Article

Short- and Long-Term Consequences of Stressor Controllability in Adolescent Rats

Article

Short- and Long-Term Consequences of Stressor Controllability in Adolescent Rats

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Abstract

Adolescence is a developmental period in which brain structures involved with stress responses, such as the medial pre-frontal cortex (mPFC), mature. Therefore, exposure to a stressor at this time may have effects that endure the lifespan. The goal of the present study was to determine whether behavioral control over an adolescent stressor mitigates the behavioral and neurochemical consequences of the stressor as occurs in adult rats. Adolescent rats (post natal day 35) were exposed to either inescapable (IS) or escapable tailshocks (ES). As in adults we observed a "stressor controllability effect"; IS reduced social exploration and activated the serotonergic dorsal raphé nucleus while ES did not. Excitotoxic lesions of the medial prefrontal cortex prevented the stressor controllability effect. We also demonstrate that a controllable adolescent stress prevents the behavioral and neurochemical consequences of IS in adulthood. Thus, the controllability of a stressor during adolescence is an important psychological factor.

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... Moreover, a single maternal deprivation was reported to produce long-term changes when applied within the stress hypo-responsive period between postnatal days 1-12 (Enthoven et al., 2008). Other studies, which applied stressors in early adolescence, have observed no specific effect on adulthood behavior (Kubala et al., 2012;Saul et al., 2012). ...
... Stress was applied either at the age of 28 days or 26-28 days either with or without stress in adulthood, at the age of 60 days or 90 days. Emotional consequences were evaluated at the age of either 60 days or 90 days (Avital and Richter-Levin, 2005;Kubala et al., 2012;Saul et al., 2012;Holder and Blaustein, 2014). Tsoory et al. (2007) have also shown anxiety-like or depressive-like behavior in rats exposed to juvenile stress. ...
... Emotional consequences were evaluated at the age of 63 days. Kubala et al. (2012) reported they did not observe any long-lasting anxiogenic effect, following uncontrollable stress in adolescence. In this study, stress was applied at the age of 35 days and emotional consequences were evaluated at the age of 36 days or 70 days. ...
Article
The exposure to stress at different developmental time points has long been postulated to have a crucial impact on various brain structures involved in mental disorders. The long-term specific effects seem to emerge as a function of timing and duration of the exposure to stress, as well as the characteristics of the stressor. Previous studies have addressed this issue with an effort to describe a single "hyper-sensitive" time point, and have led to disagreement on a particular sensitive period for stress exposure. The primary aim of our study was to investigate the hypothesis that indeed there is a developmental stress risk window in male Wistar rats. We conducted a systematic mapping of the long-term effects of an acute stress protocol, applied both prenatal (gestational days 14-16) and postnatal (days 9-151), overall at 11 different time-points during development. Stress protocol consists of 3 days of either maternal separation (for rats at postnatal days 9-19) or exposure to the stressors forced swim, elevated plus maze and restraint (for both dams and males at postnatal days 24-151). Consequences in adulthood were measured by investigating the animals' behavior in both the open field and startle box, together with the physiological measure of corticosterone. We found both behaviorally and physiologically that the pubescence time points are the most vulnerable to stress compared to all other tested time points along the developmental trajectory. Carefully considering the comparison between rat and human age, our findings may imply the importance of childhood-to-adulthood transition, as a sensitive time-point which may exacerbate a predisposition for the development of stress-induced psychopathologies. Copyright © 2014. Published by Elsevier Ltd.
... The emotional valence of a particular context can be highly individualized and there are important factors that modulate the emotional perception of contextual experiences, most notably control and predictability (e.g., Weiss 1968;Maier and Watkins 2005;Salvador 2005;Koolhaas et al. 2011;Kubala et al. 2012). If an individual perceives control over an event and the event is predictable over time, the perception of the event may be altered by creating a positive emotional valence, which may dampen the stress response to future encounters within the same context (e.g., Grissom and Bhatnagar 2009). ...
... Control and perception of control of a challenge during development can also have long-lasting behavioral effects into adulthood. Rats that experience controllable challenges during adolescence are less likely to respond negatively to uncontrollable challenges in adulthood (e.g., Kubala et al. 2012). Bland et al. (2006) further found that uncontrollable challenges down-regulate the production of new neurons whereas controllable challenges do not. ...
Article
Previous to the 1980's, the prevailing neuroscience dogma held that no new neurons were produced in the brains of adult mammals. Now, we understand that the production of new neurons, or neurogenesis, is a common and plastic process in the adult brain. To date, however, researchers have not come to a unified understanding of the functional significance of neurogenesis. Several factors have been shown to modulate hippocampal neurogenesis including spatial learning, stress, and aspects of environmental change, but questions still remain. How do these modulating factors overlap? Which aspects of environmental change induce a stress response? Is there a relationship between hippocampal neurogenesis, the stress response, and environmental change? Can this relationship be altered when taking into consideration other factors such as perception and predictability of the environment? Finally, do results from neurobiological research on laboratory rodents translate to wild systems? This review attempts to address these questions and synthesize research from the fields of ecology, psychology, and behavioral neuroscience. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.
... Animal research has provided foundational evidence for the idea that frontolimbic circuitry plays a key role in the effects of stressor controllability. In adult animals, the experience of controllable stress may determine future behavioral responses to stress by blunting activation of the dorsal raphe nucleus (DRN) and 5HT1A activation via projections between the DRN and mPFC (Baratta et al., 2007;Kubala, Christianson, Kaufman, Watkins, & Maier, 2012), and in turn, the amygdala (Amat et al., 2006;Baratta et al., 2007;Baratta & Maier, 2019;Hartley et al., 2014;Liu, Tang, & Sanford, 2009). Exposure to controllable stress also may yield plasticity that enables subsequent stressors to more easily recruit the mPFC, promoting increased prefrontal regulation of the In conclusion, studies of stressor controllability in rodents and human adults support the idea that experiencing control over a stressor may buffer against the negative effects of subsequent stress exposure. ...
... Finally, although the majority of research on control during stress exposure has been conducted in adult humans or animals, some evidence in rodents provides insight into the potential role of exposure to controllable stress during development. Rodents exposed to controllable stress during the period akin to adolescence show improved behavioral responses to stress in adulthood (Kubala et al., 2012). Thus, adolescence may be a period during which exposure to controllable stress has a stronger impact on later functioning, consistent with prior behavioral evidence of heightened active avoidance during adolescence (Bauer, 1978 (Gunnar, 1980;Lewis & Goldberg, 1968) in ways that shape stress responding and frontolimbic development later in life. ...
Article
Early‐life stress confers profound and lasting risk for developing cognitive, social, emotional, and physical health problems. The effects of stress on the developing brain contribute to this risk, with frontolimbic circuitry particularly susceptible to early experiences, possibly due to its innervation with glucocorticoid receptors and the timing of frontolimbic circuit maturation. To date, the majority of studies on stress and frontolimbic circuitry have employed a categorical approach, comparing stress‐exposed versus non‐stress‐exposed youth. However, there is vast heterogeneity in the nature of stress exposure and in outcomes. Recent forays into understanding the psychobiological effects of stress have employed a dimensional approach focused on experiential, environmental, and temporal factors that influence the association between stress and subsequent vulnerability. This review highlights empirical findings that inform a dimensional approach to understanding the effects of stress on frontolimbic circuitry. We identify the timing, type, severity, controllability, and predictability of stress, and the degree to which a caregiver is involved, as specific features of stress that may play a substantial role in differential outcomes. We propose a framework for the effects of these features of stress on frontolimbic development that may partially determine how heterogeneity in stress exposure influences this circuitry and, ultimately, mental health.
... The idea of a default stress response does correspond to modern evolutionary theoretical insights about stress, anxiety, PTSD and, more importantly, to neurobiological knowledge: the knowledge of how the brain and the nervous system works. The parts of the brain responsible for the stress response, for example the amygdala, are chronically suppressed by the prefrontal cortex (Ahern et al., 2001;Amat et al., 2005;Fragkaki, Thomaes, & Sijbrandij, 2016;Grupe & Nitschke, 2013;Kubala, Christianson, Kaufman, Watkins, & Maier, 2012;Lanius, Frewen, Tursich, Jetly, & McKinnon, 2015;Maier, 2015;Motzkin, Philippi, Wolf, Baskaya, & Koenigs, 2015). As Steve Maier and colleagues have demonstrated (Amat et al., 2005;Kubala et al., 2012;Maier, 2015), this prefrontal suppression only takes place when the brain has perceived safety. ...
... The parts of the brain responsible for the stress response, for example the amygdala, are chronically suppressed by the prefrontal cortex (Ahern et al., 2001;Amat et al., 2005;Fragkaki, Thomaes, & Sijbrandij, 2016;Grupe & Nitschke, 2013;Kubala, Christianson, Kaufman, Watkins, & Maier, 2012;Lanius, Frewen, Tursich, Jetly, & McKinnon, 2015;Maier, 2015;Motzkin, Philippi, Wolf, Baskaya, & Koenigs, 2015). As Steve Maier and colleagues have demonstrated (Amat et al., 2005;Kubala et al., 2012;Maier, 2015), this prefrontal suppression only takes place when the brain has perceived safety. If safety is no longer perceived, the pressure is immediately eased, the brake is immediately lifted, the amygdala resumes its activity and the body is instantly ready to flee or stand and fight. ...
Article
Full-text available
Stress, whether daily stress, work stress or traumatic stress, is unhealthy. This lecture covers three recent theoretical approaches in explaining the mechanisms underlying the influence of psychological stress on somatic health. It is argued that stress research should focus less on stressors themselves and put more emphasis on prolonged stress responses. Three mechanisms are identified that cause this unhealthy prolonged stress response: first, the partly-proven mechanism of perseverative cognition; second, the mechanism of unconscious stress, which is currently being explored; and third, the notion of the stress response being a default response that is inhibited only when safety is perceived. All three mechanisms are deeply rooted in millions of years of our evolution. Although the dangers of the past have virtually disappeared, many of us remain ever at the ready for events that never happen.
... From the neurobiological perspective, the prefrontal cortex normally suppresses the parts of the brain responsible for the stress response, especially the amygdala [5][6][7][8][9][10]-but only when the brain has perceived safety [4][5][6]. If safety is no longer perceived, the "brake" is immediately lifted, the amygdala resumes its high level of activity and the body is instantly ready to fight or flee away. ...
... Purportedly, the reason that these domains were largely missed by stress science is that they cannot easily be understood in terms of stressors or at least no concurrent stressors. Interestingly, some theorists even oppose including anxiety as a stress phenomenon, as being too "global" [38], while in neuroscience, stress and anxiety are commonly treated as the same subject, because of their shared neurobiology (e.g., [5][6][7][8][9]14,39]). ...
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Perseverative cognition is defined as the repetitive or sustained activation of cognitive representations of past stressful events or feared events in the future and even at non-clinical levels it causes a “fight-or-flight” action tendency, followed by a cascade of biological events, starting in the brain and ending as peripheral stress responses. In the past decade, such persistent physiological activation has proven to impact individuals’ health, potentially leading to somatic disease. As such, perseverative cognition has recently been proposed as the missing piece in the relationships between stress, psychopathology, and risk for health. Perseverative cognition is indeed a hallmark of conditions such as anxiety and mood disorders that are at increased -though still unexplained- cardiovascular risk. Although the pivotal role of ruminative and worrisome thoughts in determining the onset and maintenance of psychopathological disorders has been acknowledged for a long time, its effects on the body via reciprocal influences between mental processes and the body’s physiology have been neglected. Moreover, perseverative cognition is definitely not restricted to psychopathology, it is extremely common and likely even omnipresent, pervading daily life. The objective of the Research Topic is to provide an interdisciplinary examination of cutting-edge neuroscientific research on brain-body signatures of perseverative cognition in both healthy and psychopathological individuals. Despite the evident role of the brain in repetitive thinking and the assumption that our mind is embodied, bran-body pathways from perseverative cognition to health risk have remained largely unexplored.
... From the neurobiological perspective, the prefrontal cortex normally suppresses the parts of the brain responsible for the stress response, especially the amygdala [5][6][7][8][9][10]-but only when the brain has perceived safety [4][5][6]. If safety is no longer perceived, the "brake" is immediately lifted, the amygdala resumes its high level of activity and the body is instantly ready to fight or flee away. ...
... Purportedly, the reason that these domains were largely missed by stress science is that they cannot easily be understood in terms of stressors or at least no concurrent stressors. Interestingly, some theorists even oppose including anxiety as a stress phenomenon, as being too "global" [38], while in neuroscience, stress and anxiety are commonly treated as the same subject, because of their shared neurobiology (e.g., [5][6][7][8][9]14,39]). ...
Article
Full-text available
Prolonged physiological stress responses form an important risk factor for disease. According to neurobiological and evolution-theoretical insights the stress response is a default response that is always “on” but inhibited by the prefrontal cortex when safety is perceived. Based on these insights the Generalized Unsafety Theory of Stress (GUTS) states that prolonged stress responses are due to generalized and largely unconsciously perceived unsafety rather than stressors. This novel perspective necessitates a reconstruction of current stress theory, which we address in this paper. We discuss a variety of very common situations without stressors but with prolonged stress responses, that are not, or not likely to be caused by stressors, including loneliness, low social status, adult life after prenatal or early life adversity, lack of a natural environment, and less fit bodily states such as obesity or fatigue. We argue that in these situations the default stress response may be chronically disinhibited due to unconsciously perceived generalized unsafety. Also, in chronic stress situations such as work stress, the prolonged stress response may be mainly caused by perceived unsafety in stressor-free contexts. Thus, GUTS identifies and explains far more stress-related physiological activity that is responsible for disease and mortality than current stress theories.
... The acute effects of adolescent CST/UST were studied previously 17 , without important differences in the effects on an escape task. To our knowledge, the long-term effect (adulthood) of stress controllability during adolescence in rodents has only been addressed by Kubala et al. 18 The former study found that a single episode of CST (tail-shock) induces in adulthood an increase in social exploration, in comparison to UST or no stress, suggesting reduced anxiety. These results indicate that adolescent subjects are also sensitive to the long-term effects of controllability. ...
... A limitation of the present study is that only male rats were studied, and recent data indicate that the protective effects of controllability are not detected in females 73,74 . Another question that needs to be addressed is whether only one single stress exposure would exert the same effect as our paradigm (eight exposures across the entire adolescent period), as it has been studied that a single session of tail-shocks during this stage may induce long-term effects 18 . Finally, only D2R in dorsal striatum were analyzed and not in the PFC, as in our present conditions the expression of D2R in the PFC was very low and could not be evaluated, and other markers in addition to D2R should be also explored. ...
Article
Full-text available
Exposure to stress during adolescence exerts a long-term impact on behavior and might contribute to the development of several neuropsychiatric disorders. In adults, control over stress has been found to protect from the negative consequences of stress, but the influence of controllability at early ages has not been extensively studied. Here, we evaluated in a rodent model the effects of repeated exposure in adolescent male rats to controllable versus uncontrollable foot-shock stress (CST or UST, respectively). Rats were assigned to three groups: non-stress (stress-naïve), CST (exposed to 8 sessions of a two-way shuttle active avoidance task over a period of 22 days) and UST (receiving the same amount of shocks as CST, regardless of their actual behavior). During adulthood, different cohorts were tested in several tasks evaluating inhibitory control and cognitive flexibility: 5-choice serial reaction time, delay-discounting, gambling test and probabilistic reversal learning. Results showed that the hypothalamic-pituitary-adrenal response to the first shock session was similar in CST and UST animals, but the response to the 8th session was lower in CST animals. In adulthood, the UST animals presented impaired motor (but not cognitive) impulsivity and more perseverative behavior. The behavioral effects of UST were associated with increased number of D2 dopamine receptors in dorsomedial striatum, but not in other striatal regions. In summary, UST exposure during adolescence induced long-term impairments in impulsivity and compulsivity, whereas CST had only minor effects. These data support a critical role of stress uncontrollability on the long-lasting consequences of stress, as a risk factor for mental illnesses.
... An initial experience with exactly matched inescapable tailshocks (IS) does not produce immunization, so the immunization depends on the controllability of the initial tailshocks. Strikingly, the immunizing effects of ES persist for at least 7 days, and may persist for at least a month, depending on the outcome measure (Kubala et al., 2012;Rozeske et al., 2012). ...
... Turning a wheel to terminate a tailshock may capture a fundamental element of emotional control akin to the goal of cognitive therapy and so discerning the mechanisms underlying the behavioral immunization effect could improve cognitive therapies. The proactive effects of controllable tailshocks endure for a significant period (up to 35 days in rat, Kubala et al., 2012) and require synaptic plasticity within the medial prefrontal cortex. However, several important questions remain open: 1) what physiological and molecular mechanisms mediate plasticity underlying behavioral immunization and 2) what is the fundamental feature of a stressful event that activates the prefrontal cortex after controllable stress exposure? ...
... In the rat, exposure to a high level of GCs during pregnancy sensitises the HPA activity to stress later life [7]. The medial prefrontal cortex (mPFC) is involved in regulating the behavioral, neuroendocrine, and autonomic responses to stress [8][9][10] and also plays a pivotal role in so-called executive functions. The development of the prefrontal cortex is considered to be the last area of the cortex to mature, which continues to develop until early adulthood [11]. ...
Article
Full-text available
There is increasing evidence that maternal stress may have long-term effects on brain development in the offspring. In this study, we examined whether pre-gestational stress might affect offspring rats on the medial prefrontal cortical (mPFC) dopaminergic activity in response to acute stress in puberty and if so, whether such effects exhibited hemispheric asymmetry or sexual dimorphism. We used behavioural tests to assess the model of chronic unpredictable stress (CUS). We found that the activity in the open field test and sucrose intake test were lower for maternal rats in the CUS group than those in the control group. Offspring rats in the CUS group floated more and swam or climbed less as compared to the offsprings in the control group in the forced swimming test. The floating time was longer and swimming or climbing time was shorter in the female offspring rats than those in the males. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for CUS maternal rats and their offsprings than the respective controls. The ratio of dihydroxy-phenyl acetic acid (DOPAC) to dopamine (DA), DA transporter (DAT), norepinephrine transporter (NET) were lower in the mPFC of offspring rats in the CUS group than the control group. Levels of catechol-O-methyltransferase (COMT) in the left mPFC of female offspring rats and in the right mPFC of both female and male offspring rats were lower in the CUS group than those in the controls, but there was no difference in the left mPFC of male offspring between the CUS and control groups. DOPAC, the ratio of DOPAC to DA, NET and COMT were lower in the right mPFC than in the left mPFC of offspring rats in the CUS group. The ratio of DOPAC to DA in the right mPFC was lower in the female offspring rats than male offspring rats in the CUS group. The NET and COMT levels in both left and right mPFC were lower in the female offspring rats than those of the male offsprings in the CUS group. Our data provide evidence that the effect of pre-gestational stress on the mPFC dopaminergic activity in response to acute stress exhibited hemispheric asymmetry and sexual dimorphism in the pubertal offspring rats.
... Various animal models have been employed to demonstrate the effects of stress on adolescents. For instance, it has been shown that long-term social isolation can induce learning and memory disturbances, as well as increased levels of anxiety in young animals [4] and that in adolescent rats, inescapable tail shock stress reduces social exploration and activates the serotonergic dorsal raphe nucleus [5]. Stress-induced behavioral and physiological changes in adolescents can be longlasting and persist into adulthood [6,7]. ...
Article
Full-text available
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.
... Environmental conditions of deprivation and stress confer vulnerability to substance use disorders in humans and drugseeking behavior in animal models (Buu et al., 2009;Enoch, 2011;Gordon, 2002;Lu et al., 2003;Meaney et al., 2002;Nader et al., 2012;Pilowsky and Wu, 2006;Sinha, 2008). In contrast, experiencing control over one's environment can buffer the effects of adversity, shaping neural circuitry in ways that promote resilience to future challenges and reduce later responses to drugs of abuse (Amat et al., 2010(Amat et al., , 2008(Amat et al., , 2006Christianson et al., 2008;Kubala et al., 2012;Rozeske et al., 2012Rozeske et al., , 2011Varela et al., 2012). Interventions that provide a sense of mastery, stability and control over one's environment may therefore promote resilience to substance use disorders. ...
Article
Environmental stress and deprivation increase vulnerability to substance use disorders in humans and promote drug-seeking behavior in animal models. In contrast, experiences of mastery and stability may shape neural circuitry in ways that build resilience to future challenges. Cognitive training offers a potential intervention for reducing vulnerability in the face of environmental stress or deprivation. Here, we test the hypothesis that brief cognitive training can promote long-term resilience to one measure of drug-seeking behavior, cocaine conditioned place preference (CPP), in mice. In young adulthood, mice underwent cognitive training, received rewards while exploring a training arena (i.e. yoked control), or remained in their home cages. Beginning 4 weeks after cessation of training, we conditioned mice in a CPP paradigm and then tested them weekly for CPP maintenance or daily for CPP extinction. We found that a brief 9-day cognitive training protocol reduced maintenance of cocaine CPP when compared to standard housed and yoked conditions. This beneficial effect persisted long after cessation of the training, as mice remained in their home cages for 4 weeks between training and cocaine exposure. When mice were tested for CPP on a daily extinction schedule, we found that all trained and yoked groups that left their home cages to receive rewards in a training arena showed significant extinction of CPP, while mice kept in standard housing for the same period did not extinguish CPP. These data suggest that in early adulthood, deprivation may confer vulnerability to drug-seeking behavior and that brief interventions may promote long-term resilience. Copyright © 2015. Published by Elsevier Ltd.
... Stressor controllability and the medial prefrontal cortex circuit As noted above, behavioral control over tailshock prevents the behavioral and neurochemical effects that normally follow uncontrollable shock exposure. In addition, the experience of control over tailshock produces an enduring (at least 32 d; Kubala et al., 2012) protection against the behavioral and DRN-activating effects of later uncontrollable stressors including tailshock, social defeat and forced swim Christianson et al., 2008bChristianson et al., , 2013Rozeske et al., 2012). Because DRN activation is critical to the effects of uncontrollable stress, it was hypothesized that factors that protect against those effects would prevent DRN sensitization. ...
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Abstract Exposure to an uncontrollable stressor elicits a constellation of physiological and behavioral sequelae in laboratory rats that often reflect aspects of anxiety and other emotional disruptions. We review evidence suggesting that plasticity within the serotonergic dorsal raphe nucleus (DRN) is critical to the expression of uncontrollable stressor-induced anxiety. Specifically, after uncontrollable stressor exposure subsequent anxiogenic stimuli evoke greater 5-HT release in DRN terminal regions including the amygdala and striatum; and pharmacological blockade of postsynaptic 5-HT2C receptors in these regions prevents expression of stressor-induced anxiety. Importantly, the controllability of stress, the presence of safety signals, and a history of exercise mitigate the expression of stressor-induced anxiety. These stress-protective factors appear to involve distinct neural substrates; with stressor controllability requiring the medial prefrontal cortex, safety signals the insular cortex and exercise affecting the 5-HT system directly. Knowledge of the distinct yet converging mechanisms underlying these stress-protective factors could provide insight into novel strategies for the treatment and prevention of stress-related psychiatric disorders.
... Stress can even alter the memory systems involved in solving the task (Goodman et al. 2012; Packard and Goodman 2012 ). Moreover , the extent to which an animal has control over the stressor ultimately affects the consequence of stress on behavioral performance (Baratta et al. 2007; Christianson et al. 2013; Kubala et al. 2012; Maier et al. 2006). Recently, Hartley and colleagues (2013) demonstrated in humans that inescapable stress impairs extinction, while controllable stress actually reduces spontaneous recovery. ...
Article
Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal, spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological research are examined in light of treatment of pathological fear in humans.
... During this period, social behaviors, such as aggression, risk taking, social play, dominance establishment, and mating, as well as stress-responsive limbic [312] and cortical brain regions [185, 237] take on adult patterns. In fact, a certain amount of stress exposure or socio-environmental stimulation is probably necessary for normal development and exerts long-term stress-protective, anxiolytic, and antidepressant effects later in life [240, 277, 355, 356], especially if the adolescent stressor remains controllable [211]. Following the murine postweaning phase (postnatal days 21–30), rat/mouse adolescent days 31 to 60 include puberty and are roughly commensurate with human ages of 10 to 18 years [108]. ...
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Research has elucidated causal links between stress exposure and the development of anxiety disorders, but due to the limited use of female or sex-comparative animal models, little is known about the mechanisms underlying sex differences in those disorders. This is despite an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men, in addition to gender differences in severity and treatment efficacy. We here review human gender differences in generalized anxiety disorder, panic disorder, posttraumatic stress disorder and anxiety-relevant biological functions, discuss the limitations of classic conflict anxiety tests to measure naturally occurring sex differences in anxiety-like behaviors, describe sex-dependent manifestation of anxiety states after gestational, neonatal, or adolescent stressors, and present animal models of chronic anxiety states induced by acute or chronic stressors during adulthood. Potential mechanisms underlying sex differences in stress-related anxiety states include emerging evidence supporting the existence of two anatomically and functionally distinct serotonergic circuits that are related to the modulation of conflict anxiety and panic-like anxiety, respectively. We discuss how these serotonergic circuits may be controlled by reproductive steroid hormone-dependent modulation of crfr1 and crfr2 expression in the midbrain dorsal raphe nucleus and by estrous stage-dependent alterations of γ-aminobutyric acid (GABAergic) neurotransmission in the periaqueductal gray, ultimately leading to sex differences in emotional behavior.
... Control is often manipulated by administering shock, which will either stop upon a response (escape), or continue regardless of a subject's response (uncontrollable). The behavior measured is often an innate response to the stimulus (e.g., biting a bar) [49]. In the field of learning and memory, an organism gains control by learning to perform a behavior that can stop the aversive stimulus, or prevent it altogether (i.e., avoidance conditioning). ...
Article
Children exposed to neighborhood violence have higher rates of aggression, but it is unclear whether aggression is associated with threat, harm or the combination of factors. All animals, including humans, experience threat as they leave the safety of home and risk harm to gather resources (foraging). To better understand how selective environmental variables drive behavioral tendencies, we developed a semi-naturalistic living environment that includes the need to navigate across space to obtain resources. Rats were housed for three weeks in two tub cages, one with food and the other with water, both consistently available, but separated by a 91 cm long tunnel. After habituating for three days, half the rats (threat stress condition) received unpredictable threats (simultaneous puff of air with ferret dander, abrupt flash of light, and an abrupt sound) when crossing the central position of the tunnel (random order with p = 0.25) for 21 days. During the manipulation, the threat stress rats crossed the tunnel less and exhibited risk assessment behaviors. After cessation of the treatment conditions, the threat stress group spent more time burying a rag with ferret dander odor and was more likely to bury, and spent more time burying a highly novel stimulus. There were no group differences in symptoms of depression, avoidance, or exploration. The results suggest that repeated threats without harm increase pre-emptive defense behaviors, a form of active coping, without affecting passive forms of coping.
... In adult animal studies of fear responses, research has shown that the lateral nucleus of the amygdala influences the relationship between conditioned and unconditioned fear stimuli (Sotres-Bayon et al., 2004). In addition, although inescapable shock is not the only stressor which induces behavioral dysfunction (Forsyth, 1969;Natelson et al., 1976), adolescent rats exposed to repeated shock stress only develop behavioral dysfunction in conditions in which the shock is uncontrollable, and this effect is mediated by the mPFC (Kubala et al., 2012). Furthermore, human studies of adults with anxiety disorders have demonstrated a link between amygdala over-responsiveness and anxiety disorders . ...
Article
The genetic, biological, and environmental backgrounds of an organism fundamentally influence the balance between risk and resilience to stress. Sex, age, and environment transact with responses to trauma in ways that can mitigate or exacerbate the likelihood that post-traumatic stress disorder will develop. Translational approaches to modeling affective disorders in animals will ultimately provide novel treatments and a better understanding of the neurobiological underpinnings behind these debilitating disorders. The extant literature on trauma/stress has focused predominately on limbic and cortical structures that innervate the hypothalamic-pituitary-adrenal axis and influence glucocorticoid-mediated negative feedback. It is through these neuroendocrine pathways that a self-perpetuating fear memory can propagate the long-term effects of early life trauma. Recent work incorporating translational approaches has provided novel pathways that can be influenced by early life stress, such as the glucocorticoid receptor chaperones, including FKBP51. Animal models of stress have differing effects on behavior and endocrine pathways; however, complete models replicating clinical characteristics of risk and resilience have not been rigorously studied. This review discusses a four factor model that considers the importance of studying both risk and resilience in understanding the developmental response to trauma/stress. Consideration of the multifactorial nature of clinical populations in the design of preclinical models and the application of preclinical findings to clinical treatment approaches comprise the core of translational reciprocity which is discussed in the context of the four factor model.
... First, Such immunization effects can be quite long lasting. For example, the experience of ES in adolescence was shown to block the behavioral effects of IS in adulthood (Kubala et al., 2012). Second, immunization is trans-situational. ...
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It has been known for many years that the ability to exert behavioral control over an adverse event blunts the behavioral and neurochemical impact of the event. More recently, it has become clear that the experience of behavioral control over adverse events also produces enduring changes that reduce the effects of subsequent negative events, even if they are uncontrollable and quite different from the original event controlled. This review focuses on the mechanism by which control both limits the impact of the stressor being experienced and produces enduring, trans-situational "immunization". The evidence will suggest that control is detected by a corticostriatal circuit involving the ventral medial prefrontal cortex (mPFC) and the posterior dorsomedial striatum (DMS). Once control is detected, other mPFC neurons that project to stress-responsive brainstem (dorsal raphe nucleus, DRN) and limbic (amygdala) structures exert top-down inhibitory control over the activation of these structures that is produced by the adverse event. These structures, such as the DRN and amygdala, in turn regulate the proximate mediators of the behavioral and physiological responses produced by adverse events, and so control blunts these responses. Importantly, the joint occurrence of control and adverse events seems to produce enduring plastic changes in the top-down inhibitory mPFC system such that this system is now activated by later adverse events even if they are uncontrollable, thereby reducing the impact of these events. Other issues are discussed that include a) whether other processes such as safety signals and exercise, that lead to resistance/resilience, also use the mPFC circuitry or do so in other ways; b) whether control has similar effects and neural mediation in humans, and c) the relationship of this work to clinical phenomena.
... Exposure to juvenile or adolescent stressors (resident intruder stress, or chronic restraint) also induces social avoidance (Vidal et al., 2007), anhedonia and increased noveltyinduced locomotion (Eiland et al., 2012). However, similar to adult stressors, controllability over stress in adolescence prevents the emergence of maladaptive effects on anxiety behavior in adulthood (Kubala et al., 2012). ...
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Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.
... Given salient psychosocial characteristics of adolescence and the unique state of frontostriatal-amygdala circuitry at this time, adolescents may benefit from novel interventions that leverage opportunities for control to promote motivated action, or from optimizing existing practices in cognitive-behavioral therapies that involve behavioral activation and active coping 30 . While the effects of controllable stress on later stress responding remain to be tested during human development, exposure to controllable stress during the adolescent period in rodents mitigated the negative effects of uncontrollable stress in adulthood 31 , suggesting that systematic exposure to controllable stress during adolescence could have long-term benefits for mental health in the face of future stress. Among adolescents with a prior history of early adversity, stressors outside of one's control have been more closely linked with psychopathology than stressors at least partially influenced by the individual 32 . ...
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Adolescence is marked by heightened stress exposure and psychopathology, but also vast potential for opportunity. We highlight how researchers can leverage both developmental and individual differences in stress responding and corticolimbic circuitry to optimize interventions during this unique developmental period.
... Opposed to these results, it has frequently been shown that adversity – either as a single event or as repeated adversity – can lead to increased levels of anxiety-like behavior[29,[38][39][40][41]. However, if individuals could predict or control the adversity, their levels of anxiety-like behavior decreased[42,43]. In the present study, the animals were able to terminate the adverse environment by escaping to the Refuge cage. ...
Article
Adolescence has lately been recognized as a key developmental phase during which an individual’s behavior can be shaped. In a recent study with male mice varying in the expression of the serotonin transporter, escapable adverse social experiences during adolescence led to decreased anxiety-like behavior and increased exploratory and aggressive behavior compared to throughout beneficial experiences. Since in this study some behavioral tests took place with a delay of one week after the last social experiences have been made, it was not clear whether the observed effects really reflected the consequences of the experienced different social environments. To test this, the present study focused on the direct effects of beneficial and adverse social experiences on aggressiveness and anxiety-like behavior in C57BL/6J mice. In contrast to the previous study, behavioral testing took place immediately after the last social experiences had been made. Interestingly, whereas individuals from an escapable adverse environment showed significantly lower levels of anxiety-like and higher levels of exploratory behavior than animals from a beneficial environment, aggressive behavior was not affected. From this, we conclude that different social experiences during adolescence exert immediate effects on anxiety-like but not aggressive behavior in male mice.
... There is increasing evidence that experiences of control even appear to 'immunize' against subsequent uncontrollable situations (contexts) and generalizes across similar contexts (Maier, 2015), and adolescence may be the sensitive period for this type of learning. An experiment by Kubala, Christianson, Kaufman, Watkins, & Maier (2012) suggested that for adolescent but not adult rats, experiencing a controllable stressor (escapable shock) is not only important to 'immunize' the rat for the entire lifespan, but that it is also better than not experiencing a controllable stressor at all. Hence, it is important that organisms truly experience stressors and also develop some experience with control of stressors. ...
... In accordance with our findings, predictable chronic mild restraint stress decreases anxiety-like behavior in adult (Parihar et al., 2011) and adolescent rats (Suo et al., 2013). Similarly, Kubala and colleagues showed that adolescent rats experiencing escapable tailshocks exhibit higher levels of social exploration compared to rats encountering inescapable tailshocks and control animals (Kubala et al., 2012). Therefore, the nature of the adversity seems to be of major importance in shaping the state anxiety of an animal. ...
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Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior while the phase of adolescence has mainly been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior.
... There is increasing evidence that experiences of control even 'immunize' against successive uncontrollable situations (contexts) and generalizes across similar contexts (Maier, 2015), and adolescence may be the sensitive period for this type of learning. An experiment by Kubala et al. (2012) suggested that for adolescent rats but not adult rats, experiencing a controllable stressor (e.g. escapable shock) is not only fundamental to 'immunize' the rat for its entire lifespan, but that this is also better than not experiencing a controllable stressor at all. ...
... In contrast, as famously demonstrated in early studies of learned helplessness [70], experiences of uncontrollability decrease exploration, attention [72], and contingency learning in novel contexts [73], perhaps reflecting reduced engagement of goal-directed learning processes when past experience has suggested that they are likely to be ineffective. Such generalization effects have been proposed to reflect an adaptive calibration of cognitive effort and behavioral strategies to the degree of agency afforded by an environment [6], a process that can occur over both local and developmental timescales [3,74]. Such a bias toward controllability beliefs early in life [75] may be particularly advantageous as it reduces the potential opportunity costs of curtailing exploration and goal-directed learning when uncertainty about the true degree of environmental controllability is still high. ...
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Accurate assessment of environmental controllability enables individuals to adaptively adjust their behavior—exploiting rewards when desirable outcomes are contingent upon their actions and minimizing costly deliberation when their actions are inconsequential. However, it remains unclear how estimation of environmental controllability changes from childhood to adulthood. Ninety participants (ages 8–25) completed a task that covertly alternated between controllable and uncontrollable conditions, requiring them to explore different actions to discover the current degree of environmental controllability. We found that while children were able to distinguish controllable and uncontrollable conditions, accuracy of controllability assessments improved with age. Computational modeling revealed that whereas younger participants’ controllability assessments relied on evidence gleaned through random exploration, older participants more effectively recruited their task structure knowledge to make highly informative interventions. Age-related improvements in working memory mediated this qualitative shift toward increased use of an inferential strategy. Collectively, these findings reveal an age-related shift in the cognitive processes engaged to assess environmental controllability. Improved detection of environmental controllability may foster increasingly adaptive behavior over development by revealing when actions can be leveraged for one’s benefit.
... These effects have been repeated recently Christianson et al., 2008) and have been shown to transfer to protection against stressors that are quite different than shock including social defeat and forced swim (Christianson et al., 2013). Furthermore, the immunizing effects of stressor controllability are long-lasting, in that exposure to ES during adolescents can block the sequelae of later IS exposure in adulthood (Kubala et al., 2012). The combination of acute and long-lasting consequences of one experience with control over stress suggests that control both blunts the response to acute stress but also prepares the subject to be resilient to future stressors. ...
Article
Stressor exposure is a predisposing risk factor for many psychiatric conditions such as PTSD and depression. However, stressors do not influence all individuals equally and in response to an identical stressor some individuals may be vulnerable while others are resilient. While various biological and behavioral factors contribute to vulnerability versus resilience, an individual's degree of control over the stressor is among the most potent. Even with only one experience with control over stress, behavioral control has been shown to have acute and long-lasting stress-mitigating effects. This suggests that control both blunts the response to acute stress and prepares the subject to be resilient to future stressors. In this review, we first summarize the evidence which suggests the ventromedial prefrontal cortex (vmPFC) is a critical component of stressor controllability circuits and a locus of neuroplasticity supporting the acute and long-lasting consequences of control. We next review the central endocannabinoid (eCB) system as a possible mediator of short and long-term synaptic transmission in the vmPFC, and offer a hypothesis whereby eCBs regulate vmPFC circuits engaged when a subject has control over stress and may contribute to the encoding of acute stress coping into long lasting stressor resilience.
... Accordingly, maternal responsiveness has been proposed to provide a foundation for control expectancies in infancy [54]. Recent work in rodents suggests that experiencing control over a stressor in adolescence promotes a proactive behavioral profile in adulthood [55]. This long-lasting effect depends on the same vmPFC region that is critical for the effects of control in adulthood, suggesting that early control experiences may promote a lasting bias toward proactive coping strategies. ...
Article
The controllability of positive or negative environmental events has long been recognized as a critical factor determining their impact on an organism. In studies across species, controllable and uncontrollable reinforcement have been found to yield divergent effects on subsequent behavior. Here we present a model of the organizing influence of control, or a lack thereof, on the behavioral repertoire. We propose that individuals derive a generalizable estimate of agency from controllable and uncontrollable outcomes, which serves to calibrate their behavioral strategies in a manner that is most likely to be adaptive given their prior experience.
... It can be delivered as a low intensity or high intensity shock and can be employed as an acute procedure occurring only once or it can be used chronically over an extended period of time. Although these studies were regularly employed as a stress procedure in early preclinical studies, they are less commonly employed today with only 13% of early-life studies using this procedure when examining consequences on drug consumption outcomes and only 5% when examining behavioural outcomes (Joseph et al. 2013;Chaby et al. 2015;Lyttle et al. 2015;Li et al. 2015;Burke et al. 2011;Uysal et al. 2012;Kubala et al. 2012). Nonetheless, among alcohol studies in the literature, footshock stress was shown to be a most prominent procedure at enhancing alcohol intake (Noori et al. 2014). ...
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Background: In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. Objectives: The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. Methods: The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. Results: The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. Conclusion: The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic.
... Engagement of the PL by behavioral control is also required for its enduring stress-buffering effects against future adverse events, a protection that lasts up to two months (Amat et al., 2006;Kubala, Christianson, Kaufman, Watkins, & Maier, 2012). Efforts directed at understanding how an initial experience of coping with stress produces resistance to uncontrollable stressors experienced at a much later point in time have focused on N-methyl-D-aspartate receptor (NMDAR)-dependent processes. ...
Article
Adverse life events can lead to stable changes in brain structure and function and are considered primary sources of risk for post-traumatic stress disorder, depression, and other neuropsychiatric disorders. However, most individuals do not develop these conditions following exposure to traumatic experiences, and research efforts have identified a number of experiential factors associated with an individual's ability to withstand, adapt to, and facilitate recovery from adversity. While multiple animal models of stress resilience exist, so that the detailed biological mechanisms can be explored, studies have been disproportionately conducted in male subjects even though the prevalence and presentation of stress-linked disorders differ between sexes. This review focuses on 1) the mechanisms by which experiential factors (behavioral control over a stressor, exercise) reduce the impact of adverse events as studied in males; 2) whether other manipulations (ketamine) that buffer against stress-induced sequelae engage the same circuit features; and 3) whether these processes operate similarly in females. We argue that investigation of experiential factors that produce resistance/resilience rather than vulnerability to adversity will generate a unique set of biological mechanisms that potentially underlie sex differences in mood disorders.
... Recent years have brought a significant increase in research using animal models on the lasting impact of stressors in adolescence , and all signs indicate that this field of research is growing. For example, there were numerous presentations on adolescent stressors at the recent Society for Neuroscience (SFN) conference in November 2008 using a variety of stressor procedures such as immune challenge (Deak, Blandino, Eberle, Arakawa, & Arakawa, 2008), controllable and uncontrollable stressors (Kubala, Christianson, Watkins, & Maier, 2008), social defeat ( Novick et al., 2008), and restraint (Barha, Galea, Lieblich, & Brummelte, 2008 ) that reported persistent effects of these experiences on various brain and behaviour measures. However, as evident from the research findings summarized in this review, more research is necessary before definitive statements can be made with regard to the lasting consequences of stressors in adolescence. ...
Article
Developmental differences in hypothalamic–pituitary–adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system. Although research on this period of life is scarce compared to early life and adulthood, the available research indicates that effects of stress exposure during adolescence differ from, and may be longer-lasting than, effects of the same stress exposure in adulthood. Research progress in animal models in this field is reviewed including HPA function and the enduring effects of stress exposures in adolescence on sensitivity to drugs of abuse, learning and memory, and emotional behaviour in adulthood. The effects of adolescent stress depend on a number of factors, including the age, gender, the duration of stress exposure, the type of stressor, and the time between stress exposure and testing.
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Prior research has shown that adverse events in the lives of adolescents precipitate psychological distress, which in turn impairs self-control. This study (N = 1,343) examined the protective effects of stress mindsets—beliefs about the extent to which stress might be beneficial or strictly detrimental. The results confirmed that increasing the number of adverse life events across the school year predicted rank order increases in perceived distress, which in turn predicted rank order decreases in self-control. Adolescents who believed in the potential benefits of stress were less prone to feeling stressed in the wake of adverse life events. These findings suggest that changing the way adolescents think about stress may help protect them from acting impulsively when confronted with adversity.
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Resilience to stress is an adaptive process that varies individually. Resilience refers to the adaptation, or the ability to maintain or regain mental health, despite being subject to adverse situation. Resilience is a dynamic concept that reflects a combination of internal individual factors, including age and gender interacting with external factors such as social, cultural and environmental factors. In the last decade, we have witnessed an increase in the prevalence of anxiety disorders, including post-traumatic stress disorder. Given that stress in unavoidable, it is of great interest to understand the neurophysiological mechanisms of resilience, the individual factors that may contribute to susceptibility and promote efficacious approaches to improve resilience. Here, we address this complex question, attempting at defining clear and operational definitions that may allow us to improve our analysis of behavior incorporating individuality. We examine how individual perception of the stressor can alter the outcome of an adverse situation using as an example, the fear-conditioning paradigm and discuss how individual differences in the reward system can contribute to resilience. Given the central role of the endocannabinoid system in regulating fear responses and anxiety, we discuss the evidence that polymorphisms in several molecules of this signaling system contribute to different anxiety phenotypes. The endocannabinoid system is highly interconnected with the serotoninergic and dopaminergic modulatory systems, contributing to individual differences in stress perception and coping mechanisms. We review how the individual variability in these modulatory systems can be used towards a multivariable assessment of stress risk. Incorporating individuality in our research will allow us to define biomarkers of anxiety disorders as well as assess prognosis, towards a personalized clinical approach to mental health.
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Flexible calibration of threat responding in accordance with the environment is an adaptive process that allows an animal to avoid harm while also maintaining engagement of other goal-directed actions. This calibration process, referred to as threat response regulation, requires an animal to calculate the probability that a given encounter will result in a threat so they can respond accordingly. Here we review the neural correlates of two highly studied forms of threat response suppression: extinction and safety conditioning. We focus on how relative levels of certainty or uncertainty in the surrounding environment alter the acquisition and application of these processes. We also discuss evidence indicating altered threat response regulation following stress exposure, including enhanced fear conditioning, and disrupted extinction and safety conditioning. To conclude, we discuss research using an animal model of coping that examines the impact of stressor controllability on threat responding, highlighting the potential for previous experiences with control, or other forms of coping, to protect against the effects of future adversity.
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Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants ( N = 56; M age = 23.74, range = 18–30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.
Chapter
The neural basis of motivation is supported by brain systems that are integral in behaviors that maximize positively valued stimuli and minimize aversive stimuli. This article focuses on brain systems involved in minimization of aversive stimuli, which are extensively described by a substantial history of research on behaviors in nonhuman animals that are motivated by aversive stimuli. Such research strongly delineates a neural circuitry involving amygdala and striatum sub-nuclei that are modulated by regions of prefrontal cortex. Neuroimaging research on behaviors motivated by aversive stimuli in humans has confirmed the importance of homologous systems in humans, and allowed some understanding of the relation of these circuits to distinct behavioral responses and to clinical issues such as anxiety. We organize our review of this research around three important conceptual observations. First, active avoidance behaviors are distinguishable from passive avoidance behaviors in terms of both neural circuitry and motivational and affective consequences. Second, the perception of control over stimuli is critical for active avoidance behaviors, and influences brain systems for avoidance as well as subsequent behavior toward motivational stimuli. Third, avoidance behaviors may be adaptive in many situations but can become excessive or maladaptive in other situations. Knowledge about the neural circuitry underlying active avoidance provides an important path in understanding how avoidance behaviors are maintained and how they may change, and form a foundation for studying motivation and clinical issues such as anxiety.
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Uncontrollable stressors produce behavioral changes that do not occur if the organism can exercise behavioral control over the stressor. Previous studies suggest that the behavioral consequences of uncontrollable stress depend on hypersensitivity of serotonergic neurons in the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used ex vivo single-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT(1A) autoreceptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT(1A) receptor-mediated inhibition of DRN neuronal firing. Moreover, this effect was observed only at time points when the behavioral effects of uncontrollable stress are present. Furthermore, temporary inactivation of the medial prefrontal cortex with the GABA(A) receptor agonist muscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT(1A) receptors. Additionally, behavioral immunization, an experience with controllable stress before uncontrollable stress that prevents the behavioral outcomes of uncontrollable stress, also blocked functional desensitization of DRN 5-HT(1A) receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than downregulation of DRN 5-HT(1A) receptors. Thus, treatments that prevent controllable stress from being protective led to desensitization of 5-HT(1A) receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT(1A) receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT(1A) autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress.
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Adolescence is a period of major physical, hormonal, and psychological change. It is also characterized by a significant increase in the incidence of psychopathologies and this increase is gender-specific. Likewise, stress during adolescence is associated with the development of psychiatric disorders later in life. Previously, using a rat model of psychogenic stress (exposure to predator odor followed by placement on an elevated platform) during the pre-pubertal period (postnatal days 28-30), we reported sex-specific effects on auditory and contextual fear conditioning. Here, we study the short-term impact of psychogenic stress before and during puberty (postnatal days 28-42) on behavior (novelty seeking, risk taking, anxiety, and depression) and hypothalamus-pituitary-adrenocortical (HPA) axis activation during late adolescence (postnatal days 45-51). Peri-pubertal stress decreased anxiety-like behavior and increased risk taking and novelty seeking behaviors during late adolescence (measured with the elevated plus maze, open field and exposure to novel object tests and intake of chocopop pellets before or immediate after stress). Finally neither depressive-like behavior (measured at the forced-swim test) nor HPA response to stress (blood corticosterone and glucose) were affected by peri-pubertal stress. Nevertheless, when controlling for the basal anxiety of the mothers, animals exposed to peri-pubertal stress showed a significant decrease in corticosterone levels immediate after an acute stressor. The results from this study suggest that exposure to mild stressors during the peri-pubertal period induces a broad spectrum of behavioral changes in late adolescence, which may exacerbate the independence-building behaviors naturally happening during this transitional period (increase in curiosity, sensation-seeking, and risk-taking behaviors).
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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.
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Safety signals are learned cues that predict stress-free periods whereas behavioral control is the ability to modify a stressor by behavioral actions. Both serve to attenuate the effects of stressors such as uncontrollable shocks. Internal and external cues produced by a controlling behavior are followed by a stressor-free interval, and so it is possible that safety learning is fundamental to the effect of control. If this is the case then behavioral control and safety should recruit the same neural machinery. Interestingly, safety signals that prevented a behavioral outcome of stressor exposure that is also blocked by control (reduced social exploration) failed to inhibit activity in the dorsal raphé nucleus or use the ventromedial prefrontal cortex, the mechanisms by which behavioral control operates. However, bilateral lesions to a region of posterior insular cortex, termed the "sensory insula," prevented the effect of safety but not of behavioral control, providing a double-dissociation. These results indicate that stressor-modulators can recruit distinct neural circuitry and imply a critical role of the sensory insula in safety learning.
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The presence of behavioral control over a stressor can blunt many of the effects of the stressor. We have recently reported that uncontrollable stress (inescapable electric tailshock, IS) reduces later social exploration of a juvenile whereas controllable stress (escapable shock, ES) does not. Activation of the ventral medial prefrontal cortex (vmPFC) is crucial to blunting the effects of IS on later escape behavior (learned helplessness). The goal of the current study was to test the role of the vmPFC in modulating the effects of stressor controllability on anxiety in the social exploration test. Thus, adult male rats were implanted with cannula guides for drug microinjection into the vmPFC. In Experiment 1, temporary inactivation of the vmPFC with the GABA(A) agonist muscimol before exposure to ES prevented the protective effects of stress control, leading to reduced social exploration. In Experiment 2, excitation of the vmPFC prior to IS with the GABA-activated Cl(( - )) channel antagonist picrotoxin mimicked the stress resistance produced by control and prevented IS-induced reduction in social exploration. These results are consistent with prior work and identify the vmPFC as a critical component of the neural circuitry mediating the effects of stressor control on later behaviors. The relationship between the vmPFC, dorsal raphé nucleus, and other structures mediating stress-induced anxiety are discussed.
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Using data collected in the National Institute of Mental Health Epidemiologic Catchment Area Program, we examined the reported age at onset of selected mental disorders using life table survival methods. The examination of hazard rates suggests that adolescence and young adulthood are important periods for the development of unipolar major depression, bipolar illness, phobias, and drug and alcohol abuse/dependence. Although there are limitations in using cross-sectional data for this purpose, the findings suggest the need for more attention to the development of mental disorders in childhood and adolescence.
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This article introduces and summarizes the goals of the symposium. It also provides an overview of a conceptual framework for understanding adolescence, which emphasizes how the very nature of this developmental transition requires an interdisciplinary approach-one that focuses on brain/behavior/social-context interactions during this important maturational period. More specifically it describes a set of neurobehavioral changes that appear to be linked to pubertal development, which appear to have a significant effect on motivation and emotion, and considers these puberty-specific changes in affect in relation to a much larger set of developmental changes in adolescence. This framework is used to argue for the need for a transdisciplinary dialogue that brings together work in several areas of neuroscience (including animal models) and normal development with clinical and social policy research aimed at early intervention and prevention strategies.
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The degree of behavioral control that an organism has over a stressor is a potent modulator of the stressor's impact; uncontrollable stressors produce numerous outcomes that do not occur if the stressor is controllable. Research on controllability has focused on brainstem nuclei such as the dorsal raphe nucleus (DRN). Here we find that the infralimbic and prelimbic regions of the ventral medial prefrontal cortex (mPFCv) in rats detect whether a stressor is under the organism's control. When a stressor is controllable, stress-induced activation of the DRN is inhibited by the mPFCv, and the behavioral sequelae of uncontrollable stress are blocked. This suggests a new function for the mPFCv and implies that the presence of control inhibits stress-induced neural activity in brainstem nuclei, in contrast to the prevalent view that such activity is induced by a lack of control.
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Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are implicated in mediating learned helplessness (LH) behaviors, such as poor escape responding and expression of exaggerated conditioned fear, induced by acute exposure to uncontrollable stress. DRN 5-HT neurons are hyperactive during uncontrollable stress, resulting in desensitization of 5-HT type 1A (5-HT1A) inhibitory autoreceptors in the DRN. 5-HT1A autoreceptor downregulation is thought to induce transient sensitization of DRN 5-HT neurons, resulting in excessive 5-HT activity in brain areas that control the expression of learned helplessness behaviors. Habitual physical activity has antidepressant/anxiolytic properties and results in dramatic alterations in physiological stress responses, but the neurochemical mediators of these effects are unknown. The current study determined the effects of 6 weeks of voluntary freewheel running on LH behaviors, uncontrollable stress-induced activity of DRN 5-HT neurons, and basal expression of DRN 5-HT1A autoreceptor mRNA. Freewheel running prevented the shuttle box escape deficit and the exaggerated conditioned fear that is induced by uncontrollable tail shock in sedentary rats. Furthermore, double c-Fos/5-HT immunohistochemistry revealed that physical activity attenuated tail shock-induced activity of 5-HT neurons in the rostral-mid DRN. Six weeks of freewheel running also resulted in a basal increase in 5-HT1A inhibitory autoreceptor mRNA in the rostral-mid DRN. Results suggest that freewheel running prevents behavioral depression/LH and attenuates DRN 5-HT neural activity during uncontrollable stress. An increase in 5-HT1A inhibitory autoreceptor expression may contribute to the attenuation of DRN 5-HT activity and the prevention of LH in physically active rats.
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The degree of control that an organism has over a stressor potently modulates the impact of the stressor, with uncontrollable stressors producing a constellation of outcomes that do not occur if the stressor is behaviorally controllable. It has generally been assumed that this occurs because uncontrollability actively potentiates the effects of stressors. Here it will be suggested that in addition, or instead, the presence of control actively inhibits the impact of stressors. At least in part, this occurs because (i) the presence of control is detected by regions of the ventral medial prefrontal cortex (mPFCv); and (ii) detection of control activates mPFCv output to stress-responsive brain stem and limbic structures that actively inhibit stress-induced activation of these structures. Furthermore, an initial experience with control over stress alters the mPFCv response to subsequent stressors so that mPFCv output is activated even if the subsequent stressor is uncontrollable, thereby making the organism resilient. The general implications of these results for understanding resilience in the face of adversity are discussed.
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Childhood trauma is associated with higher rates of both mood and anxiety disorders in adulthood. The exposure of rats to stressors during juvenility has comparable effects, and was suggested as a model of induced predisposition for these disorders. The neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM are critically involved in neural development, activity-dependent synaptic plasticity, and learning processes. We examined the effects of exposure to stressors during juvenility on coping with stressors in adulthood and on NCAM and PSA-NCAM expression within the rat limbic system both soon after the exposure and in adulthood. Exposure to stressors during juvenility reduced novel-setting exploration and impaired two-way shuttle avoidance learning in adulthood. Among naive rats, a development-related decrease of about 50% was evident in the PSA-NCAM to NCAM expression ratio in the basolateral amygdala, in the CA1 and dentate gyrus regions of the hippocampus, and in the entorhinal cortex. In juvenile-stressed rats, we found no such decrease, but rather an increase in the polysialylation of NCAM ( approximately 50%), evident soon after the exposure to juvenile stress and also in adulthood. Our results suggest that exposure to stressors during juvenility alters the maturation of the limbic system, and potentially underlies the predisposition to exhibit stress-related symptoms in adulthood.
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• Using data collected in the National Institute of Mental Health Epidemiologic Catchment Area Program, we examined the reported age at onset of selected mental disorders using life table survival methods. The examination of hazard rates suggests that adolescence and young adulthood are important periods for the development of unipolar major depression, bipolar illness, phobias, and drug and alcohol abuse/dependence. Although there are limitations in using cross-sectional data for this purpose, the findings suggest the need for more attention to the development of mental disorders in childhood and adolescence.
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Human responses to stress and trauma vary widely. Some people develop trauma-related psychological disorders, such as posttraumatic stress disorder (PTSD) and depression; others develop mild to moderate psychological symptoms that resolve rapidly; still others report no new psychological symptoms in response to traumatic stress. Individual variability in how animals and humans respond to stress and trauma depends on numerous genetic, developmental, cognitive, psychological, and neurobiological risk and protective factors.
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To examine the association between an early inhibited temperament and lifetime anxiety disorders, we studied a sample of patients with major depression who were not selected on the basis of comorbid axis I anxiety disorders. One-hundred eighty-nine adults (range=17–68 years) referred to a tertiary depression unit underwent structured diagnostic interviews for depression and anxiety and completed two self-report measures of behavioral inhibition, the retrospective measure of behavioural inhibition (RMBI) [Gladstone and Parker, 2005] and the adult measure of behavioural inhibition (AMBI) [Gladstone and Parker, 2005]. Patients' scores were classified into “low,” “moderate,” or “high” inhibition. While groups did not differ in terms of depression severity, there were differences across groups in clinically diagnosed nonmelancholic status and age of onset of first episode. Those reporting a high degree of childhood inhibition were significantly more likely to qualify for a diagnosis of social phobia, and this association was independent of their scores on the AMBI. Findings are discussed in light of the existing risk-factor literature and support the hypothesis that an early inhibited temperament may be a significant precursor to later anxiety, especially social anxiety disorder. Depression and Anxiety 22:103–113, 2005. © 2005 Wiley-Liss, Inc.
Article
Research investigating how control over stressors affects behavior often utilizes freezing and shuttle escape learning as the behavioral endpoints. These endpoints have been argued to reflect anxious or depressed states, but these descriptions are problematic. The present study sought to determine the impact of stressor controllability and the dorsal raphé nucleus (DRN) on sucrose preference and juvenile social exploration, putative measures of anhedonia and anxiety that are commonly used in studies of stress per se. In Experiment 1 rats were exposed to escapable stress (ES) or yoked-inescapable stress (IS) tailshocks. In Experiment 2 ES or IS was given 7 days before all rats received IS. In Experiment 3 the DRN was inactivated during IS by microinjection of 8-OH-DPAT. Sucrose preference and social exploration were tested for several days after stress. A fourth experiment confirmed that juvenile social exploration is sensitive to traditional β-carboline and benzodiazepine manipulations. Both ES and IS reduced sucrose preference, but only IS reduced social exploration. Prior treatment with ES prevented the effect of IS on social exploration but did not prevent the effect of IS on sucrose preference and inactivation of the DRN prevented the effect of IS on social exploration but did not change sucrose preference. The present results indicate that social exploration but not sucrose preference is sensitive to prior stressor controllability, and that DRN activation mediates the effect of IS on social exploration. We argue that DRN-5-HT activation mediates a state of generalized anxiety produced by uncontrollable stress and that juvenile social exploration is a useful behavioral endpoint in stressor controllability studies.
Article
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the dorsal raphe nucleus were measured by in vivo microdialysis. In comparison to either control rats or to their own preshock baseline, rats exposed to inescapable shock showed an increase in extracellular 5-HT within 25 min of shock initiation, and 5-HT levels continued to rise during the remainder of the shock session. Rats that were exposed to comparable shock treatment, but that were given the opportunity to escape, did not show an increase in 5-HT. Rats that were restrained but not shocked also did not show an increase in 5-HT. These results add further support to suggestions that serotonergic changes occur in the dorsal raphe nucleus during inescapable shock and that such changes may contribute to the behavioral effects of inescapable shock.
Article
Adolescence is a period of heightened susceptibility to anxiety disorders, yet we have little experimental evidence on what factors may lead to psychopathology in adolescence. Preclinical models of extinction are commonly used to study the treatment of anxiety symptoms. Interestingly, recent research has shown that there are fundamental changes in the process of extinction across development, which may have implications for our understanding of psychopathology across the lifespan. Specifically, this research shows that the process of extinction parallels the nonlinear function of prefrontal cortex development, such that extinction behaviour is similar in juvenile and adult rats, but involves different processes in infancy and adolescence (periods of rapid growth and pruning, respectively). Our previous studies have shown that early-life stress accelerates the transition between infant and juvenile extinction systems. In the current series of experiments, we examined whether the same early-life stress, maternal separation (MS), would lead to an earlier transition between the juvenile and adolescent extinction systems, and between the adolescent and adult extinction systems. We show that MS adolescent rats exhibit more adult-like extinction behaviour, and that adolescent-like extinction emerges earlier in development (i.e. in pre-adolescent rats). These results may have important implications for the understanding and treatment of anxiety symptoms in adolescent populations.
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Our previous studies have shown that post-weaning social isolation of male rats leads to sensitization of serotonergic systems and increases in anxiety-like behavior in adulthood. Although studies in humans suggest that females have an increased sensitivity to stress and risk for the development of neuropsychiatric illnesses, most studies involving laboratory rats have focused on males while females have been insufficiently studied. The objective of this study was to investigate the effects of post-weaning social isolation on subsequent responses of an anxiety-related dorsal raphe nucleus (DR)-basolateral amygdala system to pharmacological challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142; a partial inverse agonist at the benzodiazepine allosteric site on the γ-aminobutyric acid (GABA)(A) receptor). Juvenile female rats were reared in isolation or in groups of three for a 3-week period from weaning to mid-adolescence, after which all rats were group-reared for an additional 2 weeks. We then used dual immunohistochemical staining for c-Fos and tryptophan hydroxylase in the DR or single immunohistochemical staining for c-Fos in the basolateral amygdala. Isolation-reared rats, but not group-reared rats, injected with FG-7142 had increased c-Fos expression within the basolateral amygdala and in serotonergic neurons in the dorsal, ventrolateral, caudal and interfascicular parts of the DR relative to appropriate vehicle-injected control groups. These data suggest that post-weaning social isolation of female rats sensitizes a DR-basolateral amygdala system to stress-related stimuli, which may lead to an increased sensitivity to stress- and anxiety-related responses in adulthood.
Article
Repeated exposure to stressors has been found to increase anxiety-like behavior in laboratory rodents, with the social anxiety induced by repeated restraint being extremely sensitive to anxiolytic effects of ethanol in both adolescent and adult rats. No studies, however, have compared social anxiogenic effects of acute stress or the capacity of ethanol to reverse this anxiety in adolescent and adult animals. Therefore, the present study was designed to investigate whether adolescent [postnatal day (P35)] Sprague-Dawley rats differ from their adult counterparts (P70) in the impact of acute restraint stress on social anxiety and in their sensitivity to the social anxiolytic effects of ethanol. Animals were restrained for 90 min, followed by examination of stress- and ethanol-induced (0, 0.25, 0.5, 0.75, and 1 g/kg) alterations in social behavior using a modified social interaction test in a familiar environment. Acute restraint stress increased anxiety, as indexed by reduced levels of social investigation at both ages, and decreased social preference among adolescents. These increases in anxiety were dramatically reversed among adolescents by acute ethanol. No anxiolytic-like effects of ethanol emerged following restraint stress in adults. The social suppression seen in response to higher doses of ethanol was reversed by restraint stress in animals of both ages. To the extent that these data are applicable to humans, the results of the present study provide some experimental evidence that stressful life events may increase the attractiveness of alcohol as an anxiolytic agent for adolescents.
Article
Adolescence is a critical developmental period during which chronic stress and binge alcohol consumption are often seen as environmental risk factors that confer vulnerability to later mental health problems. The current study modelled this using a 2×2 design where male Wistar rats were exposed to intermittent predatory stress (Stress condition: groups of 4 rats given 30 min of cat fur exposure in a large arena, once every 48 h) or intermittent alcohol (Alcohol condition: access to beer for 24 h every 2nd day), or both manipulations given on alternate days (Stress/Alcohol), or no manipulation (Control). The manipulations occurred over a 24 day adolescent window (postnatal day (PND) 33-57) giving a total of 12 cat fur exposures and/or 12 alternate days of beer access. Residual anxiety- and depressive-like behaviours were assessed in early adulthood (PND 58-77). Cat fur exposure was found to elicit a distinct defensive response in which groups of adolescent rats huddled together in the corner of the arena, either in "quads" (all 4 rats bunched together) or "triplets" (3 rats together and one outlier rat). Few approaches to the cat fur occurred and locomotor activity was suppressed relative to Control rats placed in the arena without fur. Huddling continued over the 12 repeated exposures to cat fur, and was temporarily exaggerated when fur from a novel cat was introduced. Interestingly, huddling and conditioned fear in the fur-associated context were most pronounced in rats receiving intermittent alcohol, suggesting that alternate day exposure to alcohol had anxiogenic effects, possibly linked to a hangover state on these days. Predatory stress did not affect overall alcohol consumption relative to rats given alcohol alone, but significantly inhibited weight gain through adolescence and into adulthood. In early adulthood, rats exposed to stress in adolescence, regardless of alcohol exposure, showed significantly reduced immobility in the forced swim test and signs of increased sociability with a novel conspecific in a social interaction paradigm. Overall, these findings suggest greater resilience in adulthood after chronic adolescent stress, indicating that coping with predators may be in some ways a form of early environmental enrichment.
Article
Safety signals exert a powerful buffering effect when provided during exposure to uncontrollable stressors. We evaluated the role of the sensory insular cortex (Si) and the extend amygdala in this "safety signal effect." Rats were implanted with microinjection cannula, exposed to inescapable tailshocks either with or without a safety signal, and later tested for anxiety-like behavior or neuronal Fos expression. Exposure to the uncontrollable stressor reduced later social exploration but not when safety signals were present. Temporary inhibition of Si during stressor exposure but not during later behavioral testing blocked the safety signal effect on social exploration. The stressor induced Fos in all regions of the amygdala, but safety signals significantly reduced the number of Fos immunoreactive cells in the basolateral amygdala and ventrolateral region of the bed nucleus of the stria terminalis (BNSTlv). Inhibition of BNSTlv neuronal activity during uncontrollable stressor exposure prevented the later reduction in social exploration. Finally, safety signals reduced the time spent freezing during uncontrollable stress. These data suggest that safety signals inhibit the neural fear or anxiety response that normally occurs during uncontrollable stressors and that inhibition of the BNSTlv is sufficient to prevent later anxiety. These data lend support to a growing body of evidence that chronic fear is mediated in the basolateral amygdala and BNSTlv and that environmental factors that modulate fear during stress will alter the long-term consequences of the stressor.
Article
Post-weaning social isolation of rats is utilized as a model of early life stress. We have previously demonstrated that rats exposed to post-weaning social isolation exhibit greater anxiety-like behaviors as adults. Furthermore, these rats exhibit greater density of corticotropin-releasing factor (CRF) type 2 receptors in the dorsal raphe nucleus. Therefore, we examined whether antagonism of CRF(2) receptors in the dorsal raphe nucleus reverses the effects of post-weaning social isolation on anxiety states. Male rats were reared in isolation or in groups from day of weaning (postnatal day [PND] 21) to mid-adolescence (PND42) and then allowed to develop to early adulthood housed in groups. At PND62, rats were either infused with vehicle, the CRF(1) receptor antagonist antalarmin (0.25-0.5 μg) or the CRF(2) receptor antagonist antisauvagine-30 (2 μg) into the dorsal raphe nucleus, 20 min prior to being introduced to the elevated plus maze. Isolation-reared rats showed reduced open arm behavior compared to group-reared rats, confirming the anxiogenic effects of post-weaning social isolation. Infusion of the CRF(2) receptor antagonist, but not the CRF(1) receptor antagonist, into the dorsal raphe nucleus of isolation-reared rats increased open arm behavior when compared to that of group-reared rats. Overall, the findings suggest that CRF(2) receptors within the dorsal raphe nucleus mediate anxiety-like states following post-weaning social isolation, and CRF(2) receptors may represent an important target for the treatment of anxiety disorders following early life stressors.
Article
Adolescence is a transitional phase during which the juvenile develops into an independent adult individual. In this period in particular frontal cortical brain regions and related neural circuitry are structurally remodeled to a relatively high extent resulting in a refined connectivity and functionality of these brain regions in adulthood. In this review we aim to address the question whether a high structural neuronal plasticity during adolescence makes this developmental period particularly vulnerable to lasting detrimental effects of stress. To answer this question we focus on results from experimental animal research on behavioral, physiological and neurobiological consequences of stress during adolescence. There are indeed results from animal models on stress that confirm that adolescent stress can lastingly alter adult brain and behavior. Since many studies, however, have shown that long-lasting effects of stress also occur in other phases of life as the perinatal period and adulthood the data do not suggest that adolescents are particularly vulnerable to the negative consequences of stress. The outcome of many of the studies on adolescent stress also emphasizes the high resilience of adolescent animals to develop long-lasting psychopathological changes in behavior after being exposed to adolescent stress.
Article
Transformations in affective and social behaviors, many of which involve amygdalar circuits, are hallmarks of adolescence in many mammalian species. In this study, using the rat as a model, we provide the first evidence that afferents of the basal amygdala (BA) undergo significant structural remodeling during adolescence. We used quantitative tract-tracing and gene expression profiling methods to characterize changes in the medial prefrontal cortical (mPFC) inputs to the BA across ages analogous to the late juvenile period [postnatal day (P) 25], late adolescence (P45), and adulthood (P90) in the rat. As assessed after deposition of Fluorogold into the BA, the number of BA-projecting neurons in the mPFC remained stable between P25 and P45 but decreased by about 50% between P45 and P90. Anterograde tract tracing with biotin dextran amine deposits centered in the ventral prelimbic cortex revealed that, during this period, the density of mPFC-derived axon terminals in the BA also decrease significantly, an effect particularly evident in the dorsal basolateral nucleus. Within the BA, there were also highly significant changes in gene expression indicative of neurite or synaptic plasticity, most notably in the Ras/GTPase superfamily, and in pathways that regulate cytoskeletal dynamics and steroid synthesis/lipid metabolism. These data provide convergent evidence that mPFC inputs to the BA are pruned during late adolescence or early adulthood. Moreover, the structural remodeling within these afferents may be accompanied by significant changes in neurite plasticity within the BA.
Article
One prominent feature of adolescence is the high frequency of social behaviors, such as play. Engaging in these behaviors appears necessary for proper socio-emotional development as social isolation during adolescence typically leads to behavioral dysfunctions in adulthood. The present experiments examined the effects of stress on social and nonsocial behaviors in group housed adolescent male rats. We found that acute restraint stress led to a complete inhibition of play (e.g., nape contacts and pins) and reduced social investigations in pre- (28 days), mid- (35 days), and late-adolescent (42 and 49 days) animals. A follow-up study, however, found that restraint-induced suppression of play and social investigations was transient such that experimental animals engage in these behaviors at levels similar to those of controls 1 hr after termination of the stressor. We also found that exposure to repeated restraint stress throughout adolescence led to a decrease in social investigations, while leaving play largely unaffected. Interestingly, in all of the experiments, nonsocial behaviors (e.g., eating, drinking, grooming) were unaffected by restraint, suggesting these effects of stress are specific to social behaviors. Together, these data indicate that both acute and repeated stress significantly affect social behaviors during adolescence.
Article
Depressed suicide patients have elevated expression of neuronal tryptophan hydroxylase 2 (TPH2) mRNA and protein in midbrain serotonergic neurons, as well as increases in brain serotonin turnover. The mechanisms underlying these changes are uncertain, but increased TPH2 expression and serotonin turnover could result from genetic influences, adverse early life experiences, or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to major depression. Emerging evidence suggests that there are several different stress-related subsets of serotonergic neurons, each with a unique role in the integrated stress response. Here we review our current understanding of how genetic and environmental factors may influence TPH2 mRNA expression and serotonergic neurotransmission, focusing in particular on the dorsomedial part of the dorsal raphe nucleus. This subdivision of the dorsal raphe nucleus is selectively innervated by key forebrain structures implicated in regulation of anxiety states, it gives rise to projections to a distributed neural system mediating anxiety states, and serotonergic neurons within this subdivision are selectively activated by a number of stress- and anxiety-related stimuli. A better understanding of the anatomical and functional properties of specific stress- or anxiety-related serotonergic systems should aid our understanding of the neural mechanisms underlying the etiology of anxiety and affective disorders.
Article
Exposure to chronic mild stress (CMS) is known to induce anhedonia in adult animals, and is associated with induction of depression in humans. However, the behavioral effects of CMS in young animals have not yet been characterized, and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Here, we found that CMS induces anhedonia in adult but not in young animals, as measured by a set of behavioral paradigms. Furthermore, while CMS decreased neurogenesis and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of adult animals, it increased these parameters in young animals. We also found that CMS altered alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor GluR1 subunit levels in the hippocampus and the nucleus accumbens of adult, but not young animals. Finally, no significant differences were observed between the effects of CMS on circadian corticosterone levels in the different age groups. The substantially different neurochemical effects chronic stress exerts in young and adult animals may explain the behavioral resilience to such stress young animals possess.
Article
The relation between the shuttlebox escape deficit produced by prior inescapable shock (IS) and fear during shuttlebox testing as assessed by freezing was investigated in rats. IS rats learned to escape poorly and were more fearful than either escapably shocked subjects or controls, both before and after receiving shock in the shuttlebox. However, fear and poor escape performance did not covary with the manipulation of variables designed to modulate the amount of fear and the occurrence of the escape deficit. A 72-hr interval between IS and testing eliminated the escape deficit but did not reduce preshock freezing. Diazepam before testing reduced both preshock and postshock fear in the shuttlebox but had no effect on the escape deficit. Naltrexone had no effect on fear but eliminated the escape deficit. This independence of outcomes suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects.
Article
The influence of pubertal age on the differential effect of a familiar versus an unfamiliar environment on social interaction (SI) in pairs of male rats was evaluated. The decrease in SI induced by the unfamiliar environment in adult rats is considered an anxiety-related response. Intact male rats and male rats castrated at 19 days were tested for SI at 28, 35, and 60 days of age. The results revealed that in the intact rats, decreased SI in an unfamiliar environment was evident at 35 and 60 days but not at 28 days. The behavioral composition of the environment-induced response at 35 days was different from that measured at 60 days. Prepubertal castration prevented the decrease in SI in the unfamiliar environment at both 35 and 60 days. This study demonstrated the emergence with the onset of puberty of a specific behavioral response to an anxiogenic condition. Furthermore, the development of this environment-related behavioral response was influenced by gonadal secretion(s), suggesting the importance of gonadal function to the emergence of this response.
Article
DOGS WHICH HAD 1ST LEARNED TO PANEL PRESS IN A HARNESS IN ORDER TO ESCAPE SHOCK SUBSEQUENTLY SHOWED NORMAL ACQUISITION OF ESCAPE/AVOIDANCE BEHAVIOR IN A SHUTTLE BOX. IN CONTRAST, YOKED, INESCAPABLE SHOCK IN THE HARNESS PRODUCED PROFOUND INTERFERENCE WITH SUBSEQUENT ESCAPE RESPONDING IN THE SHUTTLE BOX. INITIAL EXPERIENCE WITH ESCAPE IN THE SHUTTLE BOX LED TO ENHANCED PANEL PRESSING DURING INESCAPABLE SHOCK IN THE HARNESS AND PREVENTED INTERFERENCE WITH LATER RESPONDING IN THE SHUTTLE BOX. INESCAPABLE SHOCK IN THE HARNESS AND FAILURE TO ESCAPE IN THE SHUTTLE BOX PRODUCED INTERFERENCE WITH ESCAPE RESPONDING AFTER A 7-DAY REST. THESE RESULTS ARE INTERPRETED AS SUPPORTING A LEARNED "HELPLESSNESS" EXPLANATION OF INTERFERENCE WITH ESCAPE RESPONDING: SS FAILED TO ESCAPE SHOCK IN THE SHUTTLE BOX FOLLOWING INESCAPABLE SHOCK IN THE HARNESS BECAUSE THEY HAD LEARNED THAT SHOCK TERMINATION WAS INDEPENDENT OF RESPONDING.
Article
Effects of benzodiazepine receptor-active compounds on inescapable shock-produced changes in social interaction were studied in the rat. Inescapably shocked animals exhibited less social interaction in a novel situation than did escapably shocked or unshocked rats 24 h after shock. Administration of the selective benzodiazepine receptor antagonist flumazenil at the time of shock prevented the decrease in social interaction. Social interaction was unaffected by the same treatment at the time of measurement. Reduction in social interaction induced by inescapable stress endured for 48-72 h following stressor exposure but was absent 168 h after stress. It was subject to antagonist blockade at all measured time points. Stress-induced decreases in social interaction were also blocked by the benzodiazepine chlordiazepoxide given at the time of shock treatment. The receptor antagonist did not reverse this blockade. An inverse agonist, the beta-carboline FG 7142, administered in place of inescapable shock, produced an identical pattern of social interaction in a dose-dependent manner. The inverse agonist effect was also reversed by the antagonist. The results from antagonist, agonist, and inverse agonist treatments all suggest that an endogenous benzodiazepine receptor inverse agonist is released at the time of inescapable shock and is involved in producing the changes in social interaction subsequently measured.
Article
The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.
Article
The dorsal raphe nucleus (DRN) and its serotonergic terminal regions have been suggested to be part of the neural substrate by which exposure to uncontrollable stressors produces poor escape responding and enhanced conditioned fear expression. Such stressor exposure is thought to selectively activate DRN serotonergic neurons in such a way as to render them transiently sensitized to further input. As a result of this sensitized state, behavioral testing procedures are thought to cause excess serotonergic activity in brain regions that control these behaviors. The present studies were conducted to investigate activity in the DRN following exposure to escapable and yoked, inescapable tailshock. Neural activity was characterized using immunohistochemistry to detect the immediate early gene product Fos in serotonin-immunoreactive cells in the DRN. Inescapable tailshock led to greater serotonergic neural activity than did escapable tailshock, supporting the hypothesis that uncontrollable stressors preferentially activate serotonergic neurons in the DRN.
Article
To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.
Recent work in the learned helplessness paradigm suggests that neuronal sensitization and fatigue processes are critical to producing the behavioral impairment that follows prolonged exposure to an unsignaled inescapable stressor such as a series of electric tail shocks. Here we discuss how an interaction between serotonin (5-HT) and corticosterone (CORT) sensitizes GABA neurons early in the pretreatment session with inescapable shock. We propose that this process eventually depletes GABA, thus removing an important form of inhibition on excitatory glutamate transmission in the amygdala, hippocampus, and frontal cortex. When rats are re-exposed to shock during shuttle-escape testing 24 hrs later, the loss of inhibition (as well as other excitatory effects) results in unregulated excitation of glutamate neurons. This state of neuronal over-excitation rapidly compromises metabolic homeostasis. Metabolic fatigue results in compensatory inhibition by the nucleoside adenosine, which regulates neuronal excitation with respect to energy availability. The exceptionally potent form of inhibition associated with adenosine receptor activation yields important neuroprotective benefits under conditions of metabolic failure, but also precludes the processing of information in fatigued neurons. The substrates of adaptive behavior are removed; performance deficits ensue.
Article
Adolescence is a critical stage for the development of emotional maturity and diverse forms of psychopathology. The posterior basolateral nucleus of the amygdala is known to mediate fear and anxiety and is important in assigning emotional valence to cognitive processes. The medial prefrontal cortex, a homologue of the human anterior cingulate cortex, mediates emotional, attentional, and motivational behaviors at the cortical level. We postulate that the development of connectivity between these two corticolimbic regions contributes to an enhanced integration of emotion and cognition during the postnatal period. In order to characterize the development of this relay, injections of the anterograde tracer biocytin were stereotaxically placed within the posterior basolateral nucleus of the amygdala of rats at successive postnatal time points (postnatal days 6-120). Labeled fibers in the medial prefrontal cortex were evaluated using a combination of brightfield, confocal, and electron microscopy. We found that the density of labeled fibers originating from the posterior basolateral nucleus shows a sharp curvilinear increase within layers II and V of the anterior cingulate cortex and the infralimbic subdivisions of medial prefrontal cortex during the late postweanling period. This increase was paralleled by a linear rise in the number of axospinous and axodendritic synapses present in the neuropil. Based on these results, we propose that late maturation of amygdalo-cortical connectivity may provide an anatomical basis for the development and integration of normal and possibly abnormal emotional behavior during adolescence and early adulthood.
Article
Most research on the effects of severe psychological stress has focused on stress-related psychopathology. Here, the author develops psychobiological models of resilience to extreme stress. An integrative model of resilience and vulnerability that encompasses the neurochemical response patterns to acute stress and the neural mechanisms mediating reward, fear conditioning and extinction, and social behavior is proposed. Eleven possible neurochemical, neuropeptide, and hormonal mediators of the psychobiological response to extreme stress were identified and related to resilience or vulnerability. The neural mechanisms of reward and motivation (hedonia, optimism, and learned helpfulness), fear responsiveness (effective behaviors despite fear), and adaptive social behavior (altruism, bonding, and teamwork) were found to be relevant to the character traits associated with resilience. The opportunity now exists to bring to bear the full power of advances in our understanding of the neurobiological basis of behavior to facilitate the discoveries needed to predict, prevent, and treat stress-related psychopathology.
Article
The term 'learned helplessness' refers to a constellation of behavioral changes that follow exposure to stressors that are not controllable by means of behavioral responses, but that fail to occur if the stressor is controllable. This paper discusses the nature of learned helplessness, as well as the role of the dorsal raphe nucleus, serotonin, and corticotropin-releasing hormone in mediating the behavioral effects of uncontrollable stressors. Recent research indicates that (a) uncontrollable stressors sensitize serotonergic neurons in the dorsal raphe, and that a corticotropin-releasing factor-related ligand, acting at the Type II receptor, is essential to this sensitization process, and (b) the consequent exaggerated release of serotonin in response to subsequent input is at least in part responsible for the behavioral changes that occur. Finally, implications for the general role of corticotropin-releasing hormone in stress-related phenomena and for the learned helplessness paradigm as an animal model of either depression or anxiety are discussed.
Article
This review discusses neurobiological and psychosocial factors associated with stress-induced depression and compares these factors with those believed to characterize stress resilience. Neurobiological factors that are discussed and contrasted include serotonin, the 5-HT1A receptor, polymorphisms of the 5-HT transporter gene, norepinephrine, alpha-2 adrenergic receptors, neuropeptide Y, polymorphisms of the alpha-2 adrenergic gene, dopamine, corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), cortisol, and CRH receptors. These factors are described in the context of brain regions believed to be involved in stress, depression, and resilience to stress. Psychosocial factors associated with depression and/or stress resilience include positive emotions and optimism, humor, cognitive flexibility, cognitive explanatory style and reappraisal, acceptance, religion/spirituality, altruism, social support, role models, coping style, exercise, capacity to recover from negative events, and stress inoculation. The review concludes with potential psychological, social, spiritual, and neurobiological approaches to enhancing stress resilience, decreasing the likelihood of developing stress-induced depression/anxiety, and treating stress-induced psychopathology.
Article
Sex differences in depressive symptoms emerge during adolescence, with females more at risk than males. However, adverse life events during development have greater impact on males. An animal model that incorporates behavioral and anatomical changes following adolescent stress is needed. Sprague-Dawley rats were exposed to social stress (SS; isolation housing during P30-35) or remained group-housed (GRP) and tested in the forced swim test (FST), the triadic learned helplessness model (LH), and the elevated plus maze. Western immunoblots of myelin basic protein (MBP) and synaptophysin (SVP) and spinophillin indexed synaptic and dendritic plasticity, respectively. At P36, SS increased climbing behavior in both sexes, and decreased the latency to immobility in females following a 15 min inescapable swim in the FST. Depressive-like behaviors were differentially elevated in both sexes 24 h later. GRP females exhibited higher levels of depression-related behaviors than GRP males in both FST and LH paradigms. SS significantly increased depressive behaviors in the FST in males, and impaired their ability to escape shock previously conditioned to be controllable. SS decreased open arm time in females only. The greatest reductions in synaptic plasticity proteins were observed in the prefrontal cortex: spinophillin (19.1%), SVP (7.9%), and MBP (48.7%, males only). Smaller reductions in spinophillin were observed in the hippocampus and amygdala. Adolescent separation produces both behavioral and neural changes associated with stress-related depression and anxiety. Additional work is needed to improve our understanding of stress as it relates to depression during this vulnerable period of development.