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

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.

Growth of Triple Negative and Progesterone Positive Breast Cancer Causes Oxidative Stress and Down-Regulates Neuroprotective Transcription Factor NPAS4 and NPAS4-Regulated Genes in Hippocampal Tissues of TumorGraft Mice—an Aging Connection

“…c-Fos knockout mice exhibit significant learning impairment and hyperactivity (Velazquez et al, 2015 ). Meanwhile, downregulated FosB levels have been reported in the hippocampi of both depressed and addicted individuals (Gajewski et al, 2016 ).…”

FosB mRNA Expression in Peripheral Blood Lymphocytes in Drug Addicted Patients

“…A recent post-mortem study showed that the expression of FosB isoforms was downregulated in the hippocampus of addicted patients ( Gajewski et al, 2016 ). Differently, we are here measuring in vivo FosB gene expression in PBLs.…”

“…The use of addictive drugs has been associated with alteration of gene expression in the brain that result in long-term changes on synapses and neural circuits and consequent neuroadaptive and behavioral changes such as tolerance and craving, which may underlie the development and maintenance of drug addiction ( Nestler, 2008 ; Gajewski et al, 2016 ).…”

“…FosB gene heterodimerizes with Jun family proteins to form activator protein 1 (AP-1) complexes that bind to AP-1 sites in responsive genes to regulate transcription in all cells. There is evidence that the FosB genic expression can be modified after long-term drug exposure, increasing craving and aggravating the addictive behavior ( Nestler, 2008 ; Gajewski et al, 2016 ).…”

Medición de la comorbilidad depresiva en drogodependientes: Validez y eficacia diagnóstica del Inventario de Depresión de Beck (BDI-II) en dominicanos con múltiple consumo de sustancias

“…Entre las consecuencias negativas derivables de la depresión se encontraría la drogodependencia o el consumo abusivo de sustancia. Si bien los mecanismos neurobiológicos y cognitivos que explican esta comorbilidad aún están siendo estudiados, existe mucha evidencia de la fuerte asociación entre la depresión y diversas problemáticas de consumo de drogas (Beaulieu, et al, 2018;Crnić, Todorović, Marković, Kastratović, y Timotijević, 2016;Gajewski, Turecki, y Robison, 2016;García-García, Luque, Santos Ruiz, y Tabernero, 2017;Gómez-Coronado, et al, 2018;Hammond, Lai, Wright, y Treisman, 2016;Khalid y Kausar, 2016;Hodgson, et al, 2017;Lai, Cleary, Sitharthan, y Hunt, 2015;Lister, Ledgerwood, Lundahl, y Greenwald, 2015;Rao, 2006). Una de las principales hipótesis que se han propuesto para la explicación de esta comorbilidad entre depresión y abuso de sustancia, es la hipótesis de automedicación (self-medication hypothesis; Gómez-Coronado, et al, 2018).…”