Working memory training triggers delayed chromatin remodeling in the mouse corticostriatothalamic circuit

• A model to study working memory training was established in mice.
• Chromatin marks elicited by training were found in the striatum and the thalamus.
• A shift in gene expression towards repression was induced by training.

Working memory is a cognitive function serving goal-oriented behavior. In the last decade, working memory training has been shown to improve performance and its efficacy for the treatment of several neuropsychiatric disorders has begun to be examined. Neuroimaging studies have contributed to elucidate the brain areas involved but little is known about the underlying cellular events. A growing body of evidence has provided a link between working memory and relatively long-lasting epigenetic changes. However, the effects elicited by working memory training at the epigenetic level remain unknown.In this study we establish an animal model of working memory training and explore the changes in histone H3 acetylation (H3K9,14Ac) and histone H3 dimethylation on lysine 27 (H3K27Me2) triggered by the procedure in the brain regions of the corticostriatothalamic circuit (prelimbic/infralimbic cortex (PrL/IL), dorsomedial striatum (DMSt) and dorsomedial thalamus (DMTh)).Mice trained on a spontaneous alternation task showed improved alternation scores when tested with a retention interval that disrupts the performance of untrained animals. We then determined the involvement of the brain areas of the corticostriatothalamic circuit in working memory training by measuring the marker of neuronal activation c-fos. We observed increased c-fos levels in PrL/IL and DMSt in trained mice 90 min after training. These animals also presented lower immunoreactivity for H3K9,14Ac in DMSt 24 h but not 90 min after the procedure. Increases in H3K27Me2, a repressive chromatin mark, were found in the DMSt and DMTh 24 h after the task.Altogether, we present a mouse model to study the cellular underpinnings of working memory training and provide evidence indicating delayed chromatin remodeling towards repression triggered by the procedure.