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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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Networks of DEGs involved in circadian rhythm and corticotropin releasing factor signaling. Nodes are colored using AY_T10R1 and HC_T10R1.
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Fig4: Networks of DEGs involved in circadian rhythm and corticotropin releasing factor signaling. Nodes are colored using AY_T10R1 and HC_T10R1.

Mentions: Separation of each module, adding more member DEGs, and coloring nodes based on their expression level in HC and AY for the one-day post 10-day Agg-E group (T10R1), showed how a particular behavioral response or biological process behaves in these two important brain regions (Figures 3 and 4). For example, modular network DEGs involved in associative learning were largely induced in AY, whereas DEGs associated with aggressive and territorial behaviors were largely suppressed in AY, suggesting involvement in impaired territorial and aggressive behavior (Figure 3). This inference is also corroborated by the finding of significant reduction of urine marking. Many of the DEGs associated with circadian rhythm were suppressed in AY, suggesting a circadian rhythm disruption, whereas those involved in corticotrophin releasing hormone signaling were largely induced in AY (Figure 4), indicating aggression (trauma) potentiated hypothalamic-pituitary-adrenal (HPA)-axis signaling, thus leading to anxiety-related behavioral responses. The expression patterns of some of the important nodes showed different directions in AY and HC. The differential responses between these two important brain regions are consistent with suboptimal communication between the putative fear response center (AY) and the center associated with contextual processing (HC). Examining fewer member genes among those associated with some of stress-induced processes and pathways such as glucocorticoid receptor signaling, neurotransmitter secretion, inflammation and growth factor receptors, we still see a mix of same and opposing directions of expression of these genes between AY and HC (Additional file 1: Figure S2). Some of the DEGs involved in social withdrawal, immobility, long-term memory, and startle, anxiety and fear responses were down-regulated in AY (Additional file 1: Figure S3). Many of these down-regulated genes were also found to be associated with neurotrophic factors signaling, fear extinction, and functions related to emotional regulation.Figure 3


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)

Networks of DEGs involved in circadian rhythm and corticotropin releasing factor signaling. Nodes are colored using AY_T10R1 and HC_T10R1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Networks of DEGs involved in circadian rhythm and corticotropin releasing factor signaling. Nodes are colored using AY_T10R1 and HC_T10R1.
Mentions: Separation of each module, adding more member DEGs, and coloring nodes based on their expression level in HC and AY for the one-day post 10-day Agg-E group (T10R1), showed how a particular behavioral response or biological process behaves in these two important brain regions (Figures 3 and 4). For example, modular network DEGs involved in associative learning were largely induced in AY, whereas DEGs associated with aggressive and territorial behaviors were largely suppressed in AY, suggesting involvement in impaired territorial and aggressive behavior (Figure 3). This inference is also corroborated by the finding of significant reduction of urine marking. Many of the DEGs associated with circadian rhythm were suppressed in AY, suggesting a circadian rhythm disruption, whereas those involved in corticotrophin releasing hormone signaling were largely induced in AY (Figure 4), indicating aggression (trauma) potentiated hypothalamic-pituitary-adrenal (HPA)-axis signaling, thus leading to anxiety-related behavioral responses. The expression patterns of some of the important nodes showed different directions in AY and HC. The differential responses between these two important brain regions are consistent with suboptimal communication between the putative fear response center (AY) and the center associated with contextual processing (HC). Examining fewer member genes among those associated with some of stress-induced processes and pathways such as glucocorticoid receptor signaling, neurotransmitter secretion, inflammation and growth factor receptors, we still see a mix of same and opposing directions of expression of these genes between AY and HC (Additional file 1: Figure S2). Some of the DEGs involved in social withdrawal, immobility, long-term memory, and startle, anxiety and fear responses were down-regulated in AY (Additional file 1: Figure S3). Many of these down-regulated genes were also found to be associated with neurotrophic factors signaling, fear extinction, and functions related to emotional regulation.Figure 3

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