Corticosterone accelerates behavioral inflexibility via plasticity-related gene expression in the dorsal striatum

TL;DR

Stress hormone corticosterone makes mice less able to change their behavior by altering gene activity in brain regions linked to flexible and inflexible actions.

Contribution

This is the first study to show how corticosterone affects gene expression and epigenetic changes in brain regions linked to behavioral inflexibility.

Findings

Corticosterone reduces synaptic plasticity gene expression in the dorsomedial striatum.

Corticosterone increases synaptic plasticity gene expression in the dorsolateral striatum.

Corticosterone influences histone acetylation linked to plasticity genes in a sex- and region-specific manner.

Abstract

Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility provides efficiency and automaticity in familiar contexts, and is promoted by the dorsolateral striatum (DLS). Importantly, chronic elevation of the primary stress hormone, corticosterone (CORT) in rodents or cortisol in humans, impairs behavioral flexibility through dendritic atrophy in the DMS, and promotes inflexible behavioral response strategies through dendritic outgrowth in the DLS. However, understanding of changes in gene expression underlying behavioral inflexibility is lacking. We used a food-motivated operant task in male and female mice to define gene changes that accompany the shift to inflexible behavior with CORT. We discovered that CORT-accelerated loss of behavioral flexibility is accompanied by decreased DMS- and increased DLS-specific synaptic plasticity gene expression, and that distinct genes are either differentially expressed or spliced in the transition to inflexible behavior. Splicing analysis suggests that repressed activity in the DMS during the transition to inflexible behavior may reflect both reduced expression and increased degradation of plasticity-related mRNA transcripts. Finally, given the ability of CORT to influence histone acetylation, we defined CORT-mediated H3K9ac enrichment profiles associated with synaptic plasticity gene regulation stratified by sex and striatal subregion. This study is the first to define CORT-driven epigenetic regulation in the DMS and DLS during the CORT-accelerated transition from flexible to inflexible behavior in male and female mice.

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