliation: Integrative Systems Biology Program, U.S. Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702-5010, USA. marti.jett-tilton.civ@mail.mil.
authors.forename: Marti
authors.initials: M
authors.lastname: Jett
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002940:Circadian Rhythm / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004195:Disease Models, Animal; D005239:Fear; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008297:Male; D008568:Memory; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D003346:Corticotropin-Releasing Hormone