The Teenage Brain

The Stress Response

When an individual experiences a stressor, be it physical or psychological, two hormonal systems are activated to help the individual cope with the situation. The first is mediated by the rapid actions of the sympathetic nervous system, leading to the release of epinephrine and norepinephrine into the blood stream. It is this immediate response that mediates the transient “fight-or-flight” reaction to stress. The second is a slower, more protracted hormonal response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. This response is initiated by a group of neurons in the paraventricular nucleus of the hypothalamus (PVN), which secrete corticotropin-releasing hormone (CRH) to signal the pituitary to release adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenal glands to synthesize and secrete the glucocorticoids (i.e., cortisol in humans and corticosterone in many rodent species). Once the stressor has ended, the glucocorticoids act though negative feedback on the pituitary gland and a variety of forebrain regions, namely, the hypothalamus, hippocampus, and prefrontal cortex, ultimately terminating the response by reducing the further production and release of CRH and ACTH (Herman et al., 2003; Fig. 1). Thus, in the context of the HPA reaction to stress, the brain is both the initiator and a major target of the glucocorticoid response.

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Fig. 1.

A simplified schematic of stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, as well as the negative feedback that allows the HPA axis to recover back to baseline following termination of a stressor. ACTH = adrenocorticotropin hormone; AD = adrenal gland; AP = anterior pituitary; CORT = corticosterone; CRH = corticotropin-releasing hormone; minus sign = negative feedback; plus sign = positive drive.

The glucocorticoids are responsible for many of the adaptive physiological and behavioral responses to stressors, such as mobilizing energy stores, enhancing immune reactions, and increasing learning and memory abilities. However, chronic or more prolonged exposure to these hormones can result in numerous maladaptive outcomes, including metabolic disorders and impaired immune and cognitive functions. Thus, factors that regulate HPA reactivity and the dynamics of the hormonal stress response can have important short- and long-term consequences on an individual’s physiology and behavior (McEwen, 1998).

Adolescent Development of the Hormonal Stress Response

Although adolescence is marked by many neuroendocrine changes, the shifts in HPA function are more subtle than the relatively conspicuous increases in gonadal hormones associated with puberty. That is, though basal ACTH and glucocorticoid levels remain fairly stable throughout adolescence, it is the amount and duration of these hormones released in times of stress that show notable changes. Numerous studies in both male and female rats, for instance, indicate that animals on the cusp of adolescence (i.e., approximately 30 days of age) show significantly protracted ACTH and corticosterone responses compared with adults (i.e., > 65 days of age) following a brief exposures to a variety of stressors (e.g., foot shock, hypoxia, restraint; Goldman, Winget, Hollingshead, & Levine, 1973; Romeo, Lee, Chhua, McPherson, & McEwen, 2004; Romeo, Lee, & McEwen, 2004; Vazquez & Akil, 1993). Specifically, these hormonal stress responses can last 45 to 60 minutes longer in animals prior to adolescent maturation (Romeo, 2010a, 2010b; Fig. 2). These extended hormonal responses in preadolescent animals are different than those of neonatal preweanling rats (i.e., younger than 21 days of age), which usually demonstrate hyporesponsiveness to stressors (Sapolsky & Meaney, 1986). It is interesting that these prolonged ACTH and corticosterone responses following stress do not just gradually assume their adultlike patterns as puberty and adolescence progress but instead show relatively more abrupt shifts, with stress-induced ACTH responses maturing later (i.e., between 50 and 60 days of age) than corticosterone responses (i.e., between 30 and 40 days of age; Foilb, Lui, & Romeo, 2011; Fig. 3). These data indicate that each node along the HPA axis may have its own developmental trajectory during adolescence.

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Fig. 2.

Mean (± SEM) plasma adrenocorticotropin hormone (ACTH) and corticosterone levels in preadolescent (28 days of age) and adult (77 days of age) male rats before, during, and after a 30-minute session of restraint stress (black bar under x-axis). Asterisks indicate significant differences between the two age groups at that time point. Adapted from “Testosterone Cannot Activate an Adult-Like Stress Response in Prepubertal Male Rats,” by R. D. Romeo, S. J. Lee, N. Chhua, C. R. McPherson, and B. S. McEwen 2004, Neuroendocrinology, 79, p. 128. Copyright 2004, John Wiley & Sons. Adapted with permission.

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Fig. 3.

Mean (± SEM) plasma adrenocorticotropin hormone (ACTH) and corticosterone levels throughout pubertal and adolescent development in 30-, 40-, 50-, 60-, and 70-day-old male rats before, during, and after a 30-minute session of restraint stress (black bar under x-axis). In the upper panel, asterisks indicate significant differences from the 60- and 70-day-old rats at that time point. In the lower panel, number signs indicate that 30-day-old rats were significantly different from all other ages at that time point. Adapted from “The Transformation of Hormonal Stress Responses Throughout Puberty and Adolescence,” by A. R. Foilb, P. Lui, and R. D. Romeo, 2011, Journal of Endocrinology, 210, p. 393. Copyright 2011, Bioscientifica.

It is important to note that recent studies in human adolescents have also reported changes in hormonal responsiveness, though not exactly paralleling the rodent studies. More specifically, boys and girls in later stages of adolescence (15–17 years old) display greater stress-induced cortisol levels compared with individuals in late childhood or earlier stages of adolescence (9–13 years old; Gunnar, Wewerka, Frenn, Long, & Griggs, 2009; Stroud et al., 2009).

Contributing Factors That Mediate the Adolescent Changes in Stress Reactivity

The mechanisms that mediate these adolescent-related changes in hormonal responsiveness remain unclear. However, the changes appear to involve both the activation and feedback phases of the HPA response. In the context of activation, experiments have shown that neural activity in the PVN, particularly in the CRH-containing cells, is higher in adolescent than adult animals following stress (Romeo et al., 2006; Viau, Bingham, Davis, Lee, & Wong, 2005). These data suggest that the prolonged ACTH and corticosterone responses prior to puberty may in part be driven by greater stress-induced CRH production and release.

Along with these differences in activation, studies on negative feedback have shown that treatment with the synthetic glucocorticoid dexamethasone is less effective at blunting a stress-induced corticosterone response in prepubertal compared with adult rats (Goldman et al., 1973). Thus, these results support the notion that periadolescent animals may show less glucocorticoid-dependent negative feedback on the HPA axis than adults. Future studies will need to address what cellular mechanisms mediate these putative age-dependent changes in sensitivity to negative feedback, such as differences in glucocorticoid receptor function in the brain and pituitary. To date, however, these avenues of research have been largely unexplored.

Another factor known to significantly modulate hormonal stress reactivity in adult human and nonhuman animals is gonadal hormones (Viau, 2002). In males, testosterone tends to reduce hormonal stress responsiveness, whereas in females, estradiol often enhances stress reactivity (Viau, 2002). It is possible, therefore, that the substantial difference in gonadal hormones experienced by animals before and after puberty account for the changes in stress reactivity. However, nonhuman animal studies that have experimentally manipulated gonadal hormone levels through surgery and/or hormone replacement have shown that prepubertal animals continue to show greater stress-induced ACTH and corticosterone responses compared with adults (Romeo, Lee, Chhua, et al., 2004; Romeo, Lee, & McEwen, 2004). These results suggest, therefore, that simple differences in gonadal hormone levels before and after puberty are not responsible for these changes in HPA stress responsiveness in adolescence.

The Interaction of Adolescence and Stress History on Hormonal Responsiveness

Similar to age, previous experience with stressors can also shape one’s hormonal stress responsiveness (Grissom & Bhatnagar, 2009). For example, an adult animal repeatedly exposed to the same stressor (homotypic stress) displays a habituated hormonal response compared with an adult exposed to that stressor for the first time. By contrast, if an animal experiences the same stressor over and over again and is then hit with a novel stressor (heterotypic stress), a sensitized hormonal response is exhibited above that evoked by the novel stressor alone. These experience-dependent changes in HPA reactivity are different before and after adolescent development. In particular, homotypic stress leads to habituation in adults but not in preadolescent males (Lui et al., 2012), whereas heterotypic stress leads to a similar peak response at both ages but a slower recovery in animals prior to adolescence (Lui et al., 2012; Fig. 4). It is currently unknown at what time during adolescent development these responses to homotypic and heterotypic stressors assume their adultlike patterns.

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Fig. 4.

Mean (± SEM) plasma corticosterone levels in preadolescent (30 days of age) and adult (77 days of age) male rats before, during, and after a 30-minute session of restraint stress (black bar under x-axis) following acute-, homotypic-, or heterotypic-stress paradigms. Acute stress consisted of a single 30-minute session of restraint stress, homotypic stress of a daily 30-minute session of restraint stress for 8 consecutive days, and heterotypic stress of a daily 30-minute session of cold-room exposure (at 4°C) for 7 consecutive days followed by 30 minutes of restraint on the 8th day. Asterisks indicate significant differences between age groups at that time point. Adapted from “Divergent Stress-Induced Neuroendocrine and Behavioral Responses Prior to Puberty,” by P. Lui et al., 2012, Physiology & Behavior, 107, p. 107. Copyright 2012, Elsevier. Adapted with permission.

The mechanisms responsible for this age- and experience-dependent plasticity in HPA reactivity are unclear. Though the contribution of negative feedback to these experience-dependent changes has not yet been explored, recent evidence suggests that differential activation of the PVN may be involved. That is, similar to the greater activation of PVN neurons in adolescent animals following acute stress (Romeo et al., 2006), adolescent animals also demonstrate higher PVN activation after both homotypic and heterotypic stress compared with adults, suggesting greater stress-induced hypothalamic drive to the pituitary prior to adulthood (Lui et al., 2012). In addition to neurobiological substrates mediating these shifts in reactivity, peripheral factors may also play a role. For instance, it is possible that the adolescent pituitary and adrenal glands are more sensitive to CRH and ACTH, respectively, than they are in adulthood, thus in part potentially contributing to their greater responsiveness during adolescence. Regardless of the mechanisms that mediate these age-specific hormonal responses, these data suggest that following an acute or repeated stressor, an adolescent individual experiences greater exposure to the glucocorticoids than does an adult.

Stress and the Adolescent Brain: A Perfect Storm?

As alluded to above, the brain is a major target of the glucocorticoids, and these hormones are known to be potent modulators of many neurobiological processes, including neuronal plasticity (McEwen, 2007). In adults, chronic exposure to stress results in smaller and structurally less complex hippocampal and prefrontal cortical neurons. These morphological changes are paralleled by decreases in spatial learning and attention shifting, cognitive abilities reliant on an intact hippocampus and prefrontal cortex, respectively. Neurons in the amygdala, conversely, show stress-induced growth in adulthood, along with increased amygdala-dependent fear learning (McEwen, 2007). It is important to note that these effects of stress on the adult brain are reversible, such that if animals are allowed to recover from the stressors for at least 10 days, then these parameters revert to their prestress levels (McEwen, 2007).

Though we know relatively little about how stressors experienced during adolescence influence the immediate and long-term structure and function of the brain, many factors may converge during this stage of development that might make the adolescent brain particularly vulnerable to stressors. First, recent longitudinal structural-neuroimaging studies have indicated that the areas known to be the most sensitive to stress in adulthood, namely, the hippocampus, prefrontal cortex, and amygdala, all continue to mature during adolescence (Giedd & Rapoport, 2010). Second, the adolescent brain may be more responsive than the adult brain to glucocorticoids, given that a previous animal study indicated that an equivalent dose of corticosterone increased gene expression to a greater degree in the adolescent compared with adult hippocampus (Lee, Brandy, & Koenig, 2003). Finally, because of the increases in hormonal stress reactivity described above, it would appear that these maturing and exquisitely stress-sensitive brain regions in the adolescent would be exposed to greater and more prolonged levels of glucocorticoids. Thus, like a “perfect storm,” the convergence of these factors may render the adolescent brain especially vulnerable to perturbations and, hence, psychological morbidities (Romeo & McEwen, 2006).

Unfortunately, there is a scarcity of studies that have directly compared the effects of stress on the adolescent and adult brain and fewer that have tracked whether these effects are more enduring if the stressors occur during adolescence. Thus, support for the notion that the adolescent brain may be particularly sensitive to stress has yet to be thoroughly tested empirically. A growing body of research, however, has begun to report on the effects of acute and chronic stress exposure on the structure and function of the adolescent brain. Studies in young adult rats indicated that previous exposure to chronic stress during adolescence resulted in reduced structural plasticity in the hippocampus and prefrontal cortex and increased plasticity in the amygdala (Eiland, Ramroop, Hill, Manely, & McEwen, 2012; Isgor, Kabbaj, Akil, & Watson, 2004). Additional animal studies using models of social stress (e.g., social instability, isolation) during adolescence have also indicated decreases in markers of neural plasticity, such as neurogenesis and synaptic connectivity (Leussis & Andersen, 2008; McCormick, Nixon, Thomas, Lowie, & Dyck, 2010). These stress-induced alterations in the adolescent brain are also associated with compromised emotional function and cognitive skills (Eiland et al., 2012; Isgor et al., 2004; Leussis & Andersen, 2008).

Although from these data it would seem that the impact of chronic stress on the adolescent and adult brain is similar, one important difference may be in the reversibility of these effects. Specifically, even a month after recovery from chronic adolescent stress, some of these structural and functional changes persist (Isgor et al., 2004; Leussis & Andersen, 2008). It would therefore appear that the effects of stress on the adolescent brain may be longer lasting when compared with the adult. Future experiments will need to directly assess this possibility, as well as explore whether there are other unique effects of stress on the structure and function of the adolescent brain.

Conclusions

The data reviewed above clearly indicate that adolescence is a time of dramatic changes in HPA function and stress responsiveness. Adolescence is also a significant period of continued neural maturation, specifically within stress-sensitive limbic and cortical regions. Thus, it is possible that prolonged or repeated exposure to stress may result in a heightened sensitivity to these stressors, ultimately leading to maladaptive neurobehavioral development. Though the physiological and psychological implications of stress on the adolescent brain are far from clear, the increases in stress-related dysfunctions during adolescence, such as anxiety, depression, schizophrenia, and drug abuse, highlight the importance of a better understanding of the interaction between changes in stress reactivity and adolescent brain development.

Recommended Reading

Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434–445. A highly accessible review on the impact of stress on the prenatal, neonatal, adolescent, adult, and aged brain.

McCormick, C. M., Mathews, I. Z., Thomas, C., & Waters, P. (2010). Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models. Brain and Cognition, 72, 73–85. A more extensive review than the one presented here on the effects of adolescent stress, particularly on behavior.

McEwen, B. S. (2007). (See References). A thorough review on HPA physiology and the influence of stress on the structure and function of the brain.

Romeo, R. D. (2010b). (See References). This review provides greater detail of HPA changes during pubertal and adolescent maturation.

Spear, L. P. (2000). The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews, 24, 417–463. An extensive and accessible review on the adolescent maturation of brain and behavior.