Gains and Losses: Resilience to Social Defeat Stress in Adolescent Female Mice

Abstract

Background: Adolescence is a unique period of psychosocial growth during which social adversity can negatively influence mental health trajectories. Understanding how adolescent social stress impacts males and females and why some individuals are particularly affected is becoming increasingly urgent. Social defeat stress models for adolescent male mice have been effective in reproducing some physical/psychological aspects of bullying. Designing a model suitable for females has proven challenging.

Methods: We report a version of the adolescent male accelerated social defeat stress (AcSD) paradigm adapted for females. Early adolescent C57BL/6J female mice (N = 107) were exposed to our modified AcSD procedure twice a day for 4 days and categorized as resilient or susceptible based on a social interaction test 24 hours later. Mice were then assessed for changes in Netrin-1/DCC guidance cue expression in dopamine systems, for inhibitory control in adulthood using the Go/No-Go task, or for alterations in dopamine connectivity organization in the matured prefrontal cortex.

Results: Most adolescent females showed protection against stress-induced social avoidance, but in adulthood, these resilient females developed inhibitory control deficits and showed diminution of prefrontal cortex presynaptic dopamine sites. Female mice classified as susceptible were protected against cognitive and dopaminergic alterations. AcSD did not alter Netrin-1/DCC in early adolescent females, contrary to previous findings with males.

Conclusions: Preserving prosocial behavior in adolescent females may be important for survival advantage but seems to come at the price of developing persistent cognitive and dopamine deficiencies. The female AcSD paradigm produced findings comparable to those found in males, allowing mechanistic investigation in both sexes.

Keywords: Adolescent critical period; Guidance cues; Inhibitory control; Prefrontal cortex; Sex differences; Social defeat stress.

Figure 1.

High proportion of resilient female mice after exposure to AcSD stress. (A) Graphic representation of AcSD stress paradigm for adolescent mice. (B) Timeline of AcSD stress in female mice. (C) SIT results after AcSD in female adolescent mice; significantly different at ****p < .0001. Inset: Data reproduced from Vassilev et al. (46) showing SIT after AcSD for adolescent male mice (significantly different at ***p < .001). (D) Proportion of resilient and susceptible female mice. The proportion of the resilient phenotype was higher in females than in males. Inset: Data reproduced from (46) showing that most males exposed to AcSD in adolescence showed resilience. (E) The number of attacks between resilient and susceptible mice is not significantly different in either females or males. (F) Female mice received fewer attacks than male mice during the AcSD. (G) Results from the AcSD experiment with adolescent males exposed to the “female” pattern of attacks. The resilient vs. susceptible proportion does not differ from the one that we found using the typical male AcSD protocol. (H) Median split on the cumulative number of received attacks in female mice. The proportion of females that were categorized as susceptible or resilient does not differ between the low and high received attack groups. All data are shown as mean ± SEM. AcSD, accelerated social defeat; con, control; PND, postnatal day; res, resilient; SIT, social interaction task; sus, susceptible.

Figure 2.

AcSD in adolescent female mice did not lead to changes in risk taking–like behaviors. (A) Experimental timeline. (B) AcSD in adolescent female mice did not lead to changes in risk taking–like behavior measured by the EPM test, p = .18. (C) There was no correlation between the amount of time spent in the open arms of the EPM and the amount of time spent in the IZ during the SIT in female mice, Pearson’s r₅₃ = 0.08, p = .55. All data are shown as mean ± SEM. AcSD, accelerated social defeat; con, control; EPM, elevated plus maze; IZ, interaction zone; PND, postnatal day; res, resilient; SIT, social interaction task; sus, susceptible.

Figure 3.

Following accelerated social defeat in adolescence, there were no changes in the Netrin-1/DCC system in female mice. (A) Experimental timeline. (B) Accelerated social defeat in adolescent female mice did not lead to changes in Dcc mRNA expression in the VTA. (C) Accelerated social defeat in adolescent female mice did not lead to changes in Netrin-1 protein levels in the NAcc. All data are shown as mean ± SEM. AcSD, accelerated social defeat; con, control; mRNA, messenger RNA; NAcc, nucleus accumbens; PND, postnatal day; res, resilient; SIT, social interaction task; sus, susceptible; VTA, ventral tegmental area.

Figure 4.

Only resilient female mice showed AcSD-induced deficits in impulse control in adulthood. (A) Experimental timeline. (B) Graphic representation of the Go/No-Go task. (C) Resilient female mice maintained a higher proportion of commission errors in comparison to control and susceptible mice, significantly different at *p < .05. (D) Dendrogram showing hierarchical clustering of subjects based on percentage of commission errors during 14 days of the Go/No-Go task. (E) Cluster analysis classified cases into one of two groups, good and poor performers, based on commission error scores. Most resilient females were classified in the poor performance cluster, compared with most control and susceptible females, which were classified in the good performer cluster. All data are shown as mean ± SEM. AcSD, accelerated social defeat; con, control; PND, postnatal day; res, resilient; SIT, social interaction task; sus, susceptible.

Figure 5.

AcSD in adolescence depleted presynaptic sites from dopamine axons in the prefrontal cortex in adulthood, but only in resilient females. (A) Timeline of the experiments. (B) Photomicrographs show TH-immunolabeled dopamine axons in the Cg, PrL, and IL subregions of the prefrontal cortex (5× and 100× magnification). White arrows indicate examples of TH-positive varicosities. (C) There were no differences across groups in estimated dopamine input volume in any of the subregions. (D, E) Resilient female mice showed reduced (D) total number and (E) density of dopamine varicosities compared with control mice. All data are shown as mean ± SEM. AcSD, accelerated social defeat; Cg, cingulate; IL, infralimbic; PND, postnatal day; PrL, prelimbic; SIT, social interaction task; TH, tyrosine hydroxylase.

Figure 6.

After AcSD, defeated female mice weighed more than the control mice. (A) Weights of females during AcSD and in adulthood. Inset: difference in weight between PND 75 and PND 28, showing that defeated mice gained more weight than controls; significantly different at *p < .05. All data are shown as mean ± SEM. AcSD, accelerated social defeat; con, control; PND, postnatal day; res, resilient; sus, susceptible.