Elsevier

Neuroscience

Volume 249, 26 September 2013, Pages 258-270
Neuroscience

Adolescent social stress does not necessarily lead to a compromised adaptive capacity during adulthood: A study on the consequences of social stress in rats

https://doi.org/10.1016/j.neuroscience.2012.12.050Get rights and content

Abstract

Childhood bullying or social stress in adolescent humans is generally considered to increase the risk of developing behavioral disorders like depression in adulthood. Juveniles are hypothesized to be particularly sensitive to stressors in their environment due to the relatively late maturation of brain areas that are targeted by stress such as the prefrontal cortex and hippocampus. In our study male adolescent rats were subjected to repeated social defeat on postnatal day (PND) 28, 31 and 34 (experiment 1) or to daily social defeats between PND 35 and 42 (experiment 2). Adolescent rats in experiment 1 were socially housed in pairs with a male of similar age during and after the social defeat. In experiment 2 adolescents were housed either alone or with an age-mate for 7 days (PND 35–42) next to either a highly aggressive or a non-aggressive adult male neighbor with whom a repeated physical interaction was allowed. In experiment 1 the adolescent defeats affected subsequent play behavior with the cage mate. Socially stressed rats more frequently initiated play behavior but also adopted more frequently submissive postures during the play fights. As adults, they seemed to cope behaviorally and physiologically better with a similar exposure to a residential aggressive male rat than unstressed controls. In experiment 2 acute effects of adolescent social stress were studied on neuroplasticity markers like hippocampal cell proliferation and neurogenesis as well as hippocampal brain-derived neurotrophic factor (BDNF) levels. The 2nd experiment also studied long-term effects of the adolescent stress in the response to an adult social defeat. A few acute but minor changes in brain plasticity markers and behavior were observed but these were transient and no behavioral or physiological effects persisted into adulthood. The results from both experiments support the theory developed in the so-called “match–mismatch hypothesis” which claims that the final consequence of childhood adversity depends on how well the early life environment matches the challenges in later life. Socially stressed adolescents are rather resilient to the lasting behavioral and physiological effects of the stress exposure if they are socially housed afterward and have the ability to recover.

Highlights

► Adolescent social stress affects play behavior. ► Adolescent social stress acutely suppresses neurogenesis. ► Rats are resilient to lasting detrimental effects of social stress when adolescents are socially housed. ► Adolescent social defeat reduces subsequent behavioral and physiological response to adult defeat.

Introduction

Many animal species live in complex social structures. The interaction with conspecifics constitutes a pivotal part of their total environment as each individual depends heavily on its social environment for the maintenance of health, fitness and survival (Ren et al., 1999, Neumann, 2009, Dunbar, 2010, Weidt et al., 2012). However, the social environment not only has positive effects on physical and mental well-being. In case social interactions become unpleasant or even threatening, individuals experience social stress which may produce stress pathology in animal models reflecting for instance an increased risk for depressive disorders in humans (Brown and Prudo, 1981, Post, 1992, Cutrona et al., 2005, Kessler et al., 2010). A seriously compromised social environment is experienced by a substantial amount of children being victims of bullying peers (Juvonen et al., 2003). Some of the victims of bullying are reported to suffer from loneliness, low self-esteem, social withdrawal and have an increased risk to develop mood disorders like anxiety or depression (Bjorkqvist, 2001, Hemphill et al., 2012). Positive social interactions, however, such as social support from friends and family during a period of stress improves the chance of successfully coping with stress or recovering from psychopathologies as mentioned above (Franks et al., 1992, Weihs et al., 2005, Cosley et al., 2010, Dunbar, 2010, Weidt et al., 2012).

Because the social nature of our environment greatly influences our health and general well-being it is important to use appropriate animal models to uncover the underlying mechanisms by which our social environment may either positively or negatively affect our well-being. In male laboratory rodents the best equivalent of bullying is social defeat in the resident/intruder test (Koolhaas et al., 1997). In the resident/intruder test, the intruder is repeatedly subjected to attacks and threats from the dominant resident, and these attacks often persist even after the intruder signals defeat by displaying behavioral submission, similar to victims of bullying who are harassed and assaulted even though they do their utmost to avoid provoking the bully (Bjorkqvist, 2001, Vidal et al., 2007, Watt et al., 2009). The social defeat paradigm has been used successfully in adult laboratory rodents to elucidate some of the relevant neurobiological, physiological and behavioral changes caused by acute or chronic social defeat experience (Tornatzky and Miczek, 1993, Meerlo et al., 1996, Buwalda et al., 1999). In adult males, these effects have been demonstrated to persist long after the original defeat experience when the experimental intruder animals are singly housed following the defeat (Meerlo et al., 1996, Buwalda et al., 1999). As for the beneficial aspect of the social environment such as social support during stress, adult laboratory rodents have been shown to respond positively to the presence of a non-hostile companion much like humans respond to the presence and support from a good friend during hardship (Ruis et al., 1999, Wilson, 2001, de Jong et al., 2005, Nakayasu and Ishii, 2008, Hennessy et al., 2009, Cherng et al., 2010, Macone et al., 2011). Hence, different social housing conditions during stress may serve as a useful rodent model for studying the buffering effect of social support.

Most research on social defeat stress and social support is performed using adult laboratory rodents. Yet, human peer victimization or bullying behavior is highest in juveniles (Frisen et al., 2007). Several studies suggest that juveniles and adolescents respond differently to stress when compared with adults. Therefore, they may also be affected differently in the long term (Avital and Richter-Levin, 2005, Romeo, 2010, Bingham et al., 2011). Indeed, in response to acute restraint stress, the plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) remain elevated significantly longer in 28-day-old juvenile rats than in adults (Romeo, 2010). After repeated exposure to restraint stress the initial CORT response to restraint also remains higher in adolescents (Romeo, 2010, Bingham et al., 2011), but the recovery is faster than in adults (Romeo, 2010). When exposed to social defeat, single-housed adolescent rats (postnatal day [PND] 36) spent more time burying in the defensive burying test compared with undefeated controls, indicating a more proactive coping style, whereas the opposite effect was observed in adult defeated rats. This increase in burying behavior seems to be typical for social stress during early adolescence since the effect disappears in late adolescence (PND 51) (Bingham et al., 2011).

A possible explanation why brain and behavior of juveniles and adolescents may be affected by stress in a different or stronger way than adults is the relatively high developmental plasticity in brain areas that are targeted by stress such as the prefrontal cortex and hippocampus (Chechik et al., 1999, Leussis and Andersen, 2008, Stranahan, 2010). Compared to adults, juveniles and adolescents are suggested to be more susceptible to input from their environment as an essential part of learning about and adapting to their environment (Belsky et al., 2009, McCormick, 2010, Romeo, 2010, Jankord et al., 2011, Schmidt, 2011). Consequently, they may be particularly vulnerable to the detrimental effects of stress and adverse environment.

Not all children exposed to an adverse social environment develop psychopathologies as adults and individuals who experience a relatively trouble-free childhood may still develop mood disorders (Ellis et al., 2011, Schmidt, 2011). Even when considering genetic predisposition to stress, the connection between childhood adversity and adult mental health is complex. Since there is a clear learning component in experiencing stressful situations, it is also possible that previous confrontations with stressors lead to an enhanced ability to successfully cope with later stress situations of a similar nature. This idea is summarized in the match–mismatch hypothesis that suggests that the final consequence of childhood adversity depends on how well the early life environment matches the challenges in later life (Ellis et al., 2011, Schmidt, 2011, Daskalakis et al., 2012).

In the current study it is tested in rats whether social defeat stress during adolescence results not only in acute changes in brain and behavior but also longer lasting changes in behavior indicative of an increased susceptibility to stressors of either similar or different nature. As mentioned above, it is known that social defeat stress in adult rodents produces long-lasting effects on brain, physiology and behavior when these animals are singly housed after the defeat and that social housing ameliorates the negative consequences of the social stress (Ruis et al., 1999, de Jong et al., 2005). During development it is even more important that animals are allowed to have social interactions with their peers. Play deprivation or deprivation of social contacts can, depending on the timing, lastingly affect the development of normal social behavior which coincides with alterations in neurochemistry and neuroplasticity. Social play during adolescence, with play fighting being the most commonly expressed form, is crucial for the development of adult social competence (Einon and Morgan, 1977, van den Berg et al., 1999, Pellis and Pellis, 2007). There are critical periods for the effects of social isolation in rats. Einon and Morgan (1977) showed that depriving rats of social interactions between PND 25 and 45 leads to irreversible decreases in voluntary exploration of novel areas and objects whereas deprivation between PND 16 and 25 or after PND 45 did not lead to irreversibility in the development of these behaviors. The lasting effects of social isolation during postnatal weeks 4 and 5 on adult social behavior could be normalized by social re-housing of adolescents after the isolation period (Hol et al., 1999). For this reason we did not socially isolate our experimental adolescent animals during this crucial phase after the social stress experience. Furthermore, it can be questioned to what extent lasting social deprivation during this developmental period in combination with social defeat stress adds to the translational value of this animal model.

Two experiments were performed with the aim to study short- and long-lasting effects of adolescent social stress on brain and behavior. In the first experiment (experiment 1), male adolescent rats were confronted with a highly aggressive residential male on PND 28, 31 and 34. Since we hypothesized that severe social stress would affect social play behavior with an age-matched cage mate, we observed play behavior until adulthood. Furthermore, we studied long-term effects on anxiety and social behavior as well as the behavioral and physiological response to adult social defeat. The physiological stress response was measured using permanently implanted radiotelemetry transmitters. In a second experiment (experiment 2), the effects of more chronic social stress were studied. Male adolescent rats were housed in close contact with either a highly aggressive or a non-aggressive adult male conspecific for 1 week (PND 35–42) (Kudryavtseva et al., 1991). During these 7 days a transparent separator wall was withdrawn 10 times for 10 min allowing physical contact between the adolescent experimental animals and the adult male. Aggressive adults repeatedly attacked the experimental rats during these 10-min periods of physical contact. To study the possible protective role of social housing during this social stress period, experimental rats were housed either alone or with an age-matched male cage mate in the compartment next to the adult neighbor. Shortly after the last interaction, neuroplasticity was studied in brains of stressed and non-stressed animals in one group of animals. In a second group of animals in experiment 2 long-term effects were studied on anxiety and social behavior and on behavioral and physiological responses to adult defeat.

Section snippets

Animals

Male Wistar rats (n = 32) were obtained from the Harlan Laboratories (Horst, The Netherlands) at PND 21–23. Upon their arrival, the animals were housed in pairs in translucent plastic cages (40 × 25 × 15 cm). Food and water were supplied ad libitum with temperatures of approximately 21°C under a 12:12 h day–night regime (lights on at 20.00 to secure that all manipulations and tests were performed during the active phase (subjective night) of the animals. All animals were given 1 week to habituate to the

Effects of social defeat stress on body weight gain and play and other behavior

Adolescent defeat did not induce differences in body weight gain between groups.

Both control and defeated rats showed vivacious play behavior and social interaction with their cage mate. Comparison of the sum of the frequency of the individual behaviors (see Table 1) showed that previously defeated adolescent rats initiated play behavior with their cage mate more frequently (F(1, 15) = 4.7; p < 0.05) (Fig. 2). During these play fights they tended to show submissive behavior more often than their

Discussion

The main conclusion from this study is that the Wistar rats in experiment 1 and the Sprague–Dawley rats we used in experiment 2 are resilient to lasting negative effects of adolescent social stress. The social housing after the adolescent social stress experience may play an important role in this. In adult defeat studies it has been shown that social housing ameliorates the effects of the social stress (Ruis et al., 1999). Lasting social deprivation during this crucial period for the

Acknowledgements

The authors would like to thank Folkert Postema and Jan Keijser for their technical assistance in the immunocytochemical analyses. Undergraduate students Lourens Elzinga, Pamela Braakhuis, Anneleen Hulshof and Chris Vinke are acknowledged for their efforts in the quantification of the immunocytochemical data.

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