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How Environment “Gets Under the Skin”: The Continuous Interplay Between Biology and Environment

Nearly 20 years ago, the National Research Council published a landmark study on early childhood development, From Neurons to Neighborhoods: The Science of Early Childhood Development (National Research Council and Institute of Medicine, 2000). At a time when public discussion of child development was dominated by the question, “What is more important—nature or nurture?”, the report concluded that the nature vs. nurture debate was “overly simplistic and scientifically obsolete” (p. 6). The report emphasized that there is a continuous and adaptive interaction between biology and environment from the moment of birth and through the early childhood years. Research in the years following the report has continued to demonstrate the powerful and lasting effects of in-utero, preconception, and transgenerational influences on child development (Bohacek and Mansuy, 2015; Dias and Ressler, 2014; Entringer et al., 2015).

Since the publication of Neurons to Neighborhoods, several scientific advances have furthered our understanding of the interaction between biology and environment. Chief among these is the emergence of the science of epigenetics, which synthesizes research findings from the social and biological sciences to understand the seamless and ongoing interaction between genes and the environment, with particular interest in cataloging the numerous environmental mechanisms comprising the nongenetic influences of gene expression. In this context, “environment” encompasses all exposures or influences that can affect well-being or increase or limit opportunity, such as supportive parenting and stress.

Central to the epigenetic approach is the life-course perspective, which has long been employed in both the social sciences and epidemiology to analyze demographic and social change. It starts from the position that an individual’s current circumstances are at least partly a consequence of events and experiences that occurred earlier in the individual’s life. The epigenetic approach embraces a “trajectory” model of the life course, which posits that the trajectory of an individual’s life may be changed, negatively or positively, at each life stage (Halfon et al., 2014). The future condition of the brain and body will be affected by events that have changed the trajectory in the past and possibly by further interventions undertaken in the present.

An important feature of the trajectory model is that for much of the life course, trajectories of a person’s brain circuits and body systems show plasticity, meaning they can be altered for better or worse. If they are positively altered, enrichment can occur with life-long benefits, and similarly, if deficits or injuries have previously occurred, the person can experience resilience and recovery through compensatory mechanisms. It is well known that early childhood comprises a period of high plasticity, when young children’s brains and bodies are rapidly developing and are particularly sensitive to environmental influences. But recent scientific advances have increased our understanding of the life course such that, as described in Chapter 2, it is now clear adolescence is also a time when considerable change is possible. Adolescents exhibit heightened brain plasticity, making adolescence a sensitive period of development during which life-course trajectories can be changed for better or for worse.

Because of the interactions between the brain, the body, and the environment and the plasticity of the adolescent brain, interventions to change developmental trajectories may be particularly effective during adolescence. A healthy, or flourishing, adolescent brain is plastic and resilient and thus receptive to both individual- and societal-level influences and interventions that promote positive adaptation. By the same token, however, harmful or unhealthy influences on the brain and body can shift the trajectory for the worse.

This chapter discusses key findings from the emergent field of epigenetics that are of particular relevance to adolescence. It examines the reciprocal interactions between the brain, the body, and the environment during the adolescent period, with a focus on toxic stress and early life adversities, and reviews promising interventions for mediating and mitigating early developmental challenges in order to change trajectories.

UNDERSTANDING EPIGENETICS

Epigenetics refers to the environmental influences that shape the individual, resulting in different developmental outcomes even among individuals

with the same genome (Freund et al., 2013). Advances in epigenetics have furthered our understanding of the interplay between genes and the environment, underscoring how the influences of genetics and environment on an individual’s health and development are inseparable. Contrary to the traditional view that heredity is unchanging, current studies of gene-environment interaction and epigenetics show that the ways in which heredity is expressed in behavior depends on environmental influences. The emerging field of epigenetics, therefore, studies biological processes not as primary causes of social outcomes but rather as mechanisms with contingent effects that depend on social structures, relationships, and interactions (McEwen and McEwen, 2017).

An example of gene-environment interplay may be drawn from the field of mental health. Consider a pair of identical twins—who therefore share identical DNA—who carry genes predisposing them to schizophrenia or bipolar illness. The probability that one twin will develop either disease at the same time as the other twin is only in the range of 40 to 60 percent. Differential experiences and other environmental factors will influence their genes to the extent that the disorder is either prevented or precipitated. Such influences, for example, result in changes and divergence in the activity (methylation patterns) of the DNA as the identical twins grow older (Fraga et al., 2005).¹ This example illustrates how environmental conditions can alter gene expression—that is, when, how, and to what degree different genes become activated (and thus influential) or deactivated (and thus uninfluential)—in behavior and development. Thus, even though an individual’s DNA does not change, the expression of the information it contains can be changed by experiences; Figure 3-1 illustrates this concept. Through these mechanistic linkages, gene-environment interactions affect lifelong behavior and brain development that are particularly consequential for developmental trajectories.

Advances in epigenetics have also helped us to understand that individuals differ in how susceptible they are to environmental influences. The expression of genes in the brain is changing continuously with each person’s experiences, and each new stressor or enhancement will have different effects upon gene expression (McEwen et al., 2015b). That is, the same gene in the same person may be expressed differently through time as experiences

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¹ DNA methylation—when methyl groups are added to the DNA molecule—can change the activity of a DNA segment without changing the sequence. The example presented above describes an epigenetic mechanism in which the environment influences the CpG methylation of DNA, but there are multiple other forms of epigenetic modification (Szyf et al., 2008). These mechanisms include histone modifications that repress or activate chromatin unfolding (Allfrey, 1970) and the actions of non-coding RNA’s (Mehler, 2008), as well as transposons and retrotransposons (Griffiths and Hunter, 2014) and RNA editing (Mehler and Mattick, 2007).

change. In addition, gene expression varies from person to person. Environmental adversity or support may dramatically affect some individuals, who flourish when conditions are positive but are negatively affected in poor conditions. Conversely, others appear to be less affected by environmental adversity or support, and their outcomes remain fairly consistent in both positive and negative circumstances (Boyce and Ellis, 2005; Obradovic et al., 2010). This differentiation may result because of early experiences, temperamental variability, genetic predispositions, or some combination of these factors. Taken together, however, research demonstrates that the same environmental circumstances do not affect individuals in the same way (Obradovic and Boyce, 2009).

Figure 3-2 illustrates the epigenetic life-course perspective and shows the ways in which environmental factors influence trajectories throughout the life course. It is important to recognize that these trajectories are “not straight, linear, overly determined, or immutable” (Halfon et al., 2014, p. 352). Rather, they are likely to be in a constant state of flux, determined by the various influences occurring at different times throughout the life course (Halfon et al., 2014, p. 352).

The cumulative measure of environmental factors has been referred to as the “exposome.” According to Miller and Jones (2014, p. 2), “the exposome captures the essence of nurture; it is the summation and integration of external forces acting upon our genome throughout our lifespan.” Environmental factors comprising the exposome include where one lives, what one eats, the quality of the air one breathes, one’s social interactions and relationships, and one’s lifestyle choices, among others. Related to this concept is the large literature in the field of public health on the social determinants of health, which are the upstream factors that shape behavior and influence health. These social determinants include education, employ-

ment, health systems and services, housing, income and wealth, the physical environment, public safety, the social environment, and transportation (National Academies of Sciences, Engineering, and Medicine, 2017).

Some factors are associated with flourishing trajectories and protect individuals from entering an at-risk trajectory. For example, having supportive relationships and having positive role models are protective factors that have been shown to be associated with lower risk for depressive symptoms and anxiety in homeless youth (Tyler et al., 2017). Supportive parenting, which may also be key to developing resilience in the face of risk factors, has been shown to mitigate some of the hormonal, metabolic, and cardiovascular changes that follow childhood adversity (Brody et al., 2017b). Additional factors associated with flourishing trajectories include positive school environments and access to quality, nutritious foods, among others.

Other factors, such as toxic stress, might consign individuals to the at-risk trajectory or move them from a flourishing trajectory to an at-risk trajectory. In addition, discrimination has been shown to affect sleep quality and duration, which has been shown to have a negative impact on psychological and physical health and academic outcomes (Asarnow et al., 2014; Barnes and Meldrum, 2015; Kuo et al., 2015; Majeno et al., 2018). Box 3-1 discusses the importance of sleep for adolescents and the ways in which environmental influences affect sleep and development. Similarly, and often related to the factors just mentioned, growing up in poverty has negative implications for the maturation of brain regions such as the hippocampus

and amygdala, which contribute to learning, memory, mood, and stress reactivity (Brody et al., 2017a). Brody and colleagues (2017a), for example, found that childhood poverty was associated with reduced volume of brain limbic regions in adulthood.

The relative contributions of risks and protective factors during childhood will therefore affect the likelihood of a flourishing trajectory, but an epigenetic life-course perspective also emphasizes that resilience and recovery are possible throughout the life course and especially during adolescence. Although one cannot reverse epigenetic modifications driven by environmental experiences that have occurred in previous life periods (Gray et al., 2014), recovery from earlier experiences is possible by redirecting gene expression to compensate for what has happened, through interventions such as the Strong African American Families Program, described below. That is, although each stage of life depends on what has come before, redirection, recovery, and resilience are possible, and windows of plasticity that make this possible are to be found across the entire life course. Insofar as the brain is healthy, individuals always have the capacity for resilience. Even the social and biological transitions that occur during adulthood offer opportunities for plasticity to be exploited, so that interventions may be effective beyond the early childhood and adolescent years.

RECIPROCAL INTERACTIONS BETWEEN BRAIN, BODY, AND ENVIRONMENT

As discussed in the previous chapter, adolescence is a sensitive period of brain development, during which adolescents exhibit key developmental changes (Casey et al., 2008; Davidow et al., 2016; Steinberg, 2008). Whether these changes lead to positive or negative developmental outcomes depends on the social and physical environmental contexts of a person’s development over the life course. All environments expose individuals to experiences that will produce adaptation in brain architecture and physiological processes: biological and neurological development are sensitive to social inputs and cues in the complex sociocultural environments in which adolescents live. An individual’s environment, thus, influences the course of development and shapes developmental changes as either opportunities for flourishing trajectories or risk factors for poor trajectories. Given the continuous, reciprocal communication between the brain, body, and environment, each stage of development offers possibilities to change the trajectory of brain and body function, with consequences for the individual’s life course from that point forward (McEwen et al., 2015b; for definitions of key terms used in this section, see Box 3-2).

While neuroscience has until recently tended to ignore the influence of the rest of the body on the brain’s function, and traditional medicine

has tended to ignore the brain, it is now understood that neural activity not only regulates the immune, metabolic, autonomic, and neuroendocrine systems but also those systems “talk to” and affect each other’s activity and “talk back” to the brain, influencing its structure and function (McEwen et al., 2015b). For example, regular physical activity improves memory and mood, because activity increases neurogenesis (the formation of new neurons) in the input region (dentate gyrus) of the hippocampus, which is involved in learning and memory formation. This is mediated, in part, by the liver hormone known as insulin-like growth factor-1, entering the brain and facilitating the process (Trejo et al., 2001). In contrast, insulin resistance, which can be ameliorated by physical activity, impairs signaling mechanisms in the hippocampus, reduces neurogenesis, and contributes to depression, impaired cognitive function, and increased risk for dementia later in life (Biessels and Reagan, 2015; Grillo et al., 2015; Rasgon and McEwen, 2016).

To understand the reciprocal interactions between the brain, the body, and the environment one can consider the impact of stress on development across the life course. (In the example here we examine the effect of experiencing stress during adolescence; the pathways by which toxic stress in early childhood compromises the developing brain and body are discussed in Box 3-3.) The body and brain respond to environmental stressors through the biological stress response. Stressors range in severity from, for example, stress on the first day of school to mental or physical abuse. The type, timing, and severity of stress can have different pathophysiological outcomes (functional changes occurring with a particular disease), and stress can trigger or aggravate many diseases or pathological conditions (Yaribeygi et al., 2017).

Specifically, the autonomic nervous system (which controls bodily functions not consciously directed, such as breathing and digestion), the hypothalamic-pituitary-adrenal (HPA) axis, and the cardiovascular, metabolic, and immune systems protect the body by reacting to internal and external stress through allostasis (the ability to achieve stability through change) (McEwen, 1998; Sterling and Eyer, 1988). Efficient allostasis involves “turning on” a physiological response when needed and turning it off efficiently when the stressor is over. Examples of this are the sudden increasing of cortisol² or heart rate, or releasing the neurotransmitter glutamate. In short, the brain perceives and determines what is threatening and regulates the behavioral and physiological responses to the environmental stressor.

Both adult and developing brains possess significant structural and functional plasticity in reaction to stress, including the replacement of neurons, remodeling of dendritic connections, and turnover rate of synapse activity. This plasticity may lead to three possible outcomes: positive adaptation (good stress), negative but remediable responses (tolerable stress), or long-term pathophysiological and negative behavioral responses (toxic stress).

Positive adaptation may occur in response to brief and mild to moderate experiences of stress. For example, this type of “good” stress might occur if an adolescent has anxiety related to the first day of a new school year or experiences moderate frustration but feels rewarded at the end of the experience. If an environment of stable and supportive relationships buffers these stressors, a young person can cope with the stressful event and the stress response systems will efficiently return to baseline status. In this context, good stress becomes a growth-promoting opportunity, allowing a young person to learn healthy, adaptive responses to adverse experiences (Shonkoff and Garner, 2012).

Remedial adaptation occurs in response to tolerable stress. This occurs when an individual is exposed to non-normative experiences that present greater adversity or threat than positive stress events do, such as a serious illness or injury or a parent’s contentious divorce. These stressful events can result in tolerable stress when “protective adult relationships facilitate the child’s adaptive coping and sense of control, reducing the physiologic stress response and promoting a return to baseline status” (Shonkoff and Garner, 2012, p. e236).

Toxic stress, the most dangerous form of stress, occurs when the heightened stress response persists even after the danger or stressor passes, that is,

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² Cortisol is often referred to as the “stress hormone.” It is a steroid hormone that is released in response to stressors. Cortisol, thus, is part of the body’s “fight-or-flight” response and gives the body energy to fuel muscles during threatening conditions.

when the responses are either not turned on when needed or are not turned off appropriately. In particular, toxic stress occurs when an individual is unable to cope effectively with the stress, either due to a lack of support or less healthy brain architecture due to adverse early life experiences (McEwen and McEwen, 2017). Toxic stress contributes to long-term changes in the body and brain, referred to as “allostatic load” or “overload.”³ The maladaptation resulting from toxic stress disrupts brain circuitry and other organ and metabolic systems as well during sensitive developmental periods, which may result in damage to the regulation of these systems. That damage in turn is a precursor of later impairments in learning and behavior and can become the roots of chronic, stress-related physical and mental illness such as chronic anxiety and depression (McEwen et al., 2015b; Shonkoff and Garner, 2012).

As an example, abuse and neglect are likely to produce toxic stress in adolescents. This can lead to both short-term changes in observable behavior and less outwardly visible yet long-lasting changes in brain structure and function, including connectivity within the brain (Teicher et al., 2016). These changes may include reduced brain volume and disruption of protective myelin growth (Hair et al., 2015; Hanson et al., 2013, 2015). Exposure to toxic stress and high levels of cortisol also inhibit neurogenesis in the hippocampus, which is thought to play a role in the encoding of memory and in antidepressant functions (Cameron and Gould, 1996). The neurobiological pathways and effects of childhood and adolescent abuse and trauma are discussed in greater detail in Box 3-4.

In the absence of preventative interventions to promote positive, adaptive neuroplasticity and health-promoting behavior and physiology, stress-induced changes in the brain are likely to increase a person’s vulnerability to toxic stress and resulting allostatic overload (Eckenrode et al., 2017; Shonkoff et al., 2009).

Moreover, toxic stress hampers the hippocampus’s ability to promote contextual learning, which makes it difficult for a person to discriminate between dangerous situations and safe ones.⁴ While some of these changes may help the individual adapt to the particular social and physical environment in which he or she currently lives, they may make it more difficult to function in a different environment in the future (Del Giudice, et al., 2011). For instance, in a safe environment a normal prefrontal cortex (PFC)

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³ The concepts of allostatic load and overload help us understand the cumulative and potentially damaging, as well as protective, effects of stressors on the brain and body (McEwen, 1998; see also, McEwen and Gianaros, 2011; McEwen and Stellar, 1993; McEwen and Wingfield, 2003; McEwen et al., 2015b). A related concept is that of “allostatic state,” which represents a chronic deviation of the set point for an allostatic system such as heart rate or blood pressure.

⁴ This reaction is common in post-traumatic stress disorder (PTSD), for example.

regulates impulses and moods (through downstream control of the amygdala and nucleus accumbens) and facilitates decision making and proactive planning (McEwen and Morrison, 2013). In a dangerous environment, the orbitofrontal part of the PFC promotes vigilance for possible threat and danger. For children experiencing early adversity, the PFC develops in such a way that the child is continuously prepared for threat and danger, but this also makes the child, as they age, less able to control mood and impulse and less able to take part in thoughtful decision making and proactive planning (Gee et al., 2013a, 2013b).

In summary, as the example of the varying effects of stress highlights, the brain, the body, and the environment interact with one another in continuous and reciprocal ways, so that key life experiences influence basic neurobiological growth to shape developmental trajectories that may have profound long-term consequences.

AMELIORATING EARLY LIFE ADVERSITIES IN ADOLESCENCE

As discussed above and in Chapter 2, the heightened plasticity of the adolescent brain suggests that adolescence is a particularly sensitive period in which environmental influences may affect developmental trajectories, both positively and negatively, through a multitude of reciprocal interactions. In addition, this heightened sensitivity and responsiveness to environmental influences suggests that adolescence is a period when interventions can redirect and remediate maladaptation in brain structure and behavior that may have accumulated from earlier developmental periods.⁵

While preventing early life adversities is ideal,⁶ research shows that ameliorating and redirecting an unhealthy developmental trajectory remains possible during adolescence and later developmental periods. A number of programs and interventions are emerging that look to take advantage of the potential of adolescence—driven by the adaptive plasticity of the brain and the developmental changes occurring in adolescence—to influence not only behavior but also systemic physiology, ensuring that youth flourish. This is an area of particular importance for future research; see Chapter 10.

One such intervention is the Strong African American Families (SAAF) Program, a developmentally and culturally responsive intervention that

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⁵ In fact, opportunities to promote better physical, mental, and cognitive health continue throughout the life course. For example, pregnancy opens a window for better parenting and family and child health, as exemplified by the Nurse Family Partnership (Eckenrode et al., 2017). This particular program may be of particular relevance to adolescents who are young mothers.

⁶ For a discussion of prenatal and early childhood interventions, see the companion study authored by the Committee on Applying Neurobiological and Socio-behavioral Sciences from Prenatal through Early Childhood Development: A Health Equity Approach: www.nationalacademies.org/earlydevelopment.

promotes positive racial identity and ways for parents to learn to support youth goals and independence (Brody et al., 2017b). The program, which engaged 667 families from nine rural counties in Georgia for 7 weeks, promotes supportive parenting and the development of self-regulatory skills by the adolescents (Brody et al., 2017a, 2017b). In a randomized control trial, adolescents (ages 11 to 13) from families that received the intervention showed positive short- and long-term psychological, physiological, and neurobiological improvements, including reduced low-grade inflammation (a condition associated with many chronic diseases; see Minihane et al., 2015) (Miller et al., 2014) and reduced incidence of pre-diabetes, a condition that presumably had been elevated during adolescence due to adverse childhood experiences (Brody et al., 2017b; Yau et al., 2012). Increased locus of control (an individual’s sense that they determine their experiences, rather than external forces such as luck or fate) is a likely mediator of the beneficial effects of interventions such as this (Culpin et al., 2015).

The SAAF Program demonstrated remarkable protective effects on the brain in addition to its beneficial effects on metabolic control (Brody et al., 2017a). Using magnetic resonance imaging, assessments were conducted a decade after the intervention (at age 25) to examine young adults’ whole hippocampal region as well as amygdala volume. Both the control population and the participants in the SAAF Program were largely from backgrounds of low socioeconomic status, with 46.3 percent living below poverty thresholds, a situation that normally forecasts diminishment in the volume of the left dentate gyrus, the CA3 hippocampal subfields, and the left amygdala. The assessment found this diminishment among the young adults in the control condition but not among those who had participated in the SAAF Program. In addition, the SAAF Program was shown to reduce insulin resistance, another example of the ways in which brain-body interactions influence systemic disorders (Brody et al., 2017b).

In addition to family-based interventions such as the SAAF Program, stress-reduction interventions targeted directly at adolescents hold promise for undoing, or mitigating, the impact of early life stress on brain development. Mindfulness meditation has been associated with changes in brain regions associated with stress and attention (Tang et al., 2015). The DeStress for Success intervention teaches adolescents to cope with stress as they transition from elementary to middle school. Adolescents participating in the program are guided through a series of brief workshops that explain what stress is, how the body reacts to it, and problem-focused methods for coping (Lupien et al., 2013). This program has been found to lead to reductions in glucocorticoid levels and reductions in depressive symptoms in adolescents with high levels of anger (Lupien et al., 2013). Although the program has not yet been assessed for neurobiological im-

pacts, they are likely given the changes observed in stress hormones and mental health.

Of course, research on neuroplasticity in adolescence need not only focus on ameliorating negative early life experience. There are other programs applicable across the life course that are focused on promoting emotional well-being through mindfulness and empathy-sensitizing work, programs that promote physical activity and social integration to counteract loneliness and improve sleep, and programs that promote healthier diets and mindfulness (Cacioppo et al., 2011; Erickson et al., 2011, Tasali et al., 2008; Valk et al., 2017).

Enrichment programs involving reading and mathematics instruction and music education also have established benefits. For example, reading instruction is associated with changes in cortical thickness (Romeo, 2017; Romeo et al., 2018) and structural connectivity (Huber et al., 2018; Keller and Just, 2009), especially in children from low socioeconomic status backgrounds. Math instruction is associated with structural and functional changes in math networks (Iuculano et al., 2015; Wang et al., 2017; Weng et al., 2017) and music classes have been linked to changes in neural signatures of language processing in children from high poverty neighborhoods (Kraus et al., 2014a, 2014b, 2014c). Practice with divergent thinking (e.g., coming up with alternative uses for household objects) improves creativity and leads to changes in prefrontal function (Kleibeuker et al., 2017).

CONCLUSION

Our developing understanding of epigenetics and the ways in which environmental influences shape individuals and the genome have underscored how the influences of genetics and environment on an individual’s health and development are inseparable. Neurobiological processes can best be understood not as the cause of societal outcomes, but rather as mechanisms through which social structures, relationships, and interactions, together with other environmental influences, effect changes in the individual person. In this way, environment can be said to “get under the skin.”

Because of the heightened plasticity of the adolescent brain and the interplay between genes and the environment, adolescence is a particularly sensitive period in which environmental influences may positively or negatively shape developmental trajectories through reciprocal interactions between the brain, the body, and the environment. This heightened sensitivity and responsiveness to environmental influences implies that adolescence is ripe with the promise of discovery and intensive learning that have a lasting imprint on the life course. Heightened neural plasticity also suggests that adolescence is a period during which well-designed interventions may

be used to redirect and remediate maladaptation in brain structure and behavior from earlier developmental periods.

Thus, investments in programs and interventions that capitalize on the promise of brain plasticity during adolescence are needed to promote beneficial changes in developmental trajectories for youth who may have faced adverse experiences earlier in life or are facing them now. The challenge is to promote adaptation and change the trajectory of brain development and function so that the youth can adapt in a healthy way even when conditions change—for example from a dangerous environment to a safer one. The desired effect is to promote compensatory change in the adolescent to accommodate a more productive lifestyle in a changing environment.

Moreover, because environments and experiences interact with fundamental neurobiological developments, and because pubertal, neurobiological, cognitive, and psychosocial changes are occurring, adolescence represents a critical period of opportunity for the shaping of developmental trajectories. Adolescents are growing and learning within their environments, and each experience is an opportunity for adolescents to flourish and thrive. It is sometimes popularly said that a deviant adolescent is “incorrigible.” However, what we know about the science of adolescent development strongly supports the supposition that all adolescents have the capacity to change. No child is without the potential to succeed. From a developmental perspective, adolescence is a time of promise, resilience, hope, and opportunity for all youth.

But few adolescents can flourish without the support of caring adults, especially if the circumstances of their childhoods yielded adversity or curtailed opportunity. The focus in this chapter has been on the developmental determinants of life-course trajectories as understood through epigenetic research. However, the harsh reality is that for many youth, opportunity is severely curtailed by economic and social disadvantage. These potent societal determinants of adolescents’ life-course trajectories are discussed in the next chapter.