Chronic Cocaine Use Alters Gene Expression in the Mouse Hippocampus

Cocaine addiction is driven in part by memory association.

Drug users learn to associate the drug-taking environment with the drug itself, the paraphernalia they use, and the circumstances in which they decide to take the drug.

This type of associative learning is dependent upon gene expression changes in a brain region known as the hippocampus. However, the physiological mechanisms by which cocaine alters hippocampal gene expression are still poorly understood by scientists.

In a new study published in JNeurosci, researchers at the Michigan State University have explored further how cocaine exposure affects the expression of a gene known as FosB in the hippocampus.

The researchers adopted a mouse model to investigate differences in mouse dorsal and ventral hippocampal FosB expression in response to chronic cocaine use. Previous research has shown that these brain regions are implicated in the regulation of cocaine-related behaviors.

Mice that were administered cocaine daily demonstrated increased expression of FosB compared to mice that received saline as a control. Cocaine-mediated induction of FosB was sub-region specific, with FosB transcriptional activity in both the dorsal and ventral hippocampus being necessary for cocaine conditioned place preference.

The scientists also characterized changes in histone modifications at the FosB promoter in the hippocampus in response to chronic cocaine use. They found locus-specific epigenetic modifications that are essential for FosB induction and several hippocampus-dependent behaviors, including cocaine place preference. When the scientists blocked the changes made to FosB, the mice were unable to form associations between cocaine and the environment where they received it, implicating epigenetic regulation of the gene in drug memory formation.

The researchers suggest that collectively these results suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter region, causing FosB transcription that is critical for cocaine-related learning.

Reference: Gajewski et al. 2019. Epigenetic regulation of hippocampal FosB expression controls behavioral responses to cocaine. JNeuroSci. DOI: https://doi.org/10.1523/JNEUROSCI.0800-19.2019.