Working memory training triggers delayed chromatin remodeling in the mouse corticostriatothalamic circuit.
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 90min after training. These animals also presented lower immunoreactivity for H3K9,14Ac in DMSt 24h but not 90min after the procedure. Increases in H3K27Me2, a repressive chromatin mark, were found in the DMSt and DMTh 24h 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.
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: mcassanelli@ffyb.uba.ar.
Pablo Martín
PM
Cassanelli
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
María Laura
ML
Cladouchos
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
Georgina
G
Fernández Macedo
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
Laura
L
Sifonios
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
Laura Inés
LI
Giaccardi
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
María Laura
ML
Gutiérrez
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
María Clara
MC
Gravielle
Instituto de Investigaciones Farmacológicas (UBA-CONICET), Junín 956, 5th Floor, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina; 1ª Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, C1121ABG Ciudad Autónoma de Buenos Aires, Argentina.
Silvia
S
Wikinski
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases; D007858:Learning; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012153:Retention, Psychology; D018709:Statistics, Nonparametric
D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
Executive function; Histone acetylation; Histone methylation; Neural network; c-Fos