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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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Modular networks of DEGs associated with circadian clock, behavioral response and synaptic transmission; each module (nodes of the same color) forms a functional module.
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Fig2: Modular networks of DEGs associated with circadian clock, behavioral response and synaptic transmission; each module (nodes of the same color) forms a functional module.

Mentions: Functional and pathway enrichments of DEGs of the different brain regions led to the identification of modular-networks (functional interaction networks) consisting of genes implicated in anxiety-related behavioral responses and the underlying synaptic processes (Figure 2). Each module of this network has many more member DEGs, which were excluded for clarity (visualization) to show only representative members. Also, the list of pathway and functional modules identified were longer than shown in Figure 2 (Additional file 2: Table S1). Member DEGs involved in long-term memory, associative learning, and limbic system development were largely from the HC; DEGs associated with startle and fear responses were largely from the AY; and DEGs associated with circadian rhythm, cognition, neurogenesis, locomotory behavior, dopaminergic and serotonergic pathways were from different brain regions.Figure 2


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)

Modular networks of DEGs associated with circadian clock, behavioral response and synaptic transmission; each module (nodes of the same color) forms a functional module.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Modular networks of DEGs associated with circadian clock, behavioral response and synaptic transmission; each module (nodes of the same color) forms a functional module.
Mentions: Functional and pathway enrichments of DEGs of the different brain regions led to the identification of modular-networks (functional interaction networks) consisting of genes implicated in anxiety-related behavioral responses and the underlying synaptic processes (Figure 2). Each module of this network has many more member DEGs, which were excluded for clarity (visualization) to show only representative members. Also, the list of pathway and functional modules identified were longer than shown in Figure 2 (Additional file 2: Table S1). Member DEGs involved in long-term memory, associative learning, and limbic system development were largely from the HC; DEGs associated with startle and fear responses were largely from the AY; and DEGs associated with circadian rhythm, cognition, neurogenesis, locomotory behavior, dopaminergic and serotonergic pathways were from different brain regions.Figure 2

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