Review article
Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses

https://doi.org/10.1016/j.neubiorev.2017.01.018Get rights and content

Highlights

  • Play fighting in adolescence is essential for healthy neurobehavioral maturation.

  • Adolescents have heightened sensitivity to social stressors compared to adults.

  • Social housing is necessary for adolescent social defeat to increase cocaine taking.

  • Isolation-rearing alters CRF-serotonin interactions in raphe to increase anxiety.

  • Medial prefrontal cortex is altered by adolescent stress and important for play.

Abstract

Negative social experiences during adolescence are central features for several stress-related mental illnesses. Social play fighting behavior in rats peaks during early adolescence and is essential for the final maturation of brain and behavior. Manipulation of the rat adolescent social experience alters many neurobehavioral measurements implicated in anxiety, depression, and substance abuse. In this review, we will highlight the importance of social play and the use of three separate social stress models (isolation-rearing, social defeat, and social instability stress) to disrupt the acquisition of this adaptive behavior. Social stress during adolescence leads to the development of anxiety and depressive behavior as well as escalated drug use in adulthood. Furthermore, sex- and age-dependent effects on the hormonal stress response following adolescent social stress are also observed. Finally, manipulation of the social experience during adolescence alters stress-related neural circuits and monoaminergic systems. Overall, positive social experiences among age-matched conspecifics during rat adolescence are critical for healthy neurobehavioral maturation.

Introduction

Adverse experiences during adolescence increase risk for stress-related mental illnesses, including addiction, later in life (Andersen and Teicher, 2008, Gutman and Nemeroff, 2003, National Clearinghouse on Child Abuse and Neglect, 2005). The majority of young adults who report neglect or abuse during the course of development are diagnosed with at least one psychiatric disorder, including depression, anxiety, schizophrenia, substance use or behavioral disorders (Espejo et al., 2007, Gutman and Nemeroff, 2003, Heim et al., 2008, McFarlane et al., 2005, National Clearinghouse on Child Abuse and Neglect, 2005, Scheller-Gilkey et al., 2003). Early-life traumatic events also increase the likelihood of co-morbid psychiatric and substance abuse disorders in adulthood (Scheller-Gilkey et al., 2003). Thus, there is a great need to understand the effects of adverse experiences on the neural mechanisms underlying stress-related neuropsychiatric and substance use disorders. Although all aspects of human behavior cannot be modeled in non-human animals, animal models aid in discovery of relevant mechanisms for the effects of environmental and psychosocial stressors during adolescence in later neuropsychiatric disorders. Rat and mouse studies make up 93% of all neurodevelopmental research by one estimate (Clancy et al., 2007).

Neural and behavioral development of rodents is thought to mirror stages of human development (Adriani and Laviola, 2004, Andersen, 2003, Burke and Miczek, 2014, Laviola et al., 2003, Lukkes et al., 2009d, Spear, 2000). The specific ages when a rodent is considered an adolescent are quite variable across studies (e.g. Yetnikoff et al., 2013). For the laboratory rodent, adolescence is artificially introduced on postnatal day (P) 21 when it is separated from its mother. For the purposes of this review, P21–P34 correspond to early adolescence, P34–P46 correspond to mid-adolescence, and P46–P59 correspond to late adolescence (Burke and Miczek, 2014, Laviola et al., 2003, Lukkes et al., 2009d, McCormick and Mathews, 2007, Tirelli et al., 2003). These stages may correspond to early (10–13 years), middle (14–16 years) and late (17–21 years) stages of human adolescent life conceptualized by clinicians specializing in adolescent human health (Neinstein, 2009, Weiner et al., 2012). Physical markers of puberty typically appear in the mid-adolescent period in rats; preputial separation for males occurs around P40 to P48 and the vaginal opening for females takes place at approximately P32 to P35, but varies across studies and individuals (Lewis et al., 2002, McCormick and Mathews, 2007, Vetter-O'Hagen and Spear, 2012). While puberty takes place during adolescence, these are different constructs because puberty is a discrete measurable event, while adolescence is a gradual brain and behavioral maturation process that encompasses a more extensive portion of ontogeny (Sisk and Foster, 2004).

In humans, adolescence is a sensitive period of development that is characterized by increased risk-taking, sensation seeking, and moodiness (Fuhrmann et al., 2015, Kilford et al., 2016). During adolescence, more time is spent with peers and the quality of social interaction changes (Larson et al., 1996, Platt et al., 2013, Somerville et al., 2010). In humans, feelings of rejection become more common (Cairns et al., 1995) and psychopathology emerges (Cicchetti and Rogosch, 2002) during this time of life. During childhood, cognitive representations of peers are built that shape their future interactions and relationships with age mates based on their earlier experiences in peer groups (Cairns et al., 1995). Furthermore, a greater reliance on peers for social support during adolescence occurs and adolescents become increasingly attuned to treatment by their peers (Brown, 2004, Ladd et al., 2014). Social relationships during childhood and adolescence have a role in either maintaining or promoting the development of maladaptive behavioral patterns (Hankin et al., 1998; Patterson et al., 1992).

Interactions with age-matched conspecifics during adolescence are also important for rodents. Rats are highly social animals and adolescent rats exhibit greater preference for social stimuli than do adults in the conditioned place preference test (Douglas et al., 2004, Yates et al., 2013). These peer-directed activities have a considerable incentive value during adolescence and are crucial for the development of social competence (Douglas et al., 2004, Pellis et al., 2014, Vanderschuren and Trezza, 2014). Early adolescence is characterized by increased social play, increased monoaminergic activity, and the development of proper cognitive strategies that lead to effective coping with adult situations (Spear, 2000, Vanderschuren et al., 1997). Manipulation of the rat adolescent social experience (Fig. 1) alters many neurobehavioral measurements relevant to anxiety, depression, and substance abuse that are discussed in this review. Furthermore, the majority of studies reviewed here use male rats. If females were also examined, it will be noted within the text. The following manipulations of adolescent social experience discussed are:

  • 1.

    Social play behavior emerges as early as P17 (Bolles and Woods, 1964) and peaks between P30 and P40 (Meaney and Stewart, 1981, Panksepp, 1981, Panksepp et al., 1984, Pellis and Pellis, 1997). Juvenile play has been identified as one of the essential mechanisms for healthy maturation of the social brain and social behavior, and many studies involving humans and rodents have illustrated the negative consequences associated with limited or abnormal play exposure in adolescence (Bell et al., 2010, Darwish et al., 2001, Hol et al., 1999, Pellis and Pellis, 2007, Pellis et al., 2010b). Play fighting can be readily tested and quantified by pairing partners and scoring the various actions performed. Such measures can monitor both the frequency of play and the quality of the movements and counter movements by the partners and so assess different possible treatment effects (Himmler et al., 2013b).

  • 2.

    Social isolation of rats has the most potent effects during a sensitive phase between weaning (P21) to early adulthood (P60) (Einon and Morgan, 1977, Leng et al., 2004, Weiss et al., 2004, Wilkinson et al., 1994). These changes are long-lasting and persist even after re-socialization (Einon and Morgan, 1977, Leng et al., 2004, Lukkes et al., 2009a, Lukkes et al., 2009b, Lukkes et al., 2009c, Weiss et al., 2004, Wright et al., 1991). A large number of preclinical studies employ post-weaning social isolation as a rodent model of adolescent adversity (as reviewed in Hall, 1998, Lukkes et al., 2009d). Social isolation typically involves housing rats individually beginning on the day of weaning, which ranges from P21 and P28. Socially isolated rats are completely deprived of social contact but usually still have access to olfactory, auditory and visual cues from other rats within the holding room (Einon and Morgan, 1977, Leng et al., 2004, Weiss et al., 2004, Wilkinson et al., 1994). The controls for these experiments are typically group-reared in cages of two to four rats per cage (Einon and Morgan, 1977, Leng et al., 2004, Weiss et al., 2004). In the vast majority of studies, the rats remain in isolation for four to six weeks or more (as reviewed by Hall, 1998, Fone and Porkess, 2008, Lapiz et al., 2003) and are then tested while still being housed in isolation. More recently, the isolation-rearing method has been designed so that animals are isolated specifically during a sensitive period in life when social play is most abundant (usually P21–P42), followed by a return to group housing before any collection of dependent variables (Baarendse et al., 2014, Lukkes et al., 2012b, Lukkes et al., 2009b, Lukkes et al., 2009c, Whitaker et al., 2013). This helps ensure that any behavioral or neurochemical effects observed can be attributed to isolation-induced disruption of particular phases of development (Lukkes et al., 2009a, Lukkes et al., 2009b, Lukkes et al., 2009c). Moreover, while studies using isolation-rearing over this period are the most common, it is important to note that when rats are reared with a non-playful partner or one that plays atypically during this critical period, they show cognitive and social deficits as well as neural changes (Bell et al., 2010, Einon et al., 1978, Schneider et al., 2016). This suggests that at least some of the effects of being reared in isolation arise from the lack of gaining appropriate social experiences. For this review, the term “isolation-rearing” will be used to describe isolation performed during discrete periods of development whereas the term “isolation housing” will be used when rodents are isolated from weaning through their entire lives.

  • 3.

    Because of the importance of social learning in adolescence, it may be that the adolescent brain and hypothalamic pituitary adrenal (HPA) axis are more responsive to social context than the adult brain is when confronted with a stressor. The social instability stress (SS) model has been used in pair-housed Long Evans rats to investigate this possibility. The SS procedure is applied postnatal days 30 through 45 (mid-adolescence) in adolescents. Daily during this period, rats are removed from the colony room and isolated in small, ventilated containers for one hour. Isolation produces a robust increase in corticosterone concentrations within 30 min that is maintained for the 60 min duration (Hodges et al., 2014, McCormick et al., 2001). After isolation, rats are returned to the colony and are housed with a new cage partner that also is undergoing the SS procedure. The SS groups are compared with an isolation-only group (ISO) and a non-stressed control group (CTL). ISO rats undergo the daily one-hour isolation and return to their familiar cage partner (also undergoing ISO) each day. Pairs of CTL rats are undisturbed except for cage maintenance until the experimental test day, the last day of the SS and ISO procedures. In some studies, adolescent SS is compared to the same procedure applied in adult rats from postnatal day 70–85, which allows determination of the extent to which the effects of SS are greater when experienced in adolescence than in adulthood.

  • 4.

    Clinical studies indicate that stressful adolescent experiences increase risk for substance abuse (DeWit et al., 1999, Dube et al., 2003, Dube et al., 2006, Nelson et al., 1995, Sullivan et al., 2006, Tharp-Taylor et al., 2009, Topper et al., 2011) and addiction (Dube et al., 2002, Dube et al., 2003, Hoffmann et al., 2000, Kaltiala-Heino et al., 2000). A wide range of stressful experiences are applied to adolescent rodents for the purpose of identifying neural mechanisms that underlie stress cross-sensitization to drugs of abuse. Social defeat is an ethologically and etiologically relevant stressor for the rat (Miczek, 1991, Miczek et al., 2008). The experimenter creates an imbalance of power where the dominant rat (i.e., resident) forces submissive behavior of a subordinate rat (i.e., intruder) by repeated exposures to aggressive residents in an inescapable environment. Levels of the stress hormone, corticosterone, reach higher peaks during social defeat compared to many other stressful procedures (Koolhaas et al., 1997), and rats do not habituate to repeated confrontation with an aggressor (Covington and Miczek, 2005, Watt et al., 2009). A limited number of studies have investigated the effect of brief episodes of social defeat stress during adolescence on later sensitivity to drugs of abuse (reviewed in Burke and Miczek, 2014). The experiments discussed in this review apply social defeat to adolescent male intruders utilizing adult male residents selected for high levels of aggression. The episode of defeat is brief, typically 20 min, and occurs four or five times during mid-adolescence.

Section snippets

Social play fighting behavior during adolescence

Play fighting is a highly energetic behavior that involves bouts of close quarter wrestling, interspersed with chasing and pouncing on one another (Poole and Fish, 1976). This activity is organized around competing for access to the nape of a partner’s nape of the neck (Fig. 2), which is rubbed with the snout if contacted (Pellis and Pellis, 1987, Siviy and Panksepp, 1987). In serious fighting, bites are directed at the rump and lower dorsum (Blanchard et al., 1977). Thus, even though the

Social deprivation effects on play fighting behavior during adolescence

During the adolescent period, rats will play just as readily with unfamiliar partners as with familiar ones (Panksepp, 1981, Panksepp and Beatty, 1980, Pellis and Pellis, 1990). In natural colonies, in which multiple females synchronize their breeding (Calhoun, 1963, McClintock, 1984), young rats would have many peers, both siblings and non-siblings with whom to play, and given their penchant to play, the most likely source of novel partners is going to arise from seeking play partners. Thus,

Age differences in social and hormonal stress responses

Through its control of the production and release of glucocorticoid hormones, the HPA axis modulates many functions of the body, including energy storage, cardiovascular, immune, and reproductive functions. Thus, the HPA axis is an important means through which an organism copes with stressors because glucocorticoids can alter the functioning of many systems to meet the demands. Further, because glucocorticoid hormones influence learning and memory systems in the central nervous system (CNS),

Social defeat cross-sensitization to drugs of abuse

Brief episodes of social defeat stress activate the HPA axis in a fashion similar to the SS procedure described above. Under specific conditions, social defeat of adult rats consistently increases: 1) psychostimulant self-administration during a progressive ratio schedule of reinforcement (PR) (Covington et al., 2008, Quadros and Miczek, 2009), 2) a 24-h unlimited access binge (Covington and Miczek, 2001, Miczek et al., 2011), 3) acquisition of psychostimulant self-administration (Haney et al.,

Cortex and social play behavior

Systems related to motivation and reward (hypothalamus, ventral striatum), as well as ones related to emotional regulation and motor control (amygdala, dorsal striatum) are involved in social play behavior (Siviy and Panksepp, 2011, Trezza et al., 2010, Vanderschuren et al., 2016). Cortical systems, especially the prefrontal cortex, are activated during play (Gordon et al., 2003, Gordon et al., 2002). Increased social play, but not increased solitary play (i.e., playing with objects or engaging

Sex differences following adolescent adversity

Sex differences in stress-related neuropsychiatric disorders, such as depression and anxiety, emerge during adolescence when females are 70% more likely to develop depression and 60% more likely to experience an anxiety disorder in their lifetime compared to males, possibly due to an increased sensitivity to stress (Paus et al., 2008). Despite the evidence that females have an increased risk for the development of neuropsychiatric illnesses, most studies have focused on males, and females have

Conclusions

Social stress during adolescence has long lasting effects on both behavior and stress-related neural circuits. Increased anxiety and depressive behavior as well as heightened drug use occur when the normal developmental trajectory of social play is altered. This heightened sensitivity to social stressors in adolescence may reflect the importance of social learning and the building of the social brain in adolescence. Furthermore, the reviewed data suggest that the quality of social experiences

Disclosure

The authors declare no conflicts of interest.

Acknowledgements

The authors acknowledge financial support for part of this work from the Brain and Behavior Research Foundation for a 2013 Young Investigator Award (JLL) and the Natural Sciences and Engineering Research Council Discovery Grants (CMM, SMP).

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