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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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Related in: MedlinePlus

Differentially expressed genes (DEGs) across brain regions at different time points (T5R1, T5R10, T10R1 and T10R42). The scatter plots show both log2 -fold changes and negative log10p-values in six brain regions (across) and four time-points (down); the numbers of up- and down-regulated transcripts in each group are also shown. Key: amygdala (AY), hippocampus (HC), medial prefrontal cortex (MPFC), septal region (SE), corpus striatum (ST), and ventral striatum (VS), T: number of days of trauma or aggressor exposure; R: post-trauma tissue collection days; Agg-E: aggressor-exposed.
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Fig1: Differentially expressed genes (DEGs) across brain regions at different time points (T5R1, T5R10, T10R1 and T10R42). The scatter plots show both log2 -fold changes and negative log10p-values in six brain regions (across) and four time-points (down); the numbers of up- and down-regulated transcripts in each group are also shown. Key: amygdala (AY), hippocampus (HC), medial prefrontal cortex (MPFC), septal region (SE), corpus striatum (ST), and ventral striatum (VS), T: number of days of trauma or aggressor exposure; R: post-trauma tissue collection days; Agg-E: aggressor-exposed.

Mentions: Differentially expressed genes (DEGs), compared between Agg-E and control (C-ctrl) mice for each brain region (AY, HC, MPFC, SE, ST and VS), were identified at four different time points (T5R1, T5R10, T10R1 and T10R42) (Table 1) using Moderated T-test, p ≤ 0.05 (Figure 1). For the 10-day Agg-E groups, there were more DEGs after the longer rest period (T10R42) except for ST which showed a large decrease in DEGs as compared to the T10R1 group. The numbers of DEGs of 5-day Agg-E groups were greater at T5R1 for AY, HC and SE regions; at T5R10, the numbers of DEGs increased for MPFC, ST and VS, while by contrast the numbers were greatly decreased for HC and SE.Table 1


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)

Differentially expressed genes (DEGs) across brain regions at different time points (T5R1, T5R10, T10R1 and T10R42). The scatter plots show both log2 -fold changes and negative log10p-values in six brain regions (across) and four time-points (down); the numbers of up- and down-regulated transcripts in each group are also shown. Key: amygdala (AY), hippocampus (HC), medial prefrontal cortex (MPFC), septal region (SE), corpus striatum (ST), and ventral striatum (VS), T: number of days of trauma or aggressor exposure; R: post-trauma tissue collection days; Agg-E: aggressor-exposed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Differentially expressed genes (DEGs) across brain regions at different time points (T5R1, T5R10, T10R1 and T10R42). The scatter plots show both log2 -fold changes and negative log10p-values in six brain regions (across) and four time-points (down); the numbers of up- and down-regulated transcripts in each group are also shown. Key: amygdala (AY), hippocampus (HC), medial prefrontal cortex (MPFC), septal region (SE), corpus striatum (ST), and ventral striatum (VS), T: number of days of trauma or aggressor exposure; R: post-trauma tissue collection days; Agg-E: aggressor-exposed.
Mentions: Differentially expressed genes (DEGs), compared between Agg-E and control (C-ctrl) mice for each brain region (AY, HC, MPFC, SE, ST and VS), were identified at four different time points (T5R1, T5R10, T10R1 and T10R42) (Table 1) using Moderated T-test, p ≤ 0.05 (Figure 1). For the 10-day Agg-E groups, there were more DEGs after the longer rest period (T10R42) except for ST which showed a large decrease in DEGs as compared to the T10R1 group. The numbers of DEGs of 5-day Agg-E groups were greater at T5R1 for AY, HC and SE regions; at T5R10, the numbers of DEGs increased for MPFC, ST and VS, while by contrast the numbers were greatly decreased for HC and SE.Table 1

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