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Published in final edited form as: Child Dev Perspect. 2021 Aug 24;15(4):249–256. doi: 10.1111/cdep.12429

The Pubertal Stress Recalibration Hypothesis: Potential Neural and Behavioral Consequences

Carrie E DePasquale 1, Max P Herzberg 2, Megan R Gunnar 3
PMCID: PMC8680280  NIHMSID: NIHMS1731146  PMID: 34925549

Abstract

Recent research has suggested that the pubertal period provides an opportunity for recalibrating the stress-responsive systems in youth whose responses to stress have been altered by early adversity. Such recalibration may have cascading effects that affect brain and behavioral development. In this article, we consider a large, cross-species literature to demonstrate the potential importance of pubertal stress recalibration for understanding the development of psychopathology following early deprivation by caregivers. We review the evidence for recalibration of the hypothalamic-pituitary-adrenal axis in humans, examine research on rodents that has established mechanisms through which stress hormones affect brain structure and function, and summarize the literature on human neuroimaging to assess how these mechanisms may translate into changes in human behavior. Finally, we suggest ideas for elucidating the consequences of pubertal stress recalibration that will improve our understanding of adaptive and maladaptive adolescent behavior following early adversity.

Keywords: pubertal stress recalibration, early life stress, cortisol

Events that threaten the physical or social self, or anticipation of such events, activate physiological systems that serve defensive functions, increasing chances of survival. The body’s response to threat aims to achieve allostasis, or the maintenance of stability (i.e., functioning), through activation of stress-mediating systems (McEwen, 2000). Mammals have two core stress systems: the hypothalamic-pituitary-adrenocortical (HPA) system, with its primary glucocorticoid end product (cortisol in humans and corticosterone in rodents), and the sympathetic-adrenomedullary system and accompanying norepinephrine system in the locus coeruleus. Successfully activating these systems allows adaptation to immediate and future environments, while failing to maintain stability in response to environmental threats can lead to maladaptive outcomes. How environmental conditions shape these systems is critical to understanding the development of psychopathology, particularly following early adversity.

Studies with rodents have provided valuable insight into the malleability of stress-responsive systems, including strong evidence of a sensitive period, roughly equivalent to the third trimester of pregnancy and the first months of life in humans, for establishing set points for the reactivity and regulation of the HPA system (Lupien et al., 2009). Along with emerging longitudinal evidence in humans, rodent models suggest the possibility of a second time of heightened plasticity during the peripubertal period, when the HPA system can recalibrate, provided the level of physical and social threats in the environment has changed from the earlier sensitive period (Francis et al., 2002; Gunnar et al., 2019). Similar patterns have not been found for the sympathetic-adrenomedullary system, though no published work has investigated this question.

Plasticity in the HPA system can result in multiple stress response profiles (Gunnar & Reid, 2019). According to the pubertal stress recalibration hypothesis, a harsher environment during the pubertal period than in infancy may establish a hyper- or hypofunctioning HPA system. Alternatively, if the environment was harsh in infancy but is more benign during puberty, the HPA system might recalibrate to functioning more typical of a pup or child who encountered supportive conditions from infancy through puberty (see Figure 1). While the latter scenario may imply an improvement in other domains of psychosocial functioning like mental health, recent evidence suggests that this may not always be the case (Perry et al., 2020).

Figure 1. Hypothesized Pubertal Stress Recalibration Patterns in Human Youth as a Function of Early and Peripubertal Environments.

Figure 1

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The hypothesized acute stress recalibration (a) and hypothesized diurnal recalibration (b) among individuals with histories of threatening early environments who transition to nonthreatening adolescent environments.

From Gunnar & Reid, 2019 (p. 106)

In this article, we review evidence supporting the pubertal stress recalibration hypothesis in both rodents and humans, and examine rodent models that may elucidate the mechanisms and consequences of pubertal stress recalibration. We then outline neural studies in humans that may shed light on how pubertal stress recalibration could affect the brain and how these effects are related to changes in psychosocial functioning in puberty and into adulthood. Finally, we suggest a few areas for research to understand more fully the mechanisms and consequences of pubertal stress recalibration in humans.

Rodent Models of Pubertal Stress Recalibration

Initial evidence for the pubertal stress recalibration hypothesis came from rodent studies showing that stressors during the peripubertal period had a more prolonged impact on HPA axis reactivity than did the same stressors in adulthood (Romeo, 2018). Additionally, rats exposed to stressors prior to fear conditioning displayed fear learning that took longer to extinguish if encountered in the peripubertal period than in adulthood, thus extending heightened peripubertal stress sensitivity to other threat-defensive systems (Barbayannis et al., 2017). Chronic deprivation of maternal care in the form of low levels of licking and grooming during the neonatal period results in a hyperresponsive HPA system later in the rodent’s life (e.g., Liu et al., 1997). However, environmental enrichment during the peripubertal period reverses these effects (Francis et al., 2002) in a way that continuous adaptations and readaptations of stress systems throughout the juvenile period may not (e.g., Del Giudice et al., 2011).

Evidence of Recalibration in Humans

Corroborating these studies with rodents, children who spent their first two years in crowded orphanages showed altered cortisol stress responses (Koss et al., 2016) that lasted for years after they were placed in stable families (McLaughlin et al., 2015). In humans (Koss et al., 2016) and monkeys (Capitanio et al., 2005), the result of deprivation by caregivers in infancy seems to be a blunting of the HPA axis, although not necessarily of the extrahypothalamic corticotropin-releasing hormone (the main central releasing hormone of the HPA axis) system. In fact, chronic stress early in life has been associated with higher corticotropin-releasing hormone and lower cortisol levels in nonhuman primates (Coplan et al., 1996). These changes are likely adaptive: Increased corticotropin-releasing hormone in the amygdala may allow for enhanced fear conditioning, while decreased activity in the HPA axis may help protect the developing brain from high levels of glucocorticoids.

Unlike initial studies investigating pubertal recalibration, which focused on the cortisol-awakening response across puberty in youth with histories of early adversity (e.g, Leneman et al., 2018), the pubertal stress recalibration hypothesis is more focused on HPA reactivity to stressors. Some evidence suggests that the HPA axis becomes more reactive to stressors over puberty (Gunnar et al., 2009), at least when those stressors involve performance tasks like the Trier Social Stress Test (Stroud et al., 2009).

We tested the pubertal stress recalibration hypothesis with youth who were previously institutionalized and who started life in harsh and often unsupportive conditions but then were adopted into highly resourced and generally supportive homes; a group of never-institutionalized youth raised in their biological families were included as a comparison group. We used an accelerated longitudinal design, with children entering the study at 7 to 15 years and seen three times annually. At each visit, we conducted the Trier Social Stress Test and a nurse conducted an exam for pubertal staging. Analyzing the first session for each participant, we saw a pattern suggestive of recalibration (DePasquale et al., 2019). When the results were examined longitudinally, HPA reactivity to the Trier Social Stress Test increased in association with within-individual increases in pubertal stage, but only for the previously institutionalized youth. HPA reactivity transitioned from very hyporesponsive for previously institutionalized youth at the earliest stages of puberty to reactivity that did not differ from never-institutionalized youth by the later stages of puberty (see Figure 2; Gunnar et al., 2019). Model results also suggested that the pattern of recalibration was largely consistent across participants, not driven by a few individuals. We found no sex differences in the study, nor were there any in the human recalibration studies cited earlier.

Figure 2. Model-Implied Results of Pubertal Recalibration of Acute Stress Responses in Postinstitutionalized Compared to Nonadopted Youth by Pubertal Stage.

Figure 2

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For clarity, the data were collapsed across multiple data points per participant in the accelerated longitudinal design. For a more detailed description of the results, see Gunnar et al., 2019.

From Gunnar et al., 2019 (p. 23987)

The mechanism that leads to this recalibration is unclear. In our analysis of cortisol reactivity to the Trier Social Stress Test, we began to see recalibration in the initial stages of puberty. This raised the possibility that dehydroepiandrosterone (DHEA), an androgen that facilitates early pubertal change, might play a role (Dorn & Biro, 2011). Typically, DHEA and cortisol are correlated, but in children who have experienced early life adversity, they are not. In another study from our sample of previously institutionalized youth, as the HPA axis recalibrated, the correlation with DHEA increased for youth with a history of early adversity (Howland et al., 2020). Results were similar for another research group examining the correlation of DHEA with cortisol in youth with and without a history of early adversity using saliva samples obtained immediately after waking in the morning (King et al., 2020). However, DHEA levels did not differ between previously institutionalized and comparison youth. Since DHEA and cortisol are both released from the adrenal cortex via adrenocorticotropic hormone, this may suggest that pubertal stress recalibration occurs via changes in adrenal cortisol production and not at higher levels of the HPA axis.

This evidence suggests that, for children who have experienced severe deprivation in infancy but had a supportive caregiving environment during puberty, the HPA axis becomes more similar to that of children who were not exposed to early deprivation. Some evidence suggests that increasing HPA reactivity across puberty predicts rises in self-reported internalizing symptoms for previously institutionalized but not for never-institutionalized youth (Perry et al., 2020). This is consistent with prior research that has indicated an increase in emotional problems during adolescence in previously institutionalized youth that is greater than that observed in youth with little evidence of adverse care early in life (Wade et al., 2018). However, more research is needed to draw firm conclusions. For example, the mechanisms underlying recalibration remain unclear, as does the question of whether recalibration is unique to previously institutionalized youth. Understanding how these relatively rapid changes in HPA activity affect related neural systems and whether these neural changes help explain increases in psychosocial problems observed in youth exhibiting pubertal stress recalibration are important next steps in research on early life stress.

Insights From Rodent Models About Consequences of Pubertal Recalibration

Stress and glucocorticoid production affect the future production and release of hormones and neurotransmitters in the HPA axis as part of a negative feedback loop (Lupien et al., 2009). Pubertal stress recalibration may further alter these upstream hormones, neurotransmitters, glucocorticoid receptors, and neuronal structure due to changes in HPA activity over the pubertal transition. For example, rodent models reveal decreased volumes in the hippocampus and prefrontal cortex in response to high levels of glucocorticoids (Chattarji et al., 2015). The reduced volume is due to a reduction in dendritic spine density, a consequence of exposure to stress hormones and a possible contributor to hippocampal cell death (Conrad et al., 2007). Conversely, basolateral amygdala volume may increase (due to increased dendritic spine density) following acute and chronic HPA activation. These changes are facilitated by several processes, including alterations in brain-derived neurotrophic factor expression, N-methyl-D-aspartate receptor activity, and long-term potentiation (Chattarji et al., 2015).

Glucocorticoids have also been implicated consistently in neuroplasticity. Corticosterone regulates synaptic plasticity in the hippocampus (Peters et al., 2018), reduces the number of dendritic spines on neurons in the cortex, and can result in increased rates of neuronal cell death, leading to smaller brain volumes (Sousa & Almeida, 2012). As noted earlier, the effect of corticosterone in the amygdala is roughly opposite of the effect of it in the hypothalamus and frontal cortex, resulting in greater dendritic length (Mitra & Sapolsky, 2008). Thus, corticosterone is an important regulator of brain plasticity, delineating key mechanisms through which chronic stress alters neural structure and function.

Two types of glucocorticoid receptors may affect brain structure and function differently. Mineralocorticoid receptors are expressed in the hippocampus, amygdala, prefrontal cortex, and paraventricular nucleus of the hypothalamus, and are more likely to bind to (have stronger affinity for) glucocorticoids. In contrast, glucocorticoid receptors are expressed throughout the brain but are less likely to bind to (have lower affinity for) glucocorticoids. As a result of these differences in binding, mineralocorticoid receptors tend to be occupied by glucocorticoids in the brain even when the levels of circulating glucocorticoids are low, while glucocorticoid receptors are occupied more often when glucocorticoid concentrations are high (Joels & Baram, 2009). Substantial evidence suggests that mineralocorticoid receptors generally support plasticity (Pavlides et al., 1996), while glucocorticoid receptor-related mechanisms are responsible for some of the stress effects on the brain (Avital et al., 2006). Some evidence suggests that activation of the mineralocorticoid receptor can reverse the effect of glucocorticoid receptor activation on neuron cell death (Crochemore et al., 2005). However, glucocorticoid receptors may also support longer-term adaptive processes like regulating HPA activity and the consolidation and storage of contextual memory (de Kloet et al., 2018).

Given the reciprocal actions of glucocorticoids bound to mineralocorticoid receptors and glucocorticoid receptors, it is theorized that the balance of mineralocorticoid/glucocorticoid receptor expression and activation, in combination with HPA axis activity, is key to understanding the complex effects of glucocorticoids on the brain (de Kloet et al., 2018). Specifically, increased mineralocorticoid receptor relative to glucocorticoid receptor expression/activation generally supports adaptive synaptic plasticity while buffering against glucocorticoid receptor-mediated reductions in plasticity in the hippocampus and amygdala (de Kloet et al., 2018; Liu et al., 1997; Mitra et al., 2009). Although equating mineralocorticoid receptor-related mechanisms with adaptive outcomes and glucocorticoid receptor-related mechanisms with maladaptive outcomes is too simplistic, evidence suggests that higher levels of mineralocorticoid receptors in the basolateral amygdala can protect against anxiety- and depressive-like behaviors in rodents (Mitra et al., 2009).

Consistent with these findings on anxiety- and depressive-like behaviors, rodent models of maternal care show that early caregiving experiences alter mineralocorticoid receptor and glucocorticoid receptor density and glucocorticoid production. Specifically, rodent models of better caregiving have shown increased numbers of mineralocorticoid and glucocorticoid receptors, lower stress hormone production, and stronger HPA axis regulation in adulthood (Champagne et al., 2008; Liu et al., 1997). Because glucocorticoids are more likely to bind to mineralocorticoid receptors than to glucocorticoid receptors, lower glucocorticoid production and increased mineralocorticoid and glucocorticoid receptor expression would imply a higher ratio of mineralocorticoid/glucocorticoid receptor activation (more mineralocorticoid receptor binding and relatively less glucocorticoid receptor binding). Thus, early caregiving experiences may affect psychopathology through changes in glucocorticoid production, as well as through mineralocorticoid/glucocorticoid receptor expression and activation.

Neural Correlates of Early Life Stress, Cortisol, and Psychopathology in Adolescence

Like physiological stress systems, brain structure and function are altered by experiences of early life stress. Adolescence is a period of heightened neuronal plasticity in which hormones play a role in pubertal remodeling of the brain (Spear, 2013). Whether stressful experiences or supportive conditions during the peripubertal period exert greater impacts on the human brain than similar experiences in late childhood or adulthood is unknown. Some emerging evidence suggests that supportive experiences in adolescence are relatively more impactful than the same experiences earlier in middle childhood, based on behavioral functioning of youth who experienced early deprivation in institutions (Wade et al., 2018). In this article, we focus on differences in brain structure and function between previously institutionalized and never-institutionalized youth because research investigating brain structure and function following institutional care has reported meaningful associations with adolescent behavior, providing a road map for future research.

A substantial body of research has established structural differences in the brain following early institutional care. Smaller brain volumes in previously institutionalized than in never-institutionalized youth have often been reported in the amygdala, hippocampus, and prefrontal cortex (though evidence is mixed in the amygdala; for a brief review, see Gunnar & Reid, 2019). While many factors (e.g. nutrition, parasites and illness, stimulus deprivation) may contribute to these effects, each of these regions expresses mineralocorticoid and glucocorticoid receptors (Joels & Baram, 2009), emphasizing the potential role for cortisol concentrations in shaping neural structure. Structural connectivity, assessed via diffusion tensor imaging, also differs as a result of early caregiver deprivation (Hanson et al., 2013).

Studies of brain function following institutional care have reported that youth have elevated amygdala activity when viewing emotional images (e.g., Tottenham et al., 2011), though this has not always been observed (Silvers et al., 2017). Furthermore, on average, previously institutionalized youth do not show differentiated amygdala responses to their adopted mother’s face compared to a stranger’s face, while never-institutionalized youth do (Olsavsky et al., 2013). However, those previously institutionalized children and youth who do show decreased amygdala signal in response to a parent’s face have large reductions in anxiety over time (Callaghan et al., 2019), emphasizing the importance of amygdala activity in healthy outcomes following early caregiver deprivation.

A similar focus on the amygdala has been central to studies of functional connectivity following institutional care. One study reported accelerated maturation of the functional connectivity of the amygdala to the medial prefrontal cortex in previously institutionalized youth, compared to never-institutionalized youth, during an emotional faces task (Gee et al., 2013). The relation between caregiver deprivation and amygdala connectivity was significantly mediated by cortisol levels following a magnetic resonance imaging scan, suggesting that alterations in cortisol may contribute to different patterns of functional connectivity following early caregiving deprivation. Amygdala functional connectivity in previously institutionalized youth was also associated with separation anxiety (Gee et al., 2013). Consistent with these findings, altered resting-state functional connectivity in the dorsal attention network has also been associated with internalizing symptoms in previously institutionalized youth compared to never-institutionalized youth (Herzberg et al., 2021). These behavioral differences associated with changes in brain function are consistent with the associations between stress physiology and behavior discussed earlier, particularly increased levels of internalizing as a function of cortisol reactivity.

Cross-Species Implications of Pubertal Stress Recalibration

Together, studies of animals and humans that have examined early caregiver deprivation, stress physiology, and brain structure and function suggest an important role for pubertal recalibration in development following early adversity. Chronic early life stress may downregulate not just cortisol production (Koss et al., 2016; McLaughlin et al., 2015), but also mineralocorticoid/glucocorticoid receptor expression, as suggested by studies of rodents (Champagne et al., 2008). Then, if the caregiving environment is significantly more supportive during puberty, the HPA axis is recalibrated, resulting in increased cortisol production similar to that of peers who did not experience the same level of early life stress (Gunnar et al., 2019). However, if mineralocorticoid/glucocorticoid receptor expression in the brain is still downregulated due to the chronically low production of cortisol following institutional care, this increase in cortisol reactivity may result in an increased neural response to stressors. If consistent with rodent models (e.g. Mitra et al., 2009; Park et al., 2017), this shift to more “normative” levels of cortisol response to stressors could increase risk for internalizing psychopathology rather than protect against it (Perry et al., 2020).

Accompanying these changes in stress physiology are alterations to brain structure and function, which are consistent with mechanistic findings in research on animals and may also exhibit effects of pubertal recalibration. Recent research has implicated early caregiver deprivation in altered patterns of brain function associated with internalizing symptoms (Herzberg et al., 2021), consistent with research on rodents and humans that has implicated increased internalizing with increased cortisol reactivity. In addition, despite several findings specific to anxiety in the studies on previously institutionalized youth, the well-documented effects of cortisol on hippocampal structure (McEwen et al., 2015) and the robust association between smaller hippocampus volume and depression (Santos et al., 2018) suggest that more research is needed to address diagnostic specificity. Additional mechanistic research is also needed to provide support for the biobehavioral associations reviewed earlier, rule out other normative mechanisms of the adolescent period, and elucidate further benefits and consequences of pubertal stress recalibration.

Looking Ahead

Given the evidence we have reviewed here, the effects of pubertal stress recalibration could extend to the brain, altering neural structure and function in ways that influence adolescent behavior. However, where studies on humans need to focus next is less clear. For example, given the physiological and behavioral findings from our recent studies of previously institutionalized youth, pubertal recalibration of the HPA axis may exert effects on the brain that increase rather than reduce differences in emotional problems between these youth and never-institutionalized youth. Determining whether the increases in internalizing symptoms associated with pubertal stress recalibration persist across development is an important next step, as is directly assessing the potential of brain structure and function to mediate this relation. Research on early life stress in other populations is also needed to establish the specificity (or lack thereof) of early institutional care as a predictor of pubertal stress recalibration. Meanwhile, neurobiological mechanisms require elucidation to understand fully the possibility of adolescence as a second window of plasticity in humans.

Recent efforts have highlighted the need to identify sensitive periods in development in cross-species research, particularly as they relate to stress responses and the development of psychopathology (Luby et al., 2020). To this end, studies of rodent models that investigate sensitive periods for environmental influences on mineralocorticoid and glucocorticoid receptor density may shed light on the possible mechanisms driving increases in internalizing symptoms during pubertal stress recalibration and highlight particular circuits to interrogate in subsequent research. Furthermore, research on rodents has often used restraint stress paradigms to study the effects of early life stress on later behavior and stress physiology. However, chronic variable stress paradigms are likely more analogous to the human experiences prevalent in research on early life stress. Using these methods in a rodent model that specifically examines pubertal stress recalibration would be an important step forward for cross-species research on early life stress.

The HPA axis is only one of the systems likely involved in altered behavior, stress physiology, and neural plasticity during adolescence. We have focused on it here because it has been the focal variable in pubertal stress recalibration findings, but research on the actions of other stress-responsive systems and their interactions with the HPA axis is critical to fully understand puberty as a second window of plasticity in human development. Building a more complete understanding of the mechanisms related to pubertal stress recalibration, and the behavioral alterations that accompany it, is a crucial step toward further elucidating the developmental trajectories from early life stress to the development of psychopathology during adolescence.

Acknowledgments

The writing of this article was supported by the National Institutes of Health, grants R01 HD095904 (MRG), T32 MH015755 (CED), T32 MH100019, and TL1 TR002493 (MPH); the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.

Contributor Information

Carrie E. DePasquale, University of Minnesota.

Max P. Herzberg, Washington University School of Medicine.

Megan R. Gunnar, University of Minnesota.

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