GSE133889
H3K79me2 dynamics in medium spiny neurons mediate long-term behavioral and cell type-specific molecular effects of early life stress
Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, and show aberrant transcription across several limbic brain regions. The nucleus accumbens (NAc) in particular shows unique susceptible versus resilient phenotypes at the transcriptional, neuroanatomical, and physiological levels. Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in NAc have not yet been investigated. Here, we examined long-lasting changes in histone modifications induced in NAc by ELS and studied their underlying mechanisms in mediating heightened lifelong stress susceptibility in male and female mice. We identify methylation of lysine 79 of histone H3 (H3K79me) and the enzymes that control this modification, selectively in D2-type medium spiny neurons, as crucial for the expression of ELS-induced stress susceptibility, and reveal the transcriptional networks regulated by this mechanism. Finally, we demonstrate the potential clinical viability of this approach by showing that systemic delivery of a small molecule inhibitor of H3K79me reverses ELS-induced behavioral deficits. Overall design: Studying methylation of lysine 79 of histone H3 (H3K79me) in D2-type medium spiny neurons, studying transcriptional effects downstream of this epigenetic mechanism