Epigenetic Regulation of HippocampalFosbExpression Controls Behavioral Responses to Cocaine

Abstract

Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ⌬FosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ⌬FosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ⌬FosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ⌬FosB was subregion-specific, and that ⌬FosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampusdependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause ⌬FosB induction critical for cocaine-related learning.

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

“…Addiction is an increasingly prevalent problem in the United States, associated with progressively higher rates of morbidity and mortality. Experience with drugs of abuse results in significant transcriptional and epigenetic alterations in the nucleus accumbens (NAc) that support both synaptic and behavioral plasticity, outlasting the direct effects of the drug and contributing to the development of addiction [1][2][3][4]. Despite their various mechanisms of action, one common feature of many drugs of abuse is that they act upon the mesocorticolimbic dopamine (DA) system, which includes the ventral tegmental area (VTA), the NAc, and the prefrontal cortex [2,5].…”

cFos ensembles in the dentate gyrus rapidly segregate over time and do not form a stable map of space

“…In addition to anti-cFos staining, we used a second antibody that recognizes FosB and its truncated splice variant ΔFosB. ΔFosB accumulates in neurons and can act as a suppressor of cFos in the DG 25,42,45,46 . At the time of the second CNO stimulation, FosB/ΔFosB was strongly expressed in both DG and CA1 (Fig.…”

Rhythmic Regulation of DNA Methylation Factors and Core-Clock Genes in Brain Structures Activated by Cocaine or Sucrose: Potential Role of Chromatin Remodeling

“…Immunohistochemical staining was carried out using Orexin-A goat polyclonal antibody (C-19, Santa Cruz, sc-8070, 1:3000) or Per2 rabbit polyclonal antibody (Millipore, ab2202, 1:2000) or FosB rabbit monoclonal antibody (Cell Signaling Technology, 5G4, cs-2251, 1:2000) also recognizing the ∆FosB truncated isoform. The specificity of primary antibodies was described by the suppliers and by other studies for Orexin-A [5,48], Per2 [49,50] and FosB [51,52]. Floating sections were washed in TBS, at pH 7.6, and incubated in a solution of 3% H 2 O 2 (30% hydrogen peroxide, Sigma-Aldrich) in TBS for 10 min and rinsed with TBS for 10 min three times prior to their incubation with primary antibodies overnight at 4 • C. Biotinylated secondary antibodies were incubated for 2 h at room temperature (1:400) followed by avidin-biotin complex (ABC Vectastain Kit, Vector Laboratories) for 1 h at room temperature.…”