H3.3 dynamics in NAc are increased in human MDD and in response to chronic stress in rodents. (A) H3F3B, but not H3F3A, expression is increased in NAc of nonmedicated subjects with MDD vs. controls, an effect that is reversed with ADs (*P < 0.05, ***P < 0.0001 by one-way ANOVA followed by Dunnett’s post hoc test; n = 4–11 per group). (B) Mice were segregated into susceptible vs. resilient populations following CSDS using SI testing for subsequent molecular analyses (***P < 0.0001 by one-way ANOVA followed by Dunnett’s post hoc test; n = 8 per group). (C) H3f3b, but not H3f3a, is significantly increased in expression in NAc of susceptible, but not resilient, mice following CSDS. This effect is reversed by chronic imipramine treatments in behaviorally responsive susceptible animals (*P < 0.05 by one-way ANOVA followed by Dunnett’s post hoc test; n = 3–13 per group; in some cases, tissues from multiple animals were pooled/biological replicate). (D) ELS (maternal separation) in mice results in faster rates of H3.3 chromatin accumulation in NAc with age in comparison with SR animals. LC-MS/MS analysis [*P < 0.05, **P < 0.01 by unpaired Student’s t test; n = 3 (pooled/biological replicate) per group]. (E) EE during adolescence promotes reduced expression of H3f3b, but not H3f3a, in NAc in comparison with normally housed mice (*P < 0.05 by unpaired Student’s t test; n = 7 per group) and (F) renders animals resilient to subsequent bouts of CSDS (**P < 0.01 by unpaired Student’s t test; n = 5 per group). Data are represented as means ± SEM.