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Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder.

Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M - Mol Brain (2015)

Bottom Line: Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling.Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched.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.

View Article: PubMed Central - PubMed

Affiliation: Advanced Biomedical Computing Center, Frederick National Lab for Cancer Research, Fort Detrick, MD, 21702, USA. seid.muhie@nih.gov.

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.

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Activation pattern of anxiety-like behavior in amygdala (AY), hippocampus (HC) and medial prefrontal cortex (MPFC) and expression directions of associated genes.
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Fig5: Activation pattern of anxiety-like behavior in amygdala (AY), hippocampus (HC) and medial prefrontal cortex (MPFC) and expression directions of associated genes.

Mentions: As suppressed or induced expression of associated genes does not necessarily correspond to the activation or inhibition state of the corresponding behavioral responses, we calculated an activation z-score for each significantly enriched behavior and biological process based on the expression values of associated DEGs in each brain region at each time point. This approach is important to further identify which behavioral responses and biological processes may have been activated or inhibited. For example, Figure 5 shows the activation pattern of anxiety-like behavior in AY, HC and MPFC at both early (T5R1, T10R1) and late (T5R10, T10R42) rest periods. Here, it is more obvious how the expression direction of each DEG contributes to the predicted activation (red central node) or inhibition (blue central node) of the anxiety-like behavior (Figure 5). The pattern became clearer not only within a single network but also in comparison among different brain regions and time points. At T10R1, genes associated with anxiety-like behavior are activated in AY but inhibited in the MPFC, which is consistent with reported observations of exaggerated activation of AY and delayed regulation by MPFC during early stage amygdala-dependent fear responses [34,35]. On the other hand, at longer rest periods (T5R10, T10R42), the opposite pattern of activation occurred between AY and MPFC (Figure 5), which may indicate that the attenuation of the anxiety-like response in AY was probably due to emotional regulation by MPFC. Anxiety-like behavior also showed activation or attenuation at earlier and at later rest periods, respectively, in AY (Additional file 1: Figure S4). Activation z-scores for fear conditioning and startle response in AY, HC and MPFC also showed different activation or attenuation patterns across time points and regions (Additional file 1: Figures S5 and S6).Figure 5


Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder.

Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M - Mol Brain (2015)

Activation pattern of anxiety-like behavior in amygdala (AY), hippocampus (HC) and medial prefrontal cortex (MPFC) and expression directions of associated genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359441&req=5

Fig5: Activation pattern of anxiety-like behavior in amygdala (AY), hippocampus (HC) and medial prefrontal cortex (MPFC) and expression directions of associated genes.
Mentions: As suppressed or induced expression of associated genes does not necessarily correspond to the activation or inhibition state of the corresponding behavioral responses, we calculated an activation z-score for each significantly enriched behavior and biological process based on the expression values of associated DEGs in each brain region at each time point. This approach is important to further identify which behavioral responses and biological processes may have been activated or inhibited. For example, Figure 5 shows the activation pattern of anxiety-like behavior in AY, HC and MPFC at both early (T5R1, T10R1) and late (T5R10, T10R42) rest periods. Here, it is more obvious how the expression direction of each DEG contributes to the predicted activation (red central node) or inhibition (blue central node) of the anxiety-like behavior (Figure 5). The pattern became clearer not only within a single network but also in comparison among different brain regions and time points. At T10R1, genes associated with anxiety-like behavior are activated in AY but inhibited in the MPFC, which is consistent with reported observations of exaggerated activation of AY and delayed regulation by MPFC during early stage amygdala-dependent fear responses [34,35]. On the other hand, at longer rest periods (T5R10, T10R42), the opposite pattern of activation occurred between AY and MPFC (Figure 5), which may indicate that the attenuation of the anxiety-like response in AY was probably due to emotional regulation by MPFC. Anxiety-like behavior also showed activation or attenuation at earlier and at later rest periods, respectively, in AY (Additional file 1: Figure S4). Activation z-scores for fear conditioning and startle response in AY, HC and MPFC also showed different activation or attenuation patterns across time points and regions (Additional file 1: Figures S5 and S6).Figure 5

Bottom Line: Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling.Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched.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.

View Article: PubMed Central - PubMed

Affiliation: Advanced Biomedical Computing Center, Frederick National Lab for Cancer Research, Fort Detrick, MD, 21702, USA. seid.muhie@nih.gov.

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.

Show MeSH
Related in: MedlinePlus