Synaptic pruning during adolescence shapes adult social behavior in both males and females

Abstract

Evolutionarily conserved, peer-directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward-related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic "reward" circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. We previously demonstrated that during adolescence, in rats, microglial synaptic pruning shapes the development of NAc and social play behavior in males and females. In this report, we hypothesize that interrupting microglial pruning in NAc during adolescence will have persistent effects on male and female social behavior in adulthood. We found that inhibiting microglial pruning in the NAc during adolescence had different effects on social behavior in males and females. In males, inhibiting pruning increased familiar exploration and increased nonsocial contact. In females, inhibiting pruning did not change familiar exploration behavior but increased active social interaction. This leads us to infer that naturally occurring NAc pruning serves to reduce social behaviors toward a familiar conspecific in both males and females.

Keywords: adolescent; plasticity; rodent; sex differences; social.

FIGURE 1

Experimental design. Females and males were bred in-house and were treated with neutrophil inhibitory factor (NIF) or VEH at sex-specific times (females at P22, males at P30). At 3 months of age, animals of both sexes underwent the behavior battery discussed herein.

FIGURE 2

Social versus object choice. Inhibiting pruning in the nucleus accumbens (NAc) during adolescence did not impact the behavioral parameters measured in the social versus object choice tests in (a–d) females (VEH n = 12; neutrophil inhibitory factor [NIF] n = 14) or (e–h) males (VEH n = 16; NIF n = 15). Bar graphs represent average ± standard error of the mean. Student’s two-tailed t-test. *p < .05.

FIGURE 3

Social novelty preference. (a–d) In females, the inhibition of nucleus accumbens (NAc) pruning during adolescence did not significantly regulate the behaviors measured in the social novelty preference test. (VEH n = 12; neutrophil inhibitory factor [NIF] n = 13). (e, f) In males, inhibition of NAc pruning during adolescence did not significantly influence exploration time or %exploration of a novel partner or (g) change time spent exploring familiar partner in males. (h) Inhibiting NAc pruning during adolescence in males significantly increased %exploration of a familiar partner (VEH n = 17; NIF n = 15). Bar graphs represent average ± standard error of the mean. Student’s two-tailed t-test. *p < .05.

FIGURE 4

Novel social interaction. (a–d) In females, inhibition of nucleus accumbens (NAc) pruning during adolescence did not significantly regulate the behaviors measured in the social novelty preference test (VEH n = 13; neutrophil inhibitory factor [NIF] n = 13). (e, f) In males, the inhibition of NAc pruning during adolescence did not significantly influence exploration time or %exploration of a novel partner or (g) change time spent exploring familiar partner in males. (h) Inhibiting NAc pruning during adolescence in males significantly increased %exploration of a familiar partner (VEH n = 17; NIF n = 14). Bar graphs represent average ± standard error of the mean. Student’s two-tailed t-test. *p < .05.

FIGURE 5

Familiar social interaction. (a) Inhibiting nucleus accumbens (NAc) pruning during adolescence significantly increased active social attention and (c) significantly decreased nonsocial contact in females (VEH n = 8; neutrophil inhibitory factor [NIF] n = 14). (b, d) No significant changes were seen in passive social or nonsocial attention in females. (e and f) Inhibiting NAc pruning during adolescence did not significantly change active or passive social attention in males. (g) However, inhibiting NAc pruning during adolescence in males significantly increased nonsocial contact and (h) significantly decreased nonsocial attention (VEH n = 13; NIF n = 16). Bar graphs represent average ± standard error of the mean. Student’s t-test. *p < .05, ^**p ≤ .01.

FIGURE 6

Open field. (a) After inhibiting nucleus accumbens (NAc) pruning during adolescence, females show no statistically significant change in time spent in the inner quadrant of the open field apparatus (VEH n = 13; neutrophil inhibitory factor [NIF] n = 14). (b) In males, there is a statistically significant increase in the amount of time spent in the inner quadrant of the open field apparatus (VEH n = 17; NIF n = 16). Bar graphs represent average ± standard error of the mean. Student’s two-tailed t-test. If *, then p < .05. (c and d) Correlations between time spent in the inner zone of the open field apparatus and other social metrics in females and males. (c) In NIF-treated females, there is a significant correlation between nonsocial attentions in the novel interaction test and open field behavior (p = .0353), and in VEH-treated females, open field behavior significantly correlates with %social exploration in the social versus object choice test (p = .0104). Both these differences were found not significant following Fisher’s r-to-z transformation (NS). (d) In VEH-treated males, open field behavior correlates to %social exploration in the social versus object choice test (p = .0385). After Fisher’s r-to-z transformation, the p-value was significant (p = .0143). *p < .05, ^**p ≤ .01.