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, 11 (8), e0160355
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Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients

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Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients

Paula A Gajewski et al. PLoS One.

Abstract

Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor ΔFosB is induced in the prefrontal cortex (PFC) and hippocampus (HPC) of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their "top down" control of reward circuitry, including the nucleus accumbens (NAc). Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that ΔFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential ΔFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Diagram of dissection regions for human brain samples.
Drawings represent anterior (A) and posterior (B) coronal sections of human brain used for dissection of PFC samples, and (C) HPC samples. Red boxes highlight areas of dissection. SFG: superior frontal gyrus; MFG: middle frontal gyrus; IG: insular gyrus; FuG: fusiform gyrus.
Fig 2
Fig 2. Comparison of human and mouse FosB proteins.
(A) Western blot of hippocampal proteins with FosB antibody reveals multiple additional bands in typical human cocaine addict HPC sample compared to a chronic cocaine-treated (15 mg/kg for 7 days) mouse HPC. Novel bands are apparent at 20 kDa, 23 kDa (white arrow), and 30 kDa (black arrow). (B) Correlation and linear regression plots of protein expression for each band in the human samples with the postmortem interval (time between death and brain freezing) for each human sample. Dotted lines represent 95% confidence interval; no linear regression slope differed significantly from 0.
Fig 3
Fig 3. Expression of FosB proteins in mouse HPC after extended postmortem intervals.
The brains of mice given an acute injection of cocaine (15 mg/kg i.p.) were left in situ for 0, 1, or 8 hrs after sacrifice before harvesting HPC. Western blot reveals buildup of a 23 kDa band in the 8 hr animals, but does not show other bands found in human HPC samples.
Fig 4
Fig 4. Expression of FosB proteins in HPC and PFC of human cocaine addiction and depression patients.
(A) Western blot of FosB proteins from the HPC and PFC of human cocaine addicts (Coc) and controls (Con). (B) Quantitation reveals a cocaine-dependent decrease in many FosB proteins in the HPC but not PFC (*:p<0.05, #:p = 0.05). (C) Western blot of FosB proteins from the HPC and PFC of human depression patients off (Dep) or on antidepressants (Dep + AD) and controls (Con). (D) Quantitation reveals a depression-dependent decrease in some FosB proteins in the HPC but not PFC (*:p<0.05). Error bars indicate mean +/- SEM.
Fig 5
Fig 5. Expression of possible ΔFosB gene target proteins in HPC and PFC of human cocaine addiction and depression patients.
(A) Western blot of potential ΔFosB gene target proteins from the HPC and PFC of human cocaine abusers (Coc) and controls (Con). (B) Quantitation reveals a cocaine-dependent decrease in all GluA2 and CaMKII in the HPC but not PFC (*:p<0.05, #:p = 0.05). (C) Western blot of potential ΔFosB gene target proteins from the HPC and PFC of human depression patients off (Dep) or on antidepressants (Dep + AD) and controls (Con). (D) Quantitation reveals no depression-dependent changes. Error bars indicate mean +/- SEM.

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