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Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD.

Zhang L, Li H, Hu X, Benedek DM, Fullerton CS, Forsten RD, Naifeh JA, Li X, Wu H, Benevides KN, Le T, Smerin S, Russell DW, Ursano RJ - Transl Psychiatry (2015)

Bottom Line: Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain.This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala.Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

ABSTRACT
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P < 0.007) and in the blood (P < 0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

No MeSH data available.


Related in: MedlinePlus

Dysregulation of CPT1B in stressed-rodent model. (a) Dendrogram and heat maps of the expression of genes in amygdala of stressed (n=10) and non-stressed (n=10) rats. (b) Stress-induced overexpression of CPT1B in the rat amygdala. (c) Stress-induced overexpression of CPT1B in the rat blood. **P<0.01, ***P<0.001. CPT1B, carnitine palmitoyltransferase 1B.
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fig1: Dysregulation of CPT1B in stressed-rodent model. (a) Dendrogram and heat maps of the expression of genes in amygdala of stressed (n=10) and non-stressed (n=10) rats. (b) Stress-induced overexpression of CPT1B in the rat amygdala. (c) Stress-induced overexpression of CPT1B in the rat blood. **P<0.01, ***P<0.001. CPT1B, carnitine palmitoyltransferase 1B.

Mentions: We first quantified the scanned image into numeric data amenable to statistical analysis. The raw data set was filtered over 610 740 spots across all 174 gene chips of 20 rats (stressed and non-stressed) and 59 human subjects (PTSD and non-PTSD) by removing high-noise and low-signal spots. Data were normalized to remove spatial variability, channel imbalances and inter-array heterogeneity. Cluster approaches were next used to identify broad patterns. Using this approach, we were able to produce a visualization of the data as a hierarchical clustering. The hierarchical clustering generated dendrograms demonstrating up- and downregulated gene clusters in amygdala of rats with or without stress (Figure 1a) and subjects with or without PTSD. These unsupervised data indicated grouping of genes having similar expression patterns or clustering. The approaches are based on the assumption that the whole set of microarray data is a finite mixture of a certain type of distribution with different parameters. Stress-induced upregulated genes in rat's amygdala are listed in Table 1.


Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD.

Zhang L, Li H, Hu X, Benedek DM, Fullerton CS, Forsten RD, Naifeh JA, Li X, Wu H, Benevides KN, Le T, Smerin S, Russell DW, Ursano RJ - Transl Psychiatry (2015)

Dysregulation of CPT1B in stressed-rodent model. (a) Dendrogram and heat maps of the expression of genes in amygdala of stressed (n=10) and non-stressed (n=10) rats. (b) Stress-induced overexpression of CPT1B in the rat amygdala. (c) Stress-induced overexpression of CPT1B in the rat blood. **P<0.01, ***P<0.001. CPT1B, carnitine palmitoyltransferase 1B.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490278&req=5

fig1: Dysregulation of CPT1B in stressed-rodent model. (a) Dendrogram and heat maps of the expression of genes in amygdala of stressed (n=10) and non-stressed (n=10) rats. (b) Stress-induced overexpression of CPT1B in the rat amygdala. (c) Stress-induced overexpression of CPT1B in the rat blood. **P<0.01, ***P<0.001. CPT1B, carnitine palmitoyltransferase 1B.
Mentions: We first quantified the scanned image into numeric data amenable to statistical analysis. The raw data set was filtered over 610 740 spots across all 174 gene chips of 20 rats (stressed and non-stressed) and 59 human subjects (PTSD and non-PTSD) by removing high-noise and low-signal spots. Data were normalized to remove spatial variability, channel imbalances and inter-array heterogeneity. Cluster approaches were next used to identify broad patterns. Using this approach, we were able to produce a visualization of the data as a hierarchical clustering. The hierarchical clustering generated dendrograms demonstrating up- and downregulated gene clusters in amygdala of rats with or without stress (Figure 1a) and subjects with or without PTSD. These unsupervised data indicated grouping of genes having similar expression patterns or clustering. The approaches are based on the assumption that the whole set of microarray data is a finite mixture of a certain type of distribution with different parameters. Stress-induced upregulated genes in rat's amygdala are listed in Table 1.

Bottom Line: Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain.This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala.Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

ABSTRACT
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P < 0.007) and in the blood (P < 0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

No MeSH data available.


Related in: MedlinePlus