Abstract
BackgroundSocial-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.ResultsPathways 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0104-3) contains supplementary material, which is available to authorized users.
Highlights
Social-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD)
We identified a number of differentially expressed genes (DEGs) across different brain regions and time points
The hypothesis was further validated as we found the mice displaying many traumatic features after a long time interval
Summary
Social-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD). Muhie et al Molecular Brain (2015) 8:14 hippocampus (HC) is implicated in contextual fear learning, in trauma memory consolidation, and retrieval (intrusive re-experiencing of the traumatic event); the amygdala (AY) is associated with cue conditioning, hyper-vigilance, heightened arousal, learning, and expressing fear behavior [8,9]; the medial prefrontal cortex (MPFC) is involved in cognition, emotional regulation, and fear extinction; and the nucleus accumbens (NAc, part of the ventral striatum, VS) is associated with reward-related behavioral abnormalities such as depression [10] Other brain regions, such as corpus striatum (ST) and septal region (SE), are implicated in processing and responding to reward and aversive stimuli, lack of motivation, and recall of intrusive traumatic cues in the form of flashbacks [11,12]
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