Phenotype

Neuroscience

Central nervous system

Haploinsufficiency

Biology

Gene

Basal ganglia

Nucleus accumbens

Histone

Medium spiny neuron

Cell biology

Epigenetics

Genetics

Nature Neuroscience

Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism. Early life stress (ELS) promotes susceptibility to the effects of chronic stress in adulthood. Kronman et al. show that ELS alters H3K79me2 in D2 medium spiny neurons in the nucleus accumbens and that this underlies the susceptibility to the effects of subsequent stress.

Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons