Stress resilience as a consequence of early-life adversity

C H A P T E R

11 Stress resilience as a consequence of early-life adversity Jakob Hartmann1, Mathias V. Schmidt2 1

McLean Hospital e Harvard Medical School, Mailman Research Center, Neurobiology of Fear Laboratory, Belmont, MA, United States; 2Max Planck Institute of Psychiatry, Munich, Germany

Introduction Living in Western societies seems to become ever more unpredictable and uncontrollable, and therefore people are being exposed to substantial stressors throughout their lives. In parallel, there is a growing awareness that stress exposure can be harmful and promote a variety of diseases (de Kloet et al., 2005). As a consequence, stress has been labeled the “bad guy,” and the response to stress is often seen as maladaptive. However, it should be considered that humans evolved in a highly unpredictable and uncontrollable environment and that life during the millennia of human evolution was unlikely to be less stressful than it is today. It is therefore not surprising that even today most people are highly resilient in the face of adversity and, despite continuous exposure to a multitude of stressors, stay healthy until old age. But what differentiates individuals that suffer from stress exposure from those that are resilient? In this chapter, we will discuss evidence that suggests the answer to this question may lie in the developmental history and the interplay of experiences early and later in life.

Early-life stressddefinition of the term Before discussing the consequences of early adversity, one has to clearly define what exactly is meant by “early” and how “adversity” or “stress” is defined. For the purpose of the chapter, the early-life period will be considered to cover the prenatal and postnatal period until adolescence, both in animals and in humans. It is clear that the developmental trajectory of mice and humans is quite different depending on the physiological system or brain circuit of interest (Rice and Barone, 2000; Semple et al., 2013). However, overall, it is well accepted that during

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phases of intense brain development, the organism is most sensitive to environmental stimuli that can lastingly affect the individual (Chen and Baram, 2016; Yam et al., 2015). The term “stress,” on the other hand, is here defined in the sense of unpredictable and uncontrollable adversity, rather than a challenge to body’s homeostasis per se. Here, we are following the arguments laid out by Koolhaas and colleagues, arguing that especially the unpredictable and uncontrollable nature of a challenge is of the essence when interpreting stress in the context of disease or disease risk (Koolhaas et al., 2011).

Early-life stress is a risk factor for psychiatric disorders Stress and traumatic events are well-established risk factors for various pathologies including cardiovascular disease, obesity, diabetes, alcohol and drug abuse, and most prominently psychiatric diseases such as mood and anxiety disorders. Many epidemiological studies strongly support an association of adverse life events particularly during childhood, with increased susceptibility to develop psychopathology later in life (Lupien et al., 2009; Nemeroff, 2016; Kim and Cicchetti, 2006; Larkin and Read, 2008; Weber et al., 2008). More precisely, early-life stress, defined as neglect, physical abuse, sexual abuse, and emotional maltreatment, has been associated with an increased prevalence of depressive disorders such as major depressive disorder (MDD) (Goldberg, 1994; Chapman et al., 2004; Kaufman, 1991; Widom et al., 2007; Scott et al., 2010; Benjet et al., 2010; Maniglio, 2010; Teicher et al., 2006; Anda et al., 2002; Green et al., 2010; Danese et al., 2009), bipolar disorder (Anda et al., 2007; Gilman et al., 2015; Daruy-Filho et al., 2011; Agnew-Blais and Danese, 2016), and with increased rates of anxiety disorders including general anxiety disorder and panic disorder (Copeland et al., 2013; Scott et al., 2010; Green et al., 2010; Cougle et al., 2010). In addition, a history of childhood maltreatment has been linked to subsequent development of posttraumatic stress disorder (PTSD) (Duncan et al., 1996; Widom, 1999; Cabrera et al., 2007; Fritch et al., 2010; Scott et al., 2010) and to an increased risk for suicide attempt (Felitti et al., 1998; Dube et al., 2001; Maniglio, 2011). Notably, psychiatric disorders tend to emerge earlier in previously maltreated individuals, with greater severity, higher comorbidity rates, and with a less favorable response to treatment (Nanni et al., 2012; Alvarez et al., 2011; Leverich et al., 2002; Widom et al., 2007; Benjet et al., 2010). All of this suggests that childhood adversity can lay a fragile foundation for health across the life span.

Early-life stress shapes adult phenotypes Although the exact molecular mechanisms underlying the effects of early-life stress are not fully understood, there is strong evidence for an impairment of the hypothalamic-pituitaryadrenal (HPA) axis (Lupien et al., 2009). In response to stressful stimuli, circulating glucocorticoids (GCs), which are the main hormonal endpoint of the HPA axis, act on numerous organ tissues to execute a wide range of functions involving the immune, digestive, and endocrine systems and including the regulation of the negative feedback of the stress response mostly at the level of the hypothalamus and pituitary (de Kloet et al., 2005). GCs also affect the morphology and

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functionality of central nervous system target tissues, including those responsible for mood and cognitive functions relevant to psychiatric disorders (Abercrombie et al., 2011; de Quervain et al., 2003; Karst et al., 2002; Mitra and Sapolsky, 2010; Hartmann et al., 2017; Gershon, Sudheimer, Tirouvanziam, Williams and O’Hara, 2013; Barik et al., 2013; Tronche et al., 1999; Gass et al., 2001; Anacker et al., 2011). In fact, various types of early-life stress can alter HPA responsiveness and regulation. For instance, HPA axis hyperactivity has been documented in depressed individuals as a consequence of childhood adversity associated with social, physiological, and pharmacological stressors (Heim et al., 2000, 2002; Heim et al., 2001; Heim et al., 2008; Carvalho Fernando et al., 2012). In contrast, other studies point to blunted HPA axis activity, both in healthy subjects and in individuals with mood disorders or PTSD following early-life adversity (Ouellet-Morin et al., 2011; Carpenter et al., 2009; Carpenter et al., 2011; King et al., 2001). Thus, the direction and pattern of such HPA alterations may depend not only on various factors including, but not limited to, the nature and timing of the stressor, and severity and number of traumatic events, but also on genetic and epigenetic markers. It is indisputable that not all individuals who are exposed to early-life adversity will develop psychiatric pathology later in life. So what makes some individuals more susceptible to early-life adversity than others? It is well established that stress-related psychiatric disorders such as PTSD and MDD often originate from gene-environment interactions. Besides genetic variants (e.g., risk alleles), epigenetic modifications, such as histone modifications and DNA (de-)methylation, are thought to mediate long-lasting effects of adverse life events on gene regulation by shaping the transcriptional activity of genes without changing the underlying genetic code (Klengel and Binder, 2015; Pena et al., 2014). These molecular changes induce long-lasting alterations in gene expression and ultimately behavior. Thus, specific genetic and epigenetic markers may moderate the effects of early adversity on later psychopathology. By studying a single nucleotide polymorphism (SNP) within the gene encoding the FK506 binding protein 51 (FKBP51), Klengel et al. (2013) present compelling evidence for an epigenetic mechanism mediating gene  environment interactions that ultimately results in an increased risk to develop stress-related psychiatric disorders. FKBP51 participates in inhibition of glucocorticoid receptor (GR) activity, which is the main mediator of the HPA axis. At the same time, GR activation is involved in the induction of FKBP51 transcription, creating an intracellular, ultrashort feedback loop that regulates GR sensitivity (Wochnik et al., 2005; Touma et al., 2011; Hartmann et al., 2012; Binder, 2009). Klengel et al. elegantly showed that a functional SNP altering chromatin interaction between the transcription start site and longrange enhancers in the FKBP51 gene increases the risk of developing stress-related psychiatric disorders in adulthood through allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP51. This demethylation was associated with increased stress-dependent gene transcription followed by a long-term dysregulation of the HPA axis (Klengel et al., 2013). Along these lines, there is a large body of literature linking other genetic risk factors with increased vulnerability to early-life stress, including SNPs in 5-HTT, PACAP, PAC1, Nr3c1, and Crhr1 (Tyrka et al., 2016; Bradley et al., 2008; Caspi et al., 2003; Ressler et al., 2011). Interestingly, Arloth et al. (2015) showed that different sets of genetic variants may be involved in baseline transcriptional regulation versus regulation following environmental impact, such as trauma exposure.

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In addition to HPA axis dysregulation and specific genetic/epigenetic risk factors, there is increasing evidence for persistent structural and functional consequences of adverse early-life events on specific brain structures and circuits. Indeed, MRI-based studies revealed decreased connectivity between the amygdala and insula/hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), as well as between the hippocampus and vmPFC in individuals with a history of childhood maltreatment (van der Werff et al., 2013; Burghy et al., 2012; Herringa et al., 2013). Structural variations in the prefrontal cortex have also been shown to mediate the relationship between early childhood stress and spatial working memory (Hanson et al., 2012). Moreover, previous work has repeatedly shown that hippocampal atrophy in depressed patients is associated with a history of early-life stress (Vythilingam et al., 2002; Buss et al., 2007; Frodl et al., 2010). This raises the question whether psychiatric disorders that are linked to early-life stress occur in response to epigenetic and/or gene expression changes in specific brain circuits. Despite the presented examples, the effects of early-life stress on psychopathology in adulthood remain a challenging process to study in humans. Some of the major difficulties are the duration of such studies, the genetic diversity of humans as well as biases in the perception and reporting of early adversity. Preclinical studies using rodent models have been helpful and crucial in improving our basic knowledge about the consequences of adverse events during development on psychopathology later in life. Such models can offer better control over genetic backgrounds (e.g., inbred strains), onset, type and intensity of stressors and provide much shorter study times. Nevertheless, it is important to note that stress-related psychiatric disorders represent very complex diseases, making it impossible to model certain symptoms in rodents, for example, features of MDD (e.g., feelings of guilt, low self-esteem, or suicidality). However, other core aspects such as anhedonia, loss of motivation, sleep disturbances, anxiety, cognitive deficits, and a dysregulation of the HPA axis do have equivalents in rodents. Thus, it is possible to reach a certain level of face validity with such animal models. Various rodent early-life stress paradigms have been developed in the past. Maternal separation, models based on naturally occurring differences in maternal care, impoverished postnatal environment as well as pharmacological approaches rank among most frequently used. Numerous studies with rats have linked early maternal separation with lifelong neuroendocrine alterations, changes in HPA axis activity, and anxiety-related behavior (Ladd et al., 1996; Rots et al., 1996; Sutanto et al., 1996; Workel et al., 2001; Workel et al., 1997; Suchecki et al., 2000; Kalinichev et al., 2002; Benekareddy et al., 2011). Another model that is based on individual differences of maternal care was first introduced by the group of Michael Meaney (Liu et al., 1997). In this paradigm, abnormal maternal care is defined as increased or decreased (one standard deviation above or below the group mean) licking, grooming, and/or arched-back nursing during the first 10 days of life. Liu et al. (1997) demonstrated that as adults, the offspring of mothers that exhibited more licking and grooming of pups (LG mothers) during the postnatal observation period showed reduced HPA axis responses to acute stress, increased hippocampal GR mRNA expression, and decreased levels of hypothalamic CRF mRNA. Strikingly, each measure was correlated with the frequency of maternal licking and grooming (Liu et al., 1997). In addition, Caldji et al. (1998) reported that individual differences in the frequency of maternal care during infancy regulate the

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development of neural systems mediating the expression of fearfulness in the rat. Interestingly, this paradigm also suggests that maternal effects may modulate optimal cognitive functioning in environments varying in demand in later life, with offspring of high and low LG mothers showing enhanced learning under contexts of low and high stress, respectively (Champagne et al., 2008). The limited nesting material paradigm was first introduced by the group of Tallie Baram. In this model, the mothers (rats and mice) are provided with a limited quantity of bedding and nesting material during postnatal day 2e9 (Ivy et al., 2008; Rice et al., 2008). This manipulation induces perturbed dam-pup interactions reflected in frequent changes of maternal behavior and inconsistent or fragmented maternal care, resulting in a higher stress exposure of the offspring. This adverse environment leads to elevated basal HPA axis activity, increased anxiety-related behavior, and impaired learning and memory functions in adult mice and rats (Rice et al., 2008; Ivy et al., 2008, 2010; Wang et al., 2012; Brunson et al., 2005). Other studies focus on the postnatal application of GCs such as the synthetic GC dexamethasone (Dex) to mimic an early-life stress exposure. Neonatal Dex treatment leads to altered HPA axis activity in response to stress in adolescent and adult rats (Flagel et al., 2002; Neal et al., 2004). Moreover, rats with early-life Dex exposure also show increased anxiety- and depression-like behavior later in life (Neal et al., 2004; Ko et al., 2014; Felszeghy et al., 1993). Again, many psychiatric disorders are caused by interactions between a (epi-) genetic predisposition and environmental factors. Thus, studies assessing the joint contribution of genetic and environmental factors in the etiology of mental disorders have become increasingly important in the field of psychiatry. Rodent models of early-life stress are often combined with additional genetic or environmental (risk) factors, for example, a specific genetic knockout or a second trauma/stress exposure later in life. Applying such experimental designs, corticotropin-releasing factor (CRF) and its receptor, CRFR1 have been shown to modulate the negative effects of early-life stress on cognition and structural plasticity in mice (Wang et al., 2011). Along these lines, we were able to demonstrate that the cell adhesion molecule nectin-3 is required for the effects of CRFR1 on cognition and structural remodeling after early-life stress exposure (Wang et al., 2013). In another study, the limited nesting material paradigm led to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of the neuronal cell adhesion molecule neuroligin-2 in the hippocampus. Although hippocampal overexpression of neuroligin-2 in adult mice mimicked the early-life stresseinduced alterations, knockdown of neuroligin-2 in adulthood attenuated the early-life stresseinduced behavioral changes (Kohl et al., 2015). Recently, Peña and colleagues reported that mice subjected to a model of maternal separation were less resilient to chronic defeat in adulthood. In this study, they demonstrated that genes regulated by the transcription factor orthodenticle homeobox 2 (Otx2) in the ventral tegmental area (VTA) primed the response toward susceptibility in adulthood. Although transient juvenile knockdown of Otx2 in VTA mimics the effects of early adversity by increasing stress vulnerability, its overexpression reduces the effects of early-life stress (Pena et al., 2017). Although alterations in HPA axis activity as well as (epi-)genetic risk factors have been implicated in mediating the effects of early-life stress on later psychopathology, there is increasing belief that these changes may occur in a circuit-specific manner. Such circuitlevel framework has been extensively investigated in adult stress models. For example, the

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combination of optogenetic technology and chronic social defeat stress has identified important structural and functional alterations within the brain’s reward circuits that are associated with aspects of depression and addiction (reviewed in Russo and Nestler (2013); Han and Nestler, (2017); Sparta et. al., (2013)). However, studies focusing on circuit-specific changes in animal models of early-life stress are still largely lacking. Consequently, the utilization of novel technologies including optogenetics, chemogenetics, and diverse viral tools will be instrumental in identifying distinct neuronal populations and brain networks that are affected by early-life stress. Above we highlighted a number of pioneering human and preclinical studies on the complex subject of early-life adversity and its contribution to psychopathology in adulthood. Additional excellent examples are reviewed in Krugers et al. (2017); Nemeroff (2016); Schmidt (2010); Yam et al. (2015); Sandi and Haller (2015); Teicher et al. (2016). All of these studies underscore the ability of early-life stress to exert drastic effects on neurodevelopment and consequently impact health in adulthood. This occurs through interaction with genetic factors and/or reprogramming of the epigenome, which can induce changes in gene expression, cellular and synaptic function, circuit connectivity, and ultimately behavior.

What is the rationale for shaping adult phenotypes by early-life experiences? Although it is clear that adversity during early life has a lasting impact on an individual, the underlying rationale behind such a costly programming is often neglected. As the involved mechanisms of early-life programming have evolved over millennia and are conserved across species, it is likely that they serve an adaptive purpose. In this context, Ellis and Del Giudice proposed the adaptive calibration model (ACM) as an evolutionarydevelopmental theory of individual differences in stress responsivity (Del Giudice, Ellis and Shirtcliff, 2011; Ellis and Del Giudice, 2014). At its core, the ACM states that exposure to stress does not so much impair development per se but directs or regulates it toward strategies that are adaptive under similarly stressful conditions. As a consequence, the ACM suggests that under high-stress conditions animals adapt to a “fast lifestyle,” where, for example, heightened aggression (males) or enhanced vigilance increases individual fitness. Along the same lines, the ecologists Sheriff and Love have argued that the consequences of early-life stress exposure should be viewed under the broad concept of a life history perspective, both for the mother and the offspring (Sheriff and Love, 2013). Phenotypic traits following early-life adversity, for example, heightened anxiety, are not determining individual fitness per se but instead alter fitness upon interaction with the environment. A classic example is the predator-prey population cycle of snowshoe hares, where the maternal environment shapes the number and phenotype of the offspring in a highly adaptive fashion. Thus, the multiple examples of adverse early-life stress effects collected in both humans and animals as reviewed earlier may represent just one side of the coin and predominantly occur when early-life and adult-life environments do not match. This concept is especially relevant for psychiatric disorders, arguing that a mismatch of early-life and adult-life stress exposure might be the crucial risk factor for depression, rather than stress exposure per se (Schmidt, 2011). As the consequences of environmental stress exposure are directly related to the

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genetic susceptibility of an individual (Belsky et al., 2009; Belsky, 2016), one would expect that only individuals with a high (epi)genetic flexibility (environmental sensitivity) would thrive under matched environmental conditions, whereas for individuals with a lower environmental sensitivity, stress effects may be rather cumulative over time (Nederhof and Schmidt, 2012). It is important to point out, however, that there is a difference between the evolved, adaptive function of the stress response and apparent pathological consequences for the individual (Flinn et al., 2011). Thus, natural selection that favors evolutionary (reproductive) fitness may not maximize short-term physical and mental health. With these considerations in mind, the question arises of whether there is evidence from human or preclinical studies to support the match/mismatch hypothesis.

Evidence for the match/mismatch theory in humans Although few studies directly addressed the possibility that exposure to adversity early in life may enhance stress resilience in adulthood, there are still a number of examples where such an effect was indeed observed. Especially, exposure to moderate levels of early-life stress protects children from an overshooting HPA axis in response to the Trier Social Stress Test (TSST), compared with both severe and no early-life stress exposure (Gunnar et al., 2009). A very nice example for the beneficial effects of adversity even in healthy controls is the study from Seery and colleagues, who show that individuals with some lifetime adversity report better mental health and well-being outcomes than people with high or no lifetime adversity (Seery et al., 2010). Accordingly, healthy volunteers with a moderate history of lifetime adversity displayed less negative responses to pain and more positive psychophysiological responses compared with individuals with no or high history of lifetime adversity (Seery et al., 2013). Along the same lines, a history of moderate childhood adversity was shown to be associated with an enhanced capacity of emotional regulation that was also reflected in an active suppression of the activity in limbic brain circuits (Schweizer et al., 2016). Shapero et al. (2015) demonstrated that adolescents with a history of moderate stressful life events are significantly protected from depressiogenic effects of proximal stressful events (Shapero et al., 2015). In contrast, especially, individuals with mismatched childhood and recent stress levels have been shown to display abnormal resting state functional connectivity in pathways responsible for social and cognitive functioning (Paquola et al., 2017). Stress exposure can also still have adaptive consequences when it occurs later during development, especially during adolescence. For example, adults who are exposed to work stress as adolescents have been shown to exhibit fewer negative psychiatric health side effects from work-related stress as adults (Mortimer and Staff, 2004). Furthermore, adolescents with a history of early adversity were protected from a stress-induced increase in depression vulnerability as adults, if their attention style was categorized as highly flexible (Nederhof, 2013). Thus, people with a genetic background favoring fast and flexible adaptation benefit from matching environments early and late in life, even if both are stressful. Taken together, these examples demonstrate that early exposure to especially moderate levels of adversity may indeed facilitate the development of stress resilience, especially in individuals that are highly susceptible to environmental influences.

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Evidence for the match/mismatch theory in animal studies Although most studies in humans suffer from retrospective assessment of early-life adversity and high variability of environmental conditions, animal studies can be designed much more stringently and allow the exact control of environmental conditions. Unfortunately, most studies addressing a possible interaction of early-life and adult-life environments have not utilized a continuous exposure to moderate adversity but rather single exposures of mostly severe stressors over a short developmental period, with the majority of the developmental time consisting of standard housing without adversity. The consequent results are then often interpreted in the light of cumulative stress exposure or the two-hit hypothesis (Pena et al., 2017). An alternative explanation would be that these study designs enhance the mismatch situation of environmental conditions, as programming during the nonstress periods, which also takes place during potentially essential developmental phases, suggested a safe and stress-free environment. Nonetheless, there are still numerous examples in the preclinical literature that support the mismatch hypothesis and argue for an adaptive role of early adversity by enhancing stress resilience. Already the early and seminal work of Levine and colleagues suggested that moderate levels of stress exposure early in life may have beneficial effects when animals were exposed to threats in adulthood (Levine, 1959, 1962). Later on, Dienstbier (1989) proposed the concept of psychophysiological toughness, where defined and controllable adversity early in life fosters subsequent stress resilience. Even environmental enrichment during early life and adolescence can be viewed as form of chronic mild stress, resulting in stress inoculation and consequently resilience to stress exposure in adulthood (Crofton et al., 2015). Also more recently, these concepts could be confirmed and extended. For example, female Balb/C mice have been shown to be less affected by social isolation in adulthood when exposed to erratic maternal care because of limited nesting and bedding material following birth (Santarelli et al., 2014). Interestingly, these results were dependent on the estrous cycle phase the animals were tested in. Furthermore, early-life stress in the form of limited nesting and bedding material dampened the behavioral and endocrine response to chronic social stress in adolescence (Hsiao et al., 2016). Similarly, male mice exposed to the same earlylife stress paradigm displayed a heightened resilience to chronic social defeat stress in adulthood (Santarelli et al., 2017). Brockhurst et al. (2015) reported that experience of early chronic social stress reduced HPA axis activity and improved stress-coping and anxiety-like behavior following subsequent repeated restraint. Along these lines, prenatally stressed offspring are more likely to become subordinate in a social group as adulthood but are more resilient to that social status compared with offspring from nonstressed mothers (Scott et al., 2017). Beneficial effects seem also evident in combination with treatment, as, for example, lymphocytes from chronically stressed mice confer antidepressant-like effects to stress-naïve mice (Brachman et al., 2015), arguing that especially the immune system benefits from some form of stress inoculation early in life. There even seem to be transgenerational effects of early-life stress to promote a proresilient phenotype (Gapp et al., 2014). Stress exposure early in life also seems to be beneficial for cognitive performance, especially under challenging conditions. In rats, chronic unpredictable stress during adolescence was shown to improve foraging-related problem solving under high-threat conditions

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(Chaby et al., 2015). Along these lines, repeated social stress improves performance in an attentional set-shifting task (Chaijale et al., 2015). Furthermore, exposure to moderate peripubertal stress, where the effects of chronic mild stress were buffered by social partners in the home cage, was shown to result in an improved cognitive phenotype in aged female mice (Morrison et al., 2016). The molecular underpinnings that are responsible for the beneficial effects of moderate stress exposure for later stress resilience are far from understanding, and only a few studies have addressed this question. For example, Biggio et al. (2014) showed that maternal deprivation dampens corticosterone response to adult social isolation in rats, which was paralleled by not only hippocampal brain-derived neurotrophic factor (BDNF) expression. BDNF but also the depression risk factor SLC6A15 (Hyde et al., 2016; Kohli et al., 2011), which were also implicated as potential mechanism in the study by Santarelli et al. (2014) in female mice. Moreover, in another study, prenatal stress induced anxiety and HPA axis hyper-reactivity, which could be normalized by exposure to adolescent chronic mild stress, together with a normalization of hippocampal tryptophan hydroxylase 2 expression (Van den Hove et al., 2013). However, all of these findings are just correlational observations, and so far there is a clear lack of mechanistic studies that would shed some light on the causal relationships that lead to enhanced stress resilience following adversity during development.

Conclusions Taken together, there seems to be compelling evidence from human and animal studies that supports the match/mismatch hypothesis, while at the same time there are of course numerous reports that rather argue for a cumulative stress effect. Part of this apparent discrepancy can be explained by the different study designs, and as so often the devil is in the details. Most importantly, especially for animal studies, one has to consider the severity of the stressors and their chronicity. To trigger an adaptive long-term response, stressors likely need to be in the mild to moderate range and be present over developmentally meaningful time frames. If stress exposures are short (but severe) and interlaced with long periods of stress-free environments, successful adaptation is less likely. Finally, the genetic heritage of an individual will be decisive in their adaptive capacity to stress, so that some individuals will be more prone to suffer under chronic stress conditions, whereas others adapt and thrive (Fig. 11.1). It will be challenging to unravel the molecular and cellular mechanisms that determine this complex gene  early environment  adult environment interaction. One caveat in most of the current stress-related research is the limitation to only a few species and selected genetic backgrounds, which by itself limits the diversity and possible outcomes of stress exposure. However, these challenges can be overcome, and in the end a better understanding of the risks as well as the benefits of stress exposure will also advance our understanding of stress-related disorders and improve options of successful intervention.

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FIGURE 11.1

Schematic representation of two extremes in the reaction to early-life adversity. The black line represents a condition where the individual has a genetic background that is insensitive to environmental experiences and therefore prone to adverse cumulative effects of stress exposure. Consequently, such an individual would thrive under mild stress conditions and become more and more vulnerable to stress with higher levels of developmental stress exposure. The blue line represents the other extreme, namely an individual that has a high sensitivity to the environment. Such an individual would benefit from moderate stress levels during development and become stress resilient. In contrast, with no meaningful stress exposure during development, such an individual will have no chance to adapt its physiology to an adverse environment and will therefore be highly vulnerable to stress in adulthood. Severe early-life stress exposure is expected to be harmful under most circumstances, largely independent of the genetic background of an individual.

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