Figure 6.

Inhibition of early-life stress-activated cells in NAc reduces hypersensitivity to adult stress in male mice, but not in female mice. A, Viral expression strategy: the administration of 4-OHT to Arc-CreERT2/+ mice injected with AAV-hSyn-hM4Di-mCherry results in permanent hM4Di expression in experience-activated cells. B, Representative image of DREADD-mCherry expression in NAc from pups infused with virus on P7 shows relative specificity of injection even within pups. Scale bar, 2 mm. C, Timeline and experimental groups: mice were either reared in standard conditions or subjected to ELS from P10 to P17. Std-reared mice were given access to a running wheel before 4-OHT-induced recombination on P17. In adulthood, all mice underwent two rounds of CNSDS for 10 d. During the first round, all mice received a vehicle injection 30 min prior to each daily bout of social defeat; in the second round, all mice received 0.1 mg/kg OLZ 30 min prior to social defeat. The sensory period of CNSDS (cohousing across a barrier from an aggressor) was shortened to 3–4 h after defeat instead of overnight to account for the OLZ half-life. Mice were assessed behaviorally before and after each round of CNSDS. D, Social avoidance among male mice, presented as a social interaction ratio, where a lower ratio is associated with greater social avoidance. E, Percentage of male mice categorized as resilient, indifferent, or susceptible to CNSDS under each treatment condition. F, Representative heat maps of average mouse behavior in each group during social interaction testing with an aggressor present. G, Latency of male mice to eat in a novel arena during a novelty-suppressed feeding test. H, Time spent in the center during open-field testing among male mice. I, Representative heat maps of average mouse behavior in each group during open-field exploration. J, Latency of female mice to eat in a novel arena during a novelty-suppressed feeding test. K, Social avoidance among female mice, where a lower social interaction ratio is associated with greater social avoidance. L, Time spent in the center during open-field testing among female mice. OLZ indicates DREADD inhibition of early experience-activated cells. Data are mean ± SEM. Post hoc comparisons between corresponding conditions and prestress data are indicated by *p < 0.05, **p < 0.01, and ****p < 0.0001.