Chronic social stress during early development elicits unique behavioral changes in adulthood

Abstract

Purpose: Chronic social stress is known to induce inflammation in the brain, and early-life stress affects the brain and social behavior in adulthood. To study the relationship between social stress in childhood development and social behavior in adulthood, we subjected mice to a sequential early-life social stresses and characterized their adult behavioral phenotypes.

Methods: C57BL/6 mice were sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order. The body weights of the MS/SD/SI mice were measured. Behavioral tasks related to anxiety, depression, locomotion, learning/memory, and repetitive/compulsive-like behavior were conducted. Social behaviors suggesting sociability, social interaction, aggression, and social fear were investigated.

Results: MS/SD/SI mice weighed less than the control mice. At 7 and 8 weeks of age. These mice displayed normal behaviors in anxiety-, depression-, and learning/memory-related tasks, but they exhibited increased locomotor activity and a low level of repetitive/compulsive-like behavior. Notably, they exhibited increased social interaction, impaired empathy-related fear, reduced predator fear, and increased defensive aggressiveness.

Conclusion: Social stress during childhood development resulted in behavioral alterations, and MS/SD/SI mice generated by mimicking child abuse or maltreatment showed unique abnormalities in social behaviors. MS/SD/SI mice might be useful not only to study the relationship between social stress and brain inflammation but also psychosocial behaviors observed in individuals with brain disorders, such as psychopaths.

Keywords: Abuse; Childhood development; Mice; Social behavior; Social stress.

Figure 1.. Generation of the MS/SD/SI model

(A) Time schedule of early-life social stress paradigms (MS, SD, and SI). (B) Reduced body weight in MS/SD/SI mice. (C) Weight gain at 7 to 8 weeks of age. MS, maternal separation; SD, social defeat; SI, social isolation. **p < 0.01, Student t-test.

Figure 2.. Behavioral phenotypes of MS/SD/SI mice in tasks assessing anxiety, locomotion, depression, and learning/memory

(A) Light/dark transition test. The control (n = 12) and MS/SD/SI model (n = 18) mice spent similar times in the light or dark compartment and demonstrated a similar number of crossings between the compartments. (B) Elevated plus maze task. Although the MS/SD/SI model mice (n = 9) displayed an increased number of crossings into the open arms compared to the control mice (n = 16), the groups spent a similar amount of time in the open and closed arms. (C) In the open-field test, an increase in distance moved was observed in the MD/SD/SI model group (n = 24) compared to the control group (n = 14). (D) Forced swim test. The MS/SD/SI model mice (n = 12) displayed a similar amount of immobility time to the control mice (n = 15). (E) Tail-suspension test. The MS/SD/SI model mice (n = 10) showed a similar immobility time to the control mice (n = 12). (F–H) Fear-conditioning. During training (F), the control (n = 13) and MS/SD/SI model (n = 12) mice exhibited similar freezing durations. The horizontal line indicates the duration of a tone (28 seconds), and the vertical arrow indicates the duration of foot-shock (2 seconds). There was no difference between the groups in 24-hour contextual memory (G). No difference was found between the groups in 24-hour cued memory (H). The horizontal line indicates the duration of a tone (3 minutes). MS, maternal separation; SD, social defeat; SI, social isolation. *p < 0.05, Student t-test. ^##p < 0.01, two-way analysis of variance followed by Scheffé post hoc test.

Figure 3.. Behavioral phenotypes of MS/SD/SI mice in tasks assessing repetitive/compulsive-like behavior

(A) In the marble-burying test, the MD/SD/SI model mice (n = 9) demonstrated a decrease in the number of buried marbles compared to the control mice (n = 11). (B) Considering nest-building behavior, a lower score was recorded for the MD/SD/SI model group (n = 10) compared to the control group (n = 13). MS, maternal separation; SD, social defeat; SI, social isolation. **p < 0.01, Student t-test.

Figure 4.. Behavioral phenotypes of MS/SD/SI mice in tasks assessing social behaviors

(A) In the sociability test, the MS/SD/SI and control groups spent more time exploring a novel stranger than exploring the empty cage. (B) In the social interaction test, the MD/SD/SI model mice (n = 16) showed a significant increase in social interactions with an unfamiliar juvenile mouse than did the control mice (n = 20). (C–F) Resident-intruder task. The MD/SD/SI model (n = 12) mouse, when positioned as a resident, displayed a normal level of aggression (C, D). However, the MD/SD/SI model (n = 16) mice, when positioned as an intruder, exhibited a greater number of attacks (left) and a shorter latency to the first attack (right) than the control mice (n = 8) (E, F). (G) In observational fear-conditioning, the MD/SD/SI model mice (n = 12) exhibited a shorter freezing duration than the control mice (n = 12). (H) The MD/SD/SI model mice (n = 22) spent more time in a zone containing a rat in the predator target task compared to the control mice (n = 17). MS, maternal separation; SD, social defeat; SI, social isolation. *p < 0.05, **p < 0.01, Student t-test. ^#p < 0.05, ^##p < 0.01, two-way analysis of variance followed by Scheffé post hoc test.