Convergent actions of stress and stimulants via epigenetic regulation of neural circuitry

Abstract

The dorsal striatum integrates prior and current information to guide appropriate decision-making. Chronic stress and stimulant exposure interferes with decision-making, and can confer similar cognitive and behavioral inflexibilities. This review examines the literature on acute and chronic regulation of the epigenome by stress and stimulants. Recent evidence suggests that exposures to stress and stimulants share similarities in the manners in which they regulate the dorsal striatum epigenome through DNA methylation, transposable element activity, and histone post-translational modifications. These findings suggest that chronic stress and stimulant exposure leads to the accumulation of epigenetic modifications that impair immediate and future neuron function and activity. Such epigenetic mechanisms represent potential therapeutic targets for ameliorating convergent symptoms of stress and addiction.

Keywords: addiction; chronic stress; decision-making; dorsal striatum; transposable elements.

FIGURE 1:. Dorsal striatum connectivity to reward and mood-related circuitry.

Schematic of dorsal striatum input and output circuitry in rodents, highlighting the direct (via dMSNs) and indirect (via iMSNs) pathways through cortical and limbic structures. Of functional relevance to decision-making and related behaviors are the hippocampus (HIP), globus pallidus externa (GPe), globus pallidus interna (GPi), subthalamic nucleus (STN), ventral tegmental area (VTA), substantia nigra pars reticulata (SNr), and substantia nigra pars compacta (SNc).

FIGURE 2:. LINE-1 expression and retrotransposition in response to acute and chronic external stimuli

Long interspersed nuclear element 1 (LINE-1) loci, transcription, translation, and retrotransposition into the genome. Representative characteristics of the LINE-1 loci shown: transcriptional start site (TSS), untranslated regions (UTR), internal ribosome entry site (IRES), open reading frames (ORF), endonuclease domain (EN), and reverse transcriptase domain (RT). LINE-1 transcription, translation, and retrotransposition in response to acute or chronic stress and stimulant administration paradigms. Expression of the original LINE-1 gene is increased in response to acute stress or stimulant exposure. The increased LINE-1 activity promotes the retrotransposition of a retrotransposition-defective copy of LINE-1 throughout the genome. As external stimuli exposure becomes chronic, LINE-1 expression and retrotransposition return to baseline; however, genomic copies remain and can permanently disrupt the genome.