Social Stress In Adolescence Research Articles

P675. The Vulnerability to Social Stress in Adolescence is Sexually Dimorphic

Social stress during adolescence increases psychiatric risk, but not all individuals are affected equally, with important sex differences. Whether short term responses to adolescent social stress modify enduring effects in males and females is unknown. Psychiatric disorders that emerge during adolescence are characterized by impulse control deficits. Here, we explored whether social approach behaviour 24h after social stress in adolescence predicts impulse control in adulthood. The adolescent social stress model used allows to test and compare male and female mice.

Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex dopamine and cognition (Social stress in adolescent vs. adult male mice).

For some individuals, social stress is a risk factor for psychiatric disorders characterized by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here, we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorized them as “resilient” or “susceptible” based on social avoidance behavior. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic DA regions and would have enduring consequences on PFC DA connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behavior, AcSD in adulthood leads to a majority of susceptible mice without altering anxiety-like traits. In adolescent, but not adult mice, AcSD dysregulates DCC and Netrin-1 expression in mesolimbic DA regions. These molecular changes in adolescent mice are accompanied by changes in PFC DA connectivity. Following AcSD in adulthood, cognitive function remains unaffected, but all mice exposed to AcSD in adolescence show deficits in inhibitory control when they reach adulthood. These findings indicate that exposure to AcSD in adolescence versus adulthood has substantially different effects on brain and behavior and that stress-induced social avoidance in adolescence does not predict vulnerability to deficits in cognitive performance.

Reward Sensitivity, Cognitive Response Style, and Inflammatory Response to an Acute Stressor in Adolescents.

Inflammation is gaining support as a biological mediator between stress and many negative outcomes that have heightened risk during adolescence (e.g., mood disorders). Thus, an important line of inquiry is evaluating whether risk factors for mood psychopathology also are associated with heightened inflammatory responses to stress during this developmental period. Two prominent risk factors that interact to predict mood psychopathology are reward sensitivity and perseverative cognitive response styles, which also have been associated with heightened inflammatory proteins. These factors could influence inflammation by synergistically amplifying stress reactivity. Ninety-nine late adolescents (Mage = 18.3 years, range = 15.6-21.9 years) completed measures of reward sensitivity, cognitive response style, and blood draws before and 60-min after a modified Trier Social Stress Task to determine levels of inflammation. Higher reward drive interacted with more perseverative response style ratios (rumination relative to distraction + problem-solving) to predict larger increases in interleukin-6 (a proinflammatory protein). Follow-up analyses found that reward drive interacted with all three components of the ratio to predict change in interleukin-6. Thus, these results suggest that high reward drive and perseverative cognitive response styles are associated with increased inflammatory response to social stress in adolescents, a potential physiological mechanism linking these risk factors to mood psychopathology during this developmental period.

Fine Particle Air Pollution and Physiological Reactivity to Social Stress in Adolescence: The Moderating Role of Anxiety and Depression.

Exposure to high levels of fine particle air pollution (PM2.5) is associated with adolescent pathophysiology. It is unclear, however, if PM2.5 is associated with physiology within psychosocial contexts, such as social stress, and whether some adolescents are particularly vulnerable to PM2.5-related adverse effects. This study examined the association between PM2.5 and autonomic reactivity to social stress in adolescents and tested whether symptoms of anxiety and depression moderated this association. Adolescents from Northern California (N = 144) participated in a modified Trier Social Stress Test while providing high-frequency heart rate variability and skin conductance level data. PM2.5 data were recorded from CalEnviroScreen. Adolescents reported on their own symptoms of anxiety and depression using the Youth Self-Report, which has been used in prior studies and has good psychometric properties (Cronbach's α in this sample was .86). Adolescents residing in neighborhoods characterized by higher concentrations of PM2.5 demonstrated greater autonomic reactivity (i.e., indexed by lower heart rate variability and higher skin conductance level) (β = .27; b = .44, p = .001, 95% CI = 0.19 to 0.68) in response to social stress; this association was not accounted for by socioeconomic factors. In addition, adolescents who reported more severe anxiety and depression symptoms showed the strongest association between PM2.5 and autonomic reactivity to social stress (β = .53; b = .86, p < .001, 95% CI = 0.48 to 1.23). Exposure to PM2.5 may heighten adolescent physiological reactivity to social stressors. Moreover, adolescents who experience anxiety and depression may be particularly vulnerable to the adverse effects of PM2.5 on stress reactivity.

Sleep and Parasympathetic Activity During Rest and Stress in Healthy Adolescents and Adolescents With Bipolar Disorder.

Sleep disruption contributes to the pathophysiology of mental disorders, particularly bipolar illness, but the biobehavioral mechanisms of this relationship are insufficiently understood. This study evaluated sleep duration, timing, and variability as prospective predictors of parasympathetic nervous system activity during rest and social stress in adolescents with bipolar disorder, reflecting sleep-related interference in stress regulatory systems that may confer vulnerability to mood episodes. Participants were adolescents with bipolar disorder (n = 22) and healthy adolescents (n = 27). Sleep duration and timing were measured by actigraphy for 1 week before a laboratory social stress task, during which high-frequency heart rate variability (HF-HRV) was indexed using electrocardiography. Multilevel models were used to evaluate group, sleep characteristics, and their interactions as predictors of initial HF-HRV and change in HF-HRV during rest and stress. Associations between group and changes in HF-HRV during stress were moderated by sleep duration mean (z = 2.24, p = .025) and variability (z = -2.78, p = .006). There were also main effects of mean sleep duration on initial HF-HRV during rest (z = -5.37, p < .001) and stress (z = -2.69, p = .007). Follow-up analyses indicated that, in bipolar adolescents during stress, shorter and longer sleep durations were associated with lower initial HF-HRV (z = -5.44, p < .001), and greater variability in sleep duration was associated with less change in HF-HRV (z = -2.18, p = .029). Sleep durations that are relatively short or long, which are characteristic of mood episodes, are associated with parasympathetic vulnerability to social stress in adolescents with bipolar disorder. Obtaining regular sleep of moderate duration may favorably affect responses to stress in bipolar youth.

Social stress in adolescents induces depression and brain-region-specific modulation of the transcription factor MAX.

MAX is a conserved constitutive small phosphoprotein from a network of transcription factors that are extensively studied in tumorigenesis and whose functions affect cell proliferation, differentiation and death. Inspired by its higher expression during development and in regions involved in emotional behaviors, we hypothesized its involvement in cerebral changes caused by early-life stress. We studied the effects of repeated social stress during adolescence on behaviors and on MAX and its putative partner MYC. Thirty-day-old C57BL/6 male mice underwent brief daily social defeat stress from an adult aggressor for 21 days. Following social stress episodes and housing in social groups after each defeat, adolescent mice exhibit depressive-like, but not anxiety-like behaviors and show higher MAX nuclear immunoreactivity in hippocampal (HC) but not prefrontal cortical (PFC) neurons. Conversely, MAX immunoreactivity is lower in the striatum (ST) of defeated adolescents. The positive correlation between MAX and MYC levels in the PFC revealed disruptions in both the HC and ST. The changes in MAX protein levels are not due to differential gene expression or protein degradation in those regions, suggesting that posttranscriptional modifications occurred. These findings indicate that repeated, brief social defeat in adolescent male mice, combined with group housing, is a useful protocol to study a subtype of depression that is dissociated from generalized (non-social) anxiety. To our knowledge, this is the first report of an association between dysregulation of the MAX-MYC network in the brain and a behavior, suggesting a novel approach for exploiting the neuroplasticity associated with depression.

Gender Minority Social Stress in Adolescence: Disparities in Adolescent Bullying and Substance Use by Gender Identity

Bullying and substance use represent serious public health issues facing adolescents in the United States. Few large-sample national studies have examined differences in these indicators by gender identity. The Teen Health and Technology Study (N = 5,542) sampled adolescents ages 13 to 18 years old online. Weighted multivariable logistic regression models investigated disparities in substance use and tested a gender minority social stress hypothesis, comparing gender minority youth (i.e., who are transgender/gender nonconforming and have a gender different from their sex assigned at birth) and cisgender (i.e., whose gender identity or expression matches theirs assigned at birth). Overall, 11.5% of youth self-identified as gender minority. Gender minority youth had increased odds of past-12-month alcohol use, marijuana use, and nonmarijuana illicit drug use. Gender minority youth disproportionately experienced bullying and harassment in the past 12 months, and this victimization was associated with increased odds of all substance use indicators. Bullying mediated the elevated odds of substance use for gender minority youth compared to cisgender adolescents. Findings support the use of gender minority stress perspectives in designing early interventions aimed at addressing the negative health sequelae of bullying and harassment.

Extended Effect of Chronic Social Defeat Stress in Childhood on Behaviors in Adulthood

Individuals exposed to social stress in childhood are more predisposed to developing psychoemotional disorders in adulthood. Here we use an animal model to determine the influence of hostile social environment in adolescence on behavior during adult life. One-month-old adolescent male mice were placed for 2 weeks in a common cage with an adult aggressive male. Animals were separated by a transparent perforated partition, but the adolescent male was exposed daily to short attacks from the adult male. After exposure to social stress, some of the adolescent mice were placed for 3 weeks in comfortable conditions. Following this rest period, stressed young males and adult males were studied in a range of behavioral tests to evaluate the levels of anxiety, depressiveness, and communicativeness with an unfamiliar partner. In addition, adult mice exposed to social stress in adolescence were engaged in agonistic interactions. We found that 2 weeks of social stress result in a decrease of communicativeness in the home cage and diminished social interactions on the novel territory. Stressed adolescents demonstrated a high level of anxiety in the elevated plus-maze test and helplessness in the Porsolt test. Furthermore, the number of dividing (BrdU-positive) cells in the subgranular zone of the dentate gyrus was significantly lower in stressed adolescents. After 3 weeks of rest, most behavioral characteristics in different tests, as well as the number of BrdU-positive cells in the hippocampus, did not differ from those of the respective control mice. However, the level of anxiety remained high in adult males exposed to chronic social stress in childhood. Furthermore, these males were more aggressive in the agonistic interactions. Thus, hostile social environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life.

Effects of social instability stress in adolescence on long-term, not short-term, spatial memory performance

There is evidence that exposure to stressors in adolescence leads to lasting deficits on hippocampal-dependent tasks, but whether medial prefrontal cortical function is also impaired is unknown. We previously found that rats exposed to social instability stress in adolescence (SS; daily 1h isolation and subsequent change of cage partner between postnatal days 30 and 45) had impaired memory performance on a Spatial Object Location test and in memory for fear conditioning context, tasks that depend on the integrity of the hippocampus. Here we investigated whether impaired performance would be evident after adolescent SS in male rats on a different test of hippocampal function, spatial learning and memory in the Morris water maze (MWM) and on a working memory task for which performance depends on the integrity of the medial prefrontal cortex, the Delayed Alternation task (DAT). During MWM testing, SS rats showed greater improvements in performance across trials within days compared to control (CTL) rats, but showed less retention of learning between days (48h) compared to CTL rats. Similarly, SS rats had impaired long-term memory in the Spatial Object Location test after a long delay (240min), but not after shorter delays (15 or 60min) compared to CTL rats. No group differences were observed on the DAT, which assessed working memory across brief delays (5–90s). Thus, deficits in memory performance after chronic social stress in adolescence may be limited to long-term memory.

Short-term and long-term effects of repeated social defeat during adolescence or adulthood in female rats

Accumulating evidence suggests that adolescence represents a sensitive period during which social stressors influence adult behavior and stress reactivity. However, relatively little is known about the impact of social stress in adolescence on behaviors or stress reactivity in females. In this study, we exposed adolescent or adult female rats to the repeated social stress of defeat for seven consecutive days. Repeated defeat resulted in distinctly different behavioral repertoires during defeat in adolescent compared to adult female rats. Adolescent females exhibited more play and avoidant behaviors and adult females exhibited more active and aggressive behaviors toward the resident female. Examination of the short-term effects of social defeat using the Porsolt forced swim test (FST) indicated that adolescents, regardless of their exposure to social defeat, showed increased time immobile and decreased time swimming compared to adults. Adolescent rats exposed to defeat also exhibited increased climbing compared to their age-matched naïve counterparts. These effects dissipated with age. Interestingly, no effects of defeat were observed in adult females, however, when these females were re-assessed in the FST 30days after the end of defeat, we observed increased swimming at the expense of climbing. Using exposure to a novel restraint to assess stress reactivity, we found that stress during adolescence and adulthood led to lower basal adrenocorticotropic hormone concentrations and that both stressed and control adolescent groups exhibited a delay in recovery in adulthood compared to stressed and control adult groups. Fos protein analysis further suggested that cortical/thalamic structures serve as potential substrates that mediate these long-term impacts of stress during adolescence. Thus, repeated social stress during adolescence produces different patterns of effects as compared with repeated social stress during adulthood.

Social instability stress in adolescence increases anxiety and reduces social interactions in adulthood in male long–evans rats

We investigated the effects of social instability stress (daily 1-hr isolation, change of cage partner, postnatal day 30-45) in adolescence in male rats on open field exploration and social behavior in adulthood. Social stressed rats had longer latencies to enter the center of an open field and then took longer to approach an object placed in the center of the field. When another rat was placed in the open field, stressed rats spent less time in social interaction than control rats, particularly when paired with another stressed, rather than a control, rat. The groups did not differ in social approach tests (when a stimulus rat was separated by wire mesh) nor in novel object exploration (when controlling for open field anxiety). The results suggest social stress in adolescence increases open field anxiety while maintaining exploratory behavior, and alters social interactions in adulthood.

Social isolation in adolescence alters behaviors in the forced swim and sucrose preference tests in female but not in male rats

Social interactions in rodents are rewarding and motivating and social isolation is aversive. Accumulating evidence suggests that disruption of the social environment in adolescence has long-term effects on social interactions, on anxiety-like behavior and on stress reactivity. In previous work we showed that adolescent isolation produced increased reactivity to acute and to repeated stress in female rats, whereas lower corticosterone responses to acute stress and decreased anxiety-related behavior were noted in isolated males. These results indicate a sex specific impact on the effects of social stress in adolescence. However, little is known about whether social isolation impacts behaviors related to affect and whether it does so differently in male and female rats. The present study investigated the impact of adolescent social isolation from day 30–50 of age in male and female Sprague Dawley rats on behavior in the forced swim test at the end of adolescence and in adulthood and on behavior in the sucrose preference test in adulthood. Adult female rats that were isolated in adolescence exhibited increased climbing on the first and second day of the forced swim test and showed an increased preference for sucrose compared to adult females that were group-housed in adolescence. There were no effects in male rats. The results indicate that social isolation in adolescence produces a stable and active behavioral phenotype in adult female rats.

Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment

This study examined the hypothesis that depressed adolescents with a history of childhood maltreatment will show greater cortisol reactivity to psychological stress challenge than those without, and this relation will be moderated by level of depression severity. Seventy-one adolescents were exposed to the Trier Social Stress Test. Salivary cortisol was assessed at baseline, immediately before the challenge, after the challenge, and during an extended recovery period. Childhood maltreatment was assessed with a rigorous contextual interview and rating system. Adolescents with a history of maltreatment produced higher and more prolonged levels of cortisol in response to the challenge than did adolescents with no maltreatment, but only among those with a mild/moderate level of depression severity. Those with moderate/severe depression exhibited a blunted cortisol response regardless of child maltreatment history. These findings indicate that depression is a heterogeneous syndrome, and that both depression severity and child maltreatment history should be considered in studies examining biological stress reactivity.

Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults.

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, the authors investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague-Dawley rats were exposed to repeated social defeat for 5 days while controls were placed in a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus-maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology.

Chronic social stress in adolescence influenced both amphetamine conditioned place preference and locomotor sensitization

We previously reported that chronic social stress (SS) in adolescence, but not in adulthood, increased the locomotor-activating effects of nicotine in females, and not males, when tested in adulthood. However, SS rats had decreased locomotor response to nicotine when tested in adolescence. Here, we investigated age-related changes in the effects of SS on both conditioned place preference (CPP) and locomotor sensitization to amphetamine. In the CPP experiment, SS females tested in adolescence had increased preference for the 1.0 mg/kg dose of amphetamine, whereas SS rats of both sexes showed a decrease in CPP for the 0.5 mg/kg dose when tested as adults. Irrespective of time of testing, SS males and females had enhanced locomotor sensitization compared to controls. Thus, adolescent SS produced both immediate and enduring effects on behavioral responses to amphetamine, likely by altering the development of the mesocorticolimbic dopamine system, which holds implications for vulnerability to addiction.

Increased depressive behaviour in females and heightened corticosterone release in males to swim stress after adolescent social stress in rats

We previously reported that males undergoing chronic social stress (SS) (daily 1 h isolation and new cage partner on days 30–45 of age) in adolescence habituated (decreased corticosterone release) to the homotypic stressor, but females did not. Here, we report that adolescent males exposed to chronic social stress had potentiated corticosterone release to a heterotypic stressor (15 min of swim stress) compared to acutely stressed and control males. The three groups of males did not differ in depressive-like behaviour (time spent immobile) during the swim stress. Corticosterone release in socially stressed females was elevated 45 min after the swim stress compared to acutely stressed and control females, and socially stressed females exhibited more depressive behaviour (longer durations of immobility and shorter durations of climbing) than the other females during the swim stress. Separate groups of rats were tested as adults several weeks after the social stress, and there were no group differences in corticosterone release after the swim stress. The only group difference in behaviour among the adults was more time spent climbing in socially stressed males than in controls. Thus, there are sex-specific effects of social stress in adolescence on endocrine responses and depressive behaviour to a heterotypic stressor, but, unlike for anxiety, substantial recovery is evident in adulthood in the absence of intervening stress exposures.

Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats

Using a rat model of adolescent social stress (SS, daily 1 h isolation and change of cage partner, 30–45 days of age), we have reported sex-specific effects on neuroendocrine function over the course of SS, and enduring effects of SS in females, and not males, on drug-related behaviour. Here, we investigated both the immediate and enduring impact of SS in adolescence on anxiety-like behaviour in the elevated plus maze (EPM) and determined the temporal pattern of corticosterone release after confinement to the open arm of the EPM. When tested as adolescents, SS decreased anxiety-like behaviour in females and had no effect in males. When tested as adults several weeks after the chronic stress, overall, SS tended to increase anxiety-like behaviour in both sexes. However, estrous cycle moderated the effect in females, in that reduced anxiety-like behaviour was observed for SS females in the estrous group. Confinement to the open arm of the EPM increased plasma corticosterone concentrations, which declined markedly upon return to home cage for all except adolescent control males for which corticosterone concentrations at 45 and 90 min were elevated compared other groups. Among controls, anxiety-like behaviour decreased in females and increased in males with age, and confinement to the open arm of the EPM led to a greater increase in corticosterone concentrations in adult males compared to adolescent males. In sum, modest effects of adolescent social stress were observable several weeks after the stress exposure, indicating that sex-specific developmental trajectories and vulnerability to anxiety may be shaped by experiences in adolescence.

Cardiovascular and affective responses to social stress in adolescents with internalizing and externalizing problems

Behavioral responses to stress and challenge are based in emotional and physiological arousal reactions. Adolescents with maladaptive or problematic behavior patterns, such as internalizing or externalizing problems, are likely to show atypical emotional and physiological reactions to stress. Relations between problems and reactions to stress were examined in a sample of 55 young adolescents with normal to clinical levels of internalizing and externalizing problems. Youth had their self-reported emotional states, heart rate, and blood pressure levels measured before and after engaging in two socially challenging, evaluative manipulations. Internalizing problems were associated with less positive affect but greater anxiety and cardiovascular arousal, whereas externalizing problems predicted greater hostility and positive affect but less cardiovascular arousal. The necessity of recognizing and incorporating comorbid characteristics and multiple response systems into studies of the links between problems and reactivity is emphasized in the discussion.