Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously “reading” and adapting to the environment and “talking back” to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period.

Differential child health outcomes are shaped by developmental contexts through ongoing, interactive adaptations that begin at conception and continue throughout life.1  Although biological effects of both physical and social adversities on the brain have received the most attention in the world of early childhood policy and programs, it is clear that the mediators and moderators of challenging exposures extend well beyond neural circuitry, and researchers are documenting increasing evidence of the extraordinary importance of the prenatal period and early infancy for the developing immune system and metabolic regulation. In this article, together with its companion article,2  we provide clinicians and researchers with a synopsis of advances in developmental biomedical research and their implications for pediatric practice.

Research on health and disease in children has traditionally assessed the roles of genetic and environmental factors separately on the basis of the implicit assumption that each category can be investigated independently, irrespective of the other’s influences. Moreover, the existence of specific, temporal windows of opportunity during which environmental factors can prevent or increase the risk for impairment is increasingly acknowledged but seldom addressed empirically.3  The convergence of multiple domains of developmental biomedical research of the interactive effects of genetic and environmental factors on health trajectories for different organs, at different points in time, is dramatically changing our ability to understand the childhood origins of lifelong disease and well-being.4  These investigations provide a compelling framework for a new era in science-based pediatric practice informed by the following advances:

  • a deeper understanding of how multiple genes influence susceptibility and resilience, how genes and environmental conditions interact, and how epigenetic and metabolic processes affect the outcomes of adversity exposures5 ;

  • fresh awareness of how developmental time, as a third critical variable, can moderate the health effects of toxic stress in interaction with genetic and environmental variation6 ;

  • new knowledge of the sources and consequences of individual differences in children’s sensitivity to adversities in their families and communities7 ;

  • greater appreciation for how all biological systems respond to adversity in an integrated way, by operating together in networks, at multiple levels of biological complexity1 ;

  • a heightened awareness of how stressors in the psychosocial and physical environment co-occur, especially within disadvantaged populations8 ; and

  • the powerful role of environmental protective factors, their potential for building more effective prevention strategies, and the need for a balanced approach to studying both resilience and risk.9 

Figure 1 provides a conceptual map of this new developmental biology of adversity. This image illustrates triadic relations among genes, environments, and developmental time and their interactive roles in the foundations of health and the pathogenesis of impairments. Together, these roles describe an interactive GET framework, in which genetic differences, environmental exposures, and developmental timing act synergistically and contingently. Genetic variation that determines risk is often conditioned on environmental factors that interactively regulate gene expression through epigenetic processes.10,11  Both toxic and protective aspects of children’s environmental experiences, at the levels of family and community, exert gene transcription-modifying influences on risks for ill health and maladaptive behavior.12,13  Exposures to psychosocial stressors, such as adverse childhood experiences (ACEs) or the structural inequities of systemic racism, and physicochemical toxins, such as pollutants or excessive noise, often share common grounding in a scarcity of essential resources. On the other hand, supportive environments that buffer the effects of adversity typically include access to sufficient material assets and protective caregiving. Lastly, the temporal dimension of these 3-way interactions may include experience-dependent critical or sensitive periods, during which multiple developing systems are fine-tuned physiologically.3  Developmental plasticity and malleability are highest during these periods, but critical periods have more sharply defined beginning and end points and plasticity that is not graded over time, whereas sensitive periods have less well-defined onsets and endings, with an extended plasticity gradient.14 

FIGURE 1

An interactive GET framework. An emerging developmental biology connects the triadic interactions among genetic variation, environmental threats and supports, and developmental time in the early origins of physical and mental health outcomes. Represented by the arrow and triangle, the combined, reciprocally interactive influences of genes, environments, and time on each other all contribute to healthy or pathogenic outcomes, such as highly adaptive behavior, heightened stress reactivity, inflammation, metabolic balance and imbalance, and modified organ architecture.

FIGURE 1

An interactive GET framework. An emerging developmental biology connects the triadic interactions among genetic variation, environmental threats and supports, and developmental time in the early origins of physical and mental health outcomes. Represented by the arrow and triangle, the combined, reciprocally interactive influences of genes, environments, and time on each other all contribute to healthy or pathogenic outcomes, such as highly adaptive behavior, heightened stress reactivity, inflammation, metabolic balance and imbalance, and modified organ architecture.

Close modal

Under pathogenic conditions, GET interactions can give rise to disorders of physical and/or mental health or to intermediate phenotypes, such as emotion dysregulation, disturbed adrenocortical reactivity, inflammation, or metabolic dysfunction.4  The causal pathways linking these heightened risks for disorders of health can be mediated or influenced by factors that hasten or temporize, as well as intensify or restrain, the emergence of pathology. These include differential susceptibility to environmental conditions, immune competence, the regulation of metabolic and inflammatory processes, and the microbiomes.

It is important to underscore that the same interactions that create conditions for disorders at one end of the spectrum can strengthen the foundations of resilience at the other end. Health is not simply an avoidance of disease but a result of key protective influences during critical or sensitive developmental stages, which can enhance expression of protective genetic elements. Importantly, the frontiers of evidence in GET domains have come to bridge the boundaries among them as their influences have been increasingly revealed as fundamentally interactive.

British epidemiologist Geoffrey Rose observed that the most difficult disease risk factors to detect are, ironically, those that are most prevalent.15  For example, ubiquitous smoking in a hypothetical population would make smoking the hardest environmental risk factor to identify in the subgroup that developed lung cancer. Something similar has been at work in our recognition of toxic stress as a key etiologic factor for childhood disorders and persistent disparities in population health. Extensive evidence indicates that early adversities, including child maltreatment, family or community violence, parental substance abuse or mental disorders, and the burdens of poverty or racism, are highly prevalent, affecting at least half of children by the time they reach adolescence.16,17  Moreover, one-half of those who sustain such exposures exhibit some form of developmental psychopathology, and at least one-third of adult mental health disorders are attributable to ACEs.18 

The hardships and threats associated with systemic racism, personally experienced discrimination, and other forms of institutionalized marginalization are particularly virulent and pervasive influences on child health,19  and they are based entirely on socially constructed categories rather than any intrinsic genetic partitioning of human populations.20,21  Moreover, children experiencing the burdens of structural inequities are not only disproportionately exposed to psychosocial stressors, but also to physicochemical toxicants such as lead and pesticides.22,23  Extensive biomedical research has been frequently blinded to these converging adversity effects by both their extraordinary prevalence in human lives and by a resistance to acknowledge psychosocial influences on biological health end points.

That said, increasing research is now revealing that the health consequences of both psychosocial stressors and environmental toxicants are often conditioned by genetic variation with respect to individual susceptibility to adversity.24  The risk of developing adult psychopathology, for example, is related to an interaction between childhood trauma and a functional polymorphism in the FKBP5 gene that controls aspects of glucocorticoid responses to stress.25  Similarly, the neurodevelopmental effects of lead exposure are amplified by the presence of a sensitizing polymorphism in the gene coding for δ-aminolevulinate dehydratase, an enzyme in the heme synthesis pathway.26  Thus, although the independent biological effects of environmental factors and genetic variation can each be substantial, gene-environment interactions (GxEs) also have large effect sizes27  and appear to be far more prevalent than initially thought.28  For pediatricians, a new understanding of how individual genetic variation can play a role in the health consequences of significant environmental trauma and threats is central to advancing the practice of medicine.

This interplay between genes and environments takes at least 3 forms, as summarized in Table 1.29,30  First, gene-environment correlation (rGE) arises when individuals with certain genetic variants choose, alter, or create the social or physical environments in which they live. An adolescent with a genetic predisposition to antisocial behavior, for example, may actively seek risk-taking experiences, such as driving after drinking,31  or students with a particular genotype may gravitate to certain kinds of classroom activity while foregoing others.32  Here, genetic variation and environmental exposures are correlated but not causally interactive.

TABLE 1

Three Forms of GxE Interplay, With Mechanisms and Examples

Forms of GxE InterplayMechanismsExamples
1. rGE Individuals with certain genetic variants choose, alter, or create their environments. Children with particular genotypes may evoke specific parenting behaviors, such as harsh discipline. 
2. GxE Environmental influences are apparent only among individuals carrying a particular gene variant. Lack of early endotoxin exposure predisposes children to asthma, but only among children with a genetic variant in the CD14 gene. 
3. eGE Environmental exposures regulate or calibrate gene expression through epigenetic processes. Methylation of cytosine nucleotides within certain sets of genes is associated with increased sympathetic reactivity to stressors. 
Forms of GxE InterplayMechanismsExamples
1. rGE Individuals with certain genetic variants choose, alter, or create their environments. Children with particular genotypes may evoke specific parenting behaviors, such as harsh discipline. 
2. GxE Environmental influences are apparent only among individuals carrying a particular gene variant. Lack of early endotoxin exposure predisposes children to asthma, but only among children with a genetic variant in the CD14 gene. 
3. eGE Environmental exposures regulate or calibrate gene expression through epigenetic processes. Methylation of cytosine nucleotides within certain sets of genes is associated with increased sympathetic reactivity to stressors. 

Second, there are instances in which genetic variations come into play only in the presence of specific environmental conditions (GxE) and, alternatively, some environmental influences become apparent only among individuals carrying a particular genetic variant.28,31  The level of endotoxin exposure early in life, for example, predicts atopic sensitization leading to asthma, but only among children with a specific variant of the CD14 gene coding for a pattern recognition receptor on cell surfaces.33  In other examples, ACEs are associated with later maternal insensitivity, but only among girls with a single nucleotide polymorphism in the PRKG1 gene,34  and children carrying the 7-repeat allele of the DRD4 gene have increased fat intake when reared in socioeconomically disadvantaged conditions.35  Polymorphisms in the oxytocin and oxytocin receptor genes also predict measures of maternal-infant caregiving and maternal depression but are limited to women reporting to have themselves received poor quality early maternal care as children.36 

A third form of gene-environment interplay includes biological processes in which environmental exposures regulate or calibrate the timing and level of expression of specific sets of genes, resulting in differences in behavior or disease risk.37  These epigenetic gene-regulatory processes (eGEs) can take a variety of forms, including the following: methylation or hydroxymethylation of cytosine dinucleotides (DNA regions in which cytosine nucleotides are followed by guanine nucleotides [CpG sites]) in DNA; posttranscriptional control of gene expression by small, noncoding RNAs; and posttranslational modifications of the histone proteins that DNA is wrapped around within chromatin.38  Methylation of CpG sites within promoter regions has generally repressive effects on gene transcription, whereas epigenetic marks within gene-coding regions are more often linked to an upregulation of transcription. These epigenetic modifications have short- and long-term effects on stress-responsive biological systems and work by changing the structure of the genome’s chromatin packaging. Such epigenetic processes have been implicated in the regulation of the hypothalamic-pituitary-adrenocortical axis and the autonomic nervous system and in the acquisition of health risks from early life adversities and trauma.3840 

Each form of gene-environment interplay (rGE, GxE, and eGE) has been increasingly documented in relations among early childhood adversity, toxic stress, and disorders of health and development.41  Although doubts have sometimes arisen regarding the replicability of GxE interactions,42,43  recent meta-analyses have confirmed their key roles in pathogenesis.27,4448  Other work has suggested that genetic variants and differences in gene expression may influence outcomes not just by increasing morbidity under conditions of adversity, but also by enhancing an individual child’s sensitivity to both positive and negative environmental conditions, a so-called differential susceptibility perspective.41,49,50  New research also suggests that a deeper understanding of gene-environment interplay may be advanced by employing polygenic risk scores that incorporate the contributions of many common genetic variants across the genome,5,41  or even an omnigenic array of both core and secondary genetic networks.51  Finally, when examined explicitly, developmental timing may play an important role as a moderator of GxE effects on health and disease.52 

The well-established connection between early environmental exposures to significant adversity and modifications of the developing brain has been bolstered by growing evidence that other organs are also affected and that these collective changes render a child more susceptible to “second or third hits” by physical or psychosocial stressors later in life.5355  Stressors produce chemical mediators that trigger adaptive mechanisms in multiple organ systems, termed allostasis, with the goal of maintaining homeostatic balance. Continued exposure to adversity, however, can result in an allostatic load or overload condition, in which neural circuit and cardiometabolic changes have lasting costs in dysfunction and disease.56  There is also increasing evidence from both animal and human studies that persistently elevated systemic inflammation can produce enduring molecular and structural remodeling of multiple organ systems, increasing the risk of later impairments in both physical and mental health.57 

Children experiencing the stressors of poverty, racism, unsupportive caregiving, and/or maltreatment have increased incidences of inflammation-related obesity and elevated blood pressure.58,59  Heightened cardiometabolic risk has also been documented in adolescents who grew up during the recession that followed the 2007–2008 financial crisis.60  Unsupportive parenting in childhood can similarly lead to increased inflammatory reactivity to major life events,58  likely through sympathetic activation of inflammatory cytokine production. Increased inflammation is associated with insulin resistance, type 2 diabetes, increased BMI, and altered myelin structure in the developing brain.61,62  Over the life course, insulin resistance is associated with increased risk of a subtype of major depression as well as Alzheimer disease.63 

This pathogenic cascade of adversity-associated morbidities appears to begin with a chronic proinflammatory state. Major hardships or threats in the family environment, for example, are associated in childhood with upregulation of Nuclear Factor-κ B-responsive genes in peripheral blood mononuclear cells, such as lymphocytes and monocytes,64  and this effect may persist into adulthood.65  Nuclear Factor-κ B is a transcription factor that plays a role as master regulator in many critical responses to environmental stimuli, including cell survival, DNA transcription, and cytokine production during acute infection. Its dysregulation may result in chronic inflammation leading to multiorgan remodeling and a host of chronic illnesses.

These conclusions are supported by a comprehensive meta-analysis of >40 studies assessing associations between childhood trauma and peripheral levels of 3 key inflammatory markers in adults: c-reactive protein, interleukin 6 (IL-6), and tumor necrosis factor α.66  Findings revealed a significant association between early adversity and all biomarkers studied, with the largest effect sizes for tumor necrosis factor α, followed by IL-6 and C-reactive protein. A deeper understanding of these associations between childhood stressors and adult proinflammatory signaling could lead to more effective strategies for preventing many chronic conditions, including cardiovascular disease,60,67  viral hepatitis,68  liver cancer,69  asthma,70  chronic obstructive pulmonary disease,57  autoimmune diseases,71  poor dental health,72  and depression.73 

As noted earlier, among many possible mechanisms for the connection between childhood trauma and inflammatory phenotypes, epigenetic processes controlling gene expression are worthy of attention. Peripheral blood mononuclear cells in adults who were exposed to emotional neglect or violence in childhood exhibit increased IL-6 responses after exposure to social stress tests, especially in subjects who had diminished DNA methylation of the IL-6 gene promoter.74  These results suggest the future possibility that susceptibility to excessive, early adversity could be assessed by screening the epigenome to identify children most at risk for later disease. By using a proportionate universality strategy,75  in which interventions are attuned to children’s differential sensitivities and family resources, needs, and preferences, maximal efficacy of protective and therapeutic services may be achievable.

There is also mounting evidence implicating chronic, systemic inflammation in the composition of the microbiome in both the gut and airways. Recent studies also indicate that there are critical periods in infancy when disruptions of microbial colonization of mucosal tissues can lead to persistent defects in the development of specific T-cell subsets with lifelong impacts on physical health.76  In neonates, isolation of certain bacterial species from the upper airway or specific microbial populations in the gut is associated with the subsequent risk of asthma.77,78  Specific gut microbiome communities have also been reported in children who become overweight or obese.79  These findings are stimulating further examination of the intriguing hypothesis that alterations in the dynamic relation between the immune system and mucosal microbes (the so-called microbial-mucosal unit80 ) may occur early in life and predispose young children to greater risk for chronic inflammatory conditions.81 

Although there are currently no data on humans revealing a direct association between excessive, early adversity and the microbiome, a diverse set of animal models has shown that infant-maternal separation and other experimental models of early adversity may result in microbiome effects that persist into adulthood.82  These findings suggest a new causal pathway to chronic disease: excessive, early adversity leading to disruption of the microbial-mucosal unit. Chronic inflammation and subsequent illness are also associated with higher levels of family stress. This hypothesized cascade of biological disruptions in the child and emergent adversities within the family suggests scalable possibilities for prevention that begin with maintaining or restoring specific microbiota.

Finally, there is evidence that maternal warmth and responsive relationships in adolescence can buffer the adverse effects of chronic immune system activation. As one example, a family-based intervention provided for African-American youth who had grown up under early conditions of poverty produced reductions in inflammation,83  a decreased incidence of prediabetes,84  and the promotion of healthy brain development.85  Preventive interventions to mitigate the effects of early adversity, combined with identifying highly susceptible children, offer the potential to prevent diseases that account for a large proportion of US annual health expenditures.1,86 

The basic concept of critical or sensitive periods in the development of brain circuitry refers to windows of plasticity during which identified regions are most sensitive to the effects of experience.87  Beyond this well-established cornerstone of neurobiology, specific temporal patterns of gene expression have been identified that provide the molecular ingredients (eg, structural and signaling proteins, transcription factors, receptors, and ion channels) for the development of the specialized cells in many other organs and systems.88,89  Over time, these cells build the capacity to respond to intrinsic cross-talk among systems (eg, gastrointestinal, immune, and neural) as well as to extrinsic information from prenatal (eg, maternal, placental, sensory) and postnatal (eg, nutritional, physical environment, social relationship, sensory) factors.90,91  The varying degrees to which different cells and organs respond to external influences define their sensitivity, and this typically occurs during specific periods in development that may overlap or vary by physiologic system.92 

These common principles described above operate across systems and at varying levels of biological complexity. Current understanding of the origins of peanut allergy provides one illustrative example of how timed exposures can influence sensitivity. Severe (and often life-threatening) allergic responses to ingested peanuts have increased significantly during the last decades, and the exact cause is still unknown. Until recently, the accepted strategy for preventing peanut allergy was to avoid ingestion early in life. In stark contrast, a recent clinical trial showed that systematic, oral administration of peanuts to high-risk infants who were not already sensitized markedly reduced the incidence of subsequent allergy.93  These results indicate that the response to the peanut allergen is dependent on timing and amount, with exposure being either tolerated or sensitizing depending on whether it occurs before or after the selection of specific cells that mediate the allergic response.

Perhaps the most familiar examples of differential plasticity over time come from extensive brain research demonstrating that some neural circuits respond within months to experiences promoting maturation of function (eg, sensory processing), whereas other circuits remain sensitive to external influences for decades (eg, executive functioning).94,95  At the end of the 20th century, neuroscientists characterized the critical or sensitive period for a particular sensory function (including its onset, peak, and reduced sensitivity to experience, which together drive changes in circuit organization and function), irrespective of whether the circuit was on a normal trajectory (eg, in binocular visual acuity) or disrupted developmentally (eg, in amblyopia). Within that framework, changes induced by experiences during the critical or sensitive period can occur at the structural (ie, wiring diagram), molecular (ie, epigenome), and physiologic (ie, cell signaling) levels.1,96 

Recent breakthrough research has revealed that the gut microbiome (in both human infants and animal models) exhibits the same critical or sensitive period effect because the infant gut microbiome is established through maternal transmission and early environmental seeding.97  There is also evidence that microbial colonization influences lifelong immune function, either directly through immune modulation or indirectly through metabolites generated by gut bacteria. These influences have been documented for respiratory, gastrointestinal, and brain functions.98 

The developmental mechanisms that establish the gut microbiome and can result in increased health risks are a rich area of current clinical and basic research. Evidence for critical or sensitive period development in other peripheral systems in humans is more limited. Given highly conserved biological adaptation and plasticity to environmental cues (from insects to humans),99  it is likely that, in the next decade, breakthrough discoveries in this domain of investigation will be realized.

Although issues related to critical and sensitive periods in brain development used to be considered relevant primarily for sensory systems, research now reveals that neural circuits involved in emotional regulation and cognition are also sensitive to the timing of experiences, and these periods determine relative responsiveness to stressors. For example, the Bucharest Early Intervention Project randomly assigned infants and toddlers living in orphanages into foster care homes at different times, largely after 12 months of age.100  The unavoidable differences in placement timing were dependent on the limited availability of foster care families, which created a natural experiment to investigate the impact of enriched environments at different ages. Extensive follow-up data demonstrated significantly better outcomes in cognitive (eg, language, IQ) and emotion regulatory functions (eg, stress responsiveness, attachment, stereotypies) for children who received foster care placements, with the best outcomes for those placed at younger ages (particularly before 2 years).3  These findings illustrate 2 core features of neuroplasticity6,101 : (1) although the identification of specific circuits is continuing to emerge, cognitive and socioemotional functions appear to exhibit critical or sensitive periods of development and adaptation; and (2) timing varies across functions.

Different neural circuits and the functions they mediate exhibit varied responsiveness to experiences depending on timing, and differences in timing for specific experiences can result in different functional outcomes. For example, during the first 10 days after birth, a rodent pup exposed to a negative stimulus paired with maternal odor will paradoxically exhibit enhanced attraction to that odor. In contrast, when elicited after day 10, the same procedure results in the expected, conditioned aversion to maternal odor, except in the mother’s presence.102 

As the complexity of developmental plasticity has become increasingly apparent over the past decade, 2 discoveries have generated a clearer understanding of the opening and closing of critical or sensitive periods in the cerebral cortex. The first is the identification of molecular and cellular accelerators and brakes that regulate onset, duration, and cessation.103,104  This led to the discovery that the balance between neuronal excitation and inhibition is highly conserved, including in humans. This balance is essential for the ability to process complex information and has been shown to be disrupted in certain mental illnesses.105  Subsequent investigations have defined the excitatory and inhibitory neuronal cell types responsible for setting parameters that mediate plasticity through their own pace of maturation. Research has even identified the specific type of inhibitory neurons for which changes in the timing of maturation influence experiential effects on connections during critical or sensitive periods. Both genetic and environmental factors control the expression of specific molecules during development that can accelerate, keep open, or halt such periods.106108  Implicit in these discoveries is the future potential for targeted manipulation of critical period timing to optimize the impact of preventive interventions.

Another breakthrough discovery is the recognition that specific experiences occurring well past the end of a critical or sensitive period can still change functional outcomes, although at a higher physiologic cost. This finding comes from both animal and human research in which the balance between excitatory and inhibitory influences was manipulated in various ways (eg, by environmental stress, physical exercise, disrupted cellular metabolism, and genetic or pharmacologic manipulation of γ-aminobutyric acid neurotransmission) to demonstrate that the duration, and even the reopening, of critical periods is malleable.109  Examples of this phenomenon are the ability to teach perfect pitch to human adults,110  the restoration of binocular vision in animal models after critical period closure,111  and the extension of treatment age range for human amblyopia.112  Recent research on correcting gut microbiome balance past the infancy period, in which healthy patterns are generally established, represents another frontier of investigation for which new discoveries are on the horizon.113 

Current research on plasticity during critical or sensitive periods is challenging long-standing principles related to health promotion and disease prevention. There is growing evidence that factors affecting critical or sensitive period timing can modify onset, duration, and closure. The discovery that significant adversity can accelerate the opening and closure of critical periods for the maturation of fear circuitry in animal models has compelling implications for early intervention in humans.114  The recognition that critical period timing is likely to vary among children presents both a challenge and an opportunity for developing preventive interventions in the early childhood years and for assessing their effectiveness at different ages.87  Finally, a deeper understanding of developmental biology is pointing to the need for fresh thinking about the importance of critical or sensitive periods for all developing organs and biological systems, not just the brain.

Advances in our understanding of how genes, environments, and developmental timing interact dynamically provide a compelling opportunity for leveraging 21st-century science to inform new approaches to health promotion and disease prevention in the context of pediatric practice. One of the most salient discoveries over recent decades is the integrated nature of the developmental process across biological systems. Equally important, pathologic processes for a range of disorders begin early, even prenatally, and many exert their most potent and long-lasting effects in the first few years after birth. Genetic variation plays a powerful role in susceptibility to specific morbidities, but its consequences are frequently altered by environmental and temporal effects on gene transcription. In a complementary fashion, the strong impacts of both toxic and health-promoting environments on child well-being can be either augmented or blunted by genome-derived susceptibility or the developmental timing of the exposures. The provision of responsive caregiving environments that are attuned to the varied assets and needs of young children, the targeting of specific prevention strategies or treatments on the basis of differential susceptibility, and the timing of interventions to coincide with critical or sensitive periods of optimal receptivity are all examples of how the future of pediatric practice must be guided by a deeper understanding of the mutual, interactive influences of genes, environments, and time.

Members of the National Scientific Council on the Developing Child and The JPB Research Network on Toxic Stress provided helpful comments on early drafts of this article.

Dr Boyce took the lead for the content on gene-environment interaction and developmental variation; Dr Levitt took the lead for the content on plasticity and critical periods; Dr Martinez took the lead for the content on the immune system and microbiome; Dr Shonkoff took the lead for aligning the scientific content of the article with a complementary article addressing implications for pediatric practice; and all authors worked together to conceptualize the article, draft the initial manuscript, and review and revise the manuscript, and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work (with the exception of Dr McEwen, who died during the review process).

FUNDING: The integrative thinking that guided the development of this article was facilitated by grants from the Buffett Early Childhood Fund, The JPB Foundation, the J.B. and M.K. Pritzker Family Foundation, the Chan Zuckerberg Initiative, the Omidyar Network and Imaginable Futures, and the Simms/Mann Family Institute. The content of the article is the sole responsibility of the authors.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-3845.

     
  • ACE

    adverse childhood experience

  •  
  • eGE

    epigenetic gene-regulatory process

  •  
  • GET

    gene-environment-time

  •  
  • GxE

    gene-environment interaction

  •  
  • IL-6

    interleukin 6

  •  
  • rGE

    gene-environment correlation

1
Shonkoff
JP
,
Boyce
WT
,
McEwen
BS
.
Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention
.
JAMA
.
2009
;
301
(
21
):
2252
2259
2
Shonkoff
JP
,
Boyce
WT
,
Levitt
P
,
Martinez
FD
,
McEwen
B
.
Leveraging the biology of adversity and resilience to transform pediatric practice
.
Pediatrics
.
2021
;
147
(
2
):
e20193845
3
Nelson
CA
 III
,
Zeanah
CH
,
Fox
NA
.
How early experience shapes human development: the case of psychosocial deprivation
.
Neural Plast
.
2019
;
2019
:
1676285
4
Boyce
WT
,
Sokolowski
MB
,
Robinson
GE
.
Genes and environments, development and time
.
Proc Natl Acad Sci U S A
.
2020
;
117
(
38
):
23235
23241
5
Hari Dass
SA
,
McCracken
K
,
Pokhvisneva
I
, et al
.
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions
.
EBioMedicine
.
2019
;
42
:
188
202
6
Reh
RK
,
Dias
BG
,
Nelson
CA
 III
, et al
.
Critical period regulation across multiple timescales
.
Proc Natl Acad Sci U S A
.
2020
;
117
(
38
):
23242
23251
7
Ellis
BJ
,
Boyce
WT
.
Differential susceptibility to the environment: toward an understanding of sensitivity to developmental experiences and context
.
Dev Psychopathol
.
2011
;
23
(
1
):
1
5
8
Stein
LJ
,
Gunier
RB
,
Harley
K
,
Kogut
K
,
Bradman
A
,
Eskenazi
B
.
Early childhood adversity potentiates the adverse association between prenatal organophosphate pesticide exposure and child IQ: the CHAMACOS cohort
.
Neurotoxicology
.
2016
;
56
:
180
187
9
Ozer
EJ
,
Lavi
I
,
Douglas
L
,
Wolf
JP
.
Protective factors for youth exposed to violence in their communities: a review of family, school, and community moderators
.
J Clin Child Adolesc Psychol
.
2017
;
46
(
3
):
353
378
10
Cameron
JL
,
Eagleson
KL
,
Fox
NA
,
Hensch
TK
,
Levitt
P
.
Social origins of developmental risk for mental and physical illness
.
J Neurosci
.
2017
;
37
(
45
):
10783
10791
11
McEwen
BS
,
Bowles
NP
,
Gray
JD
, et al
.
Mechanisms of stress in the brain
.
Nat Neurosci
.
2015
;
18
(
10
):
1353
1363
12
McDade
TW
,
Ryan
C
,
Jones
MJ
, et al
.
Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood
.
Proc Natl Acad Sci U S A
.
2017
;
114
(
29
):
7611
7616
13
Merrill
SM
,
Gladish
N
,
Kobor
MS
.
Social environment and epigenetics
.
Curr Top Behav Neurosci
.
2019
;
42
:
83
126
14
Colombo
J
,
Gustafson
KM
,
Carlson
SE
.
Critical and sensitive periods in development and nutrition
.
Ann Nutr Metab
.
2019
;
75
(
suppl 1
):
34
42
15
Rose
G
.
Sick individuals and sick populations
.
Int J Epidemiol
.
1985
;
14
(
1
):
32
38
16
Kessler
RC
,
McLaughlin
KA
,
Green
JG
, et al
.
Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys
.
Br J Psychiatry
.
2010
;
197
(
5
):
378
385
17
McLaughlin
KA
,
Greif Green
J
,
Gruber
MJ
,
Sampson
NA
,
Zaslavsky
AM
,
Kessler
RC
.
Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents
.
Arch Gen Psychiatry
.
2012
;
69
(
11
):
1151
1160
18
McLaughlin
KA
,
Weissman
D
,
Bitrán
D
.
Childhood adversity and neural development: a systematic review
.
Annu Rev Dev Psychol
.
2019
;
1
:
277
312
19
Trent
M
,
Dooley
DG
,
Dougé
J
;
Section on Adolescent Health
;
Council on Community Pediatrics
;
Committee on Adolescence
.
The impact of racism on child and adolescent health
.
Pediatrics
.
2019
;
144
(
2
):
e20191765
20
Witherspoon
DJ
,
Wooding
S
,
Rogers
AR
, et al
.
Genetic similarities within and between human populations
.
Genetics
.
2007
;
176
(
1
):
351
359
21
Yudell
M
,
Roberts
D
,
DeSalle
R
,
Tishkoff
S
.
Science and society. Taking race out of human genetics
.
Science
.
2016
;
351
(
6273
):
564
565
22
Rauh
VA
,
Landrigan
PJ
,
Claudio
L
.
Housing and health: intersection of poverty and environmental exposures
.
Ann N Y Acad Sci
.
2008
;
1136
:
276
288
23
Suglia
SF
,
Duarte
CS
,
Sandel
MT
,
Wright
RJ
.
Social and environmental stressors in the home and childhood asthma. [published correction appears in J Epidemiol Community Health. 2010;64(12):1105]
.
J Epidemiol Community Health
.
2010
;
64
(
7
):
636
642
24
Boyce
WT
.
Differential susceptibility of the developing brain to contextual adversity and stress
.
Neuropsychopharmacology
.
2016
;
41
(
1
):
142
162
25
Klengel
T
,
Mehta
D
,
Anacker
C
, et al
.
Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions
.
Nat Neurosci
.
2013
;
16
(
1
):
33
41
26
Wetmur
JG
,
Lehnert
G
,
Desnick
RJ
.
The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes
.
Environ Res
.
1991
;
56
(
2
):
109
119
27
Hawn
SE
,
Sheerin
CM
,
Lind
MJ
, et al
.
GxE effects of FKBP5 and traumatic life events on PTSD: a meta-analysis
.
J Affect Disord
.
2019
;
243
:
455
462
28
Knowles
DA
,
Davis
JR
,
Edgington
H
, et al
.
Allele-specific expression reveals interactions between genetic variation and environment
.
Nat Methods
.
2017
;
14
(
7
):
699
702
29
Rutter
M
,
Moffitt
TE
,
Caspi
A
.
Gene-environment interplay and psychopathology: multiple varieties but real effects
.
J Child Psychol Psychiatry
.
2006
;
47
(
3–4
):
226
261
30
Sokolowski
MB
,
Boyce
WT
. Gene-Environment Interplay and Epigenetic Processes. In:
Tremblay
RE
,
Boivin
M
,
Peters
RD
, eds.
Encyclopedia on Early Childhood Development
.
Quebec, Canada
:
Centre of Excellence for Early Childhood Development (CEECD), Université de Montréal Strategic Knowledge Cluster on Early Child Development (SKC-ECD), Université Laval
;
2017
31
Kim
YS
,
Leventhal
BL
.
Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders
.
Biol Psychiatry
.
2015
;
77
(
1
):
66
74
32
Anreiter
I
,
Sokolowski
HM
,
Sokolowski
M
.
Gene–environment interplay and individual differences in behavior
.
Mind Brain Educ
.
2018
;
12
(
4
):
200
211
33
Guerra
S
,
Martinez
FD
.
Asthma genetics: from linear to multifactorial approaches
.
Annu Rev Med
.
2008
;
59
:
327
341
34
Sokolowski
HM
,
Vasquez
OE
,
Unternaehrer
E
, et al
.
The Drosophila foraging gene human orthologue PRKG1 predicts individual differences in the effects of early adversity on maternal sensitivity
.
Cogn Dev
.
2017
;
42
:
62
73
35
Silveira
PP
,
Gaudreau
H
,
Atkinson
L
, et al
.
Genetic differential susceptibility to socioeconomic status and childhood obesogenic behavior: why targeted prevention may be the best societal investment
.
JAMA Pediatr
.
2016
;
170
(
4
):
359
364
36
Mileva-Seitz
V
,
Steiner
M
,
Atkinson
L
, et al
.
Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood
.
PLoS One
.
2013
;
8
(
4
):
e61443
37
Meaney
MJ
. Epigenetics and the Biology of Gene X Environment Interaction. In:
Tolan
PH
,
Leventhal
BL
, eds.
Gene-Environment Transactions in Developmental Psychopathology: The Role in Intervention Research
.
Cham, Switzerland
:
Springer
;
2017
:
59
94
38
Boyce
WT
,
Kobor
MS
.
Development and the epigenome: the ‘synapse’ of gene-environment interplay
.
Dev Sci
.
2015
;
18
(
1
):
1
23
39
Klengel
T
,
Binder
EB
.
Epigenetics of stress-related psychiatric disorders and gene × environment interactions
.
Neuron
.
2015
;
86
(
6
):
1343
1357
40
Allis
CD
,
Jenuwein
T
.
The molecular hallmarks of epigenetic control
.
Nat Rev Genet
.
2016
;
17
(
8
):
487
500
41
Halldorsdottir
T
,
Binder
EB
.
Gene × environment interactions: from molecular mechanisms to behavior
.
Annu Rev Psychol
.
2017
;
68
:
215
241
42
Duncan
LE
,
Keller
MC
.
A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry
.
Am J Psychiatry
.
2011
;
168
(
10
):
1041
1049
43
Risch
N
,
Herrell
R
,
Lehner
T
, et al
.
Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. [published correction appears in JAMA. 2009;302(5):492]
.
JAMA
.
2009
;
301
(
23
):
2462
2471
44
Caspi
A
,
Hariri
AR
,
Holmes
A
,
Uher
R
,
Moffitt
TE
.
Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits
.
Am J Psychiatry
.
2010
;
167
(
5
):
509
527
45
Karg
K
,
Burmeister
M
,
Shedden
K
,
Sen
S
.
The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation
.
Arch Gen Psychiatry
.
2011
;
68
(
5
):
444
454
46
Sharpley
CF
,
Palanisamy
SKA
,
Glyde
NS
,
Dillingham
PW
,
Agnew
LL
.
An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings
.
Behav Brain Res
.
2014
;
273
:
89
105
47
Bleys
D
,
Luyten
P
,
Soenens
B
,
Claes
S
.
Gene-environment interactions between stress and 5-HTTLPR in depression: a meta-analytic update
.
J Affect Disord
.
2018
;
226
:
339
345
48
Matosin
N
,
Halldorsdottir
T
,
Binder
EB
.
Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model
.
Biol Psychiatry
.
2018
;
83
(
10
):
821
830
49
Ellis
BJ
,
Boyce
WT
,
Belsky
J
,
Bakermans-Kranenburg
MJ
,
van Ijzendoorn
MH
.
Differential susceptibility to the environment: an evolutionary–neurodevelopmental theory
.
Dev Psychopathol
.
2011
;
23
(
1
):
7
28
50
Belsky
J
,
Pluess
M
.
Beyond diathesis stress: differential susceptibility to environmental influences
.
Psychol Bull
.
2009
;
135
(
6
):
885
908
51
Boyle
EA
,
Li
YI
,
Pritchard
JK
.
An expanded view of complex traits: from polygenic to omnigenic
.
Cell
.
2017
;
169
(
7
):
1177
1186
52
Zalsman
G
,
Gutman
A
,
Shbiro
L
,
Rosenan
R
,
Mann
JJ
,
Weller
A
.
Genetic vulnerability, timing of short-term stress and mood regulation: a rodent diffusion tensor imaging study
.
Eur Neuropsychopharmacol
.
2015
;
25
(
11
):
2075
2085
53
McEwen
BS
,
Akil
H
.
Revisiting the stress concept: implications for affective disorders
.
J Neurosci
.
2020
;
40
(
1
):
12
21
54
Bale
TL
.
Lifetime stress experience: transgenerational epigenetics and germ cell programming
.
Dialogues Clin Neurosci
.
2014
;
16
(
3
):
297
305
55
Peña
CJ
,
Kronman
HG
,
Walker
DM
, et al
.
Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2
.
Science
.
2017
;
356
(
6343
):
1185
1188
56
McEwen
BS
.
Protective and damaging effects of stress mediators
.
N Engl J Med
.
1998
;
338
(
3
):
171
179
57
Yao
H
,
Rahman
I
.
Current concepts on the role of inflammation in COPD and lung cancer
.
Curr Opin Pharmacol
.
2009
;
9
(
4
):
375
383
58
Chen
E
,
Miller
GE
,
Yu
T
,
Brody
GH
.
Unsupportive parenting moderates the effects of family psychosocial intervention on metabolic syndrome in African American youth
.
Int J Obes
.
2018
;
42
(
4
):
634
640
59
Danese
A
,
Tan
M
.
Childhood maltreatment and obesity: systematic review and meta-analysis
.
Mol Psychiatry
.
2014
;
19
(
5
):
544
554
60
Miller
GE
,
Chen
E
,
Yu
T
,
Brody
GH
.
Metabolic syndrome risks following the great recession in rural black young adults
.
J Am Heart Assoc
.
2017
;
6
(
9
):
e006052
61
Gianaros
PJ
,
Marsland
AL
,
Sheu
LK
,
Erickson
KI
,
Verstynen
TD
.
Inflammatory pathways link socioeconomic inequalities to white matter architecture
.
Cereb Cortex
.
2013
;
23
(
9
):
2058
2071
62
Verstynen
TD
,
Weinstein
AM
,
Schneider
WW
,
Jakicic
JM
,
Rofey
DL
,
Erickson
KI
.
Increased body mass index is associated with a global and distributed decrease in white matter microstructural integrity
.
Psychosom Med
.
2012
;
74
(
7
):
682
690
63
Rasgon
NL
,
McEwen
BS
.
Insulin resistance-a missing link no more
.
Mol Psychiatry
.
2016
;
21
(
12
):
1648
1652
64
Robles
TF
,
Repetti
RL
,
Reynolds
BM
,
Chung
PJ
,
Arevalo
JMG
,
Cole
SW
.
Family environments and leukocyte transcriptome indicators of a proinflammatory phenotype in children and parents
.
Dev Psychopathol
.
2018
;
30
(
1
):
235
253
65
Pace
TWW
,
Wingenfeld
K
,
Schmidt
I
,
Meinlschmidt
G
,
Hellhammer
DH
,
Heim
CM
.
Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder
.
Brain Behav Immun
.
2012
;
26
(
1
):
13
17
66
Baumeister
D
,
Akhtar
R
,
Ciufolini
S
,
Pariante
CM
,
Mondelli
V
.
Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α
.
Mol Psychiatry
.
2016
;
21
(
5
):
642
649
67
Danese
A
,
Caspi
A
,
Williams
B
, et al
.
Biological embedding of stress through inflammation processes in childhood
.
Mol Psychiatry
.
2011
;
16
(
3
):
244
246
68
Heydtmann
M
,
Adams
DH
.
Chemokines in the immunopathogenesis of hepatitis C infection
.
Hepatology
.
2009
;
49
(
2
):
676
688
69
Berasain
C
,
Castillo
J
,
Perugorria
MJ
,
Latasa
MU
,
Prieto
J
,
Avila
MA
.
Inflammation and liver cancer: new molecular links
.
Ann N Y Acad Sci
.
2009
;
1155
:
206
221
70
Chen
E
,
Miller
GE
.
Stress and inflammation in exacerbations of asthma
.
Brain Behav Immun
.
2007
;
21
(
8
):
993
999
71
Li
M
,
Zhou
Y
,
Feng
G
,
Su
SB
.
The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases
.
Curr Mol Med
.
2009
;
9
(
3
):
365
374
72
Chen
E
,
Miller
GE
,
Kobor
MS
,
Cole
SW
.
Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood
.
Mol Psychiatry
.
2011
;
16
(
7
):
729
737
73
Danese
A
,
Moffitt
TE
,
Pariante
CM
,
Ambler
A
,
Poulton
R
,
Caspi
A
.
Elevated inflammation levels in depressed adults with a history of childhood maltreatment. [published correction appears in Arch Gen Psychiatry. 2008;65(6):725]
.
Arch Gen Psychiatry
.
2008
;
65
(
4
):
409
415
74
Janusek
LW
,
Tell
D
,
Gaylord-Harden
N
,
Mathews
HL
.
Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: an epigenetic link
.
Brain Behav Immun
.
2017
;
60
:
126
135
75
Canadian Academy of Health Sciences Expert Panel
.
Early Child Development
.
Ottawa, Canada
:
Royal Society of Canada
;
2012
76
Gensollen
T
,
Iyer
SS
,
Kasper
DL
,
Blumberg
RS
.
How colonization by microbiota in early life shapes the immune system
.
Science
.
2016
;
352
(
6285
):
539
544
77
Bisgaard
H
,
Hermansen
MN
,
Buchvald
F
, et al
.
Childhood asthma after bacterial colonization of the airway in neonates
.
N Engl J Med
.
2007
;
357
(
15
):
1487
1495
78
Fujimura
KE
,
Sitarik
AR
,
Havstad
S
, et al
.
Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation
.
Nat Med
.
2016
;
22
(
10
):
1187
1191
79
Serino
M
,
Nicolas
S
,
Trabelsi
MS
,
Burcelin
R
,
Blasco-Baque
V
.
Young microbes for adult obesity
.
Pediatr Obes
.
2017
;
12
(
4
):
e28
e32
80
Martinez
FD
.
The human microbiome. Early life determinant of health outcomes
.
Ann Am Thorac Soc
.
2014
;
11
(
suppl 1
):
S7
S12
81
Baldwin
JR
,
Arseneault
L
,
Caspi
A
, et al
.
Childhood victimization and inflammation in young adulthood: a genetically sensitive cohort study
.
Brain Behav Immun
.
2018
;
67
:
211
217
82
O’Mahony
SM
,
Clarke
G
,
Dinan
TG
,
Cryan
JF
.
Early-life adversity and brain development: is the microbiome a missing piece of the puzzle?
Neuroscience
.
2017
;
342
:
37
54
83
Miller
GE
,
Brody
GH
,
Yu
T
,
Chen
E
.
A family-oriented psychosocial intervention reduces inflammation in low-SES African American youth
.
Proc Natl Acad Sci U S A
.
2014
;
111
(
31
):
11287
11292
84
Brody
GH
,
Yu
T
,
Chen
E
,
Miller
GE
.
Family-centered prevention ameliorates the association between adverse childhood experiences and prediabetes status in young black adults
.
Prev Med
.
2017
;
100
:
117
122
85
Brody
GH
,
Gray
JC
,
Yu
T
, et al
.
Protective prevention effects on the association of poverty with brain development
.
JAMA Pediatr
.
2017
;
171
(
1
):
46
52
86
Agency for Healthcare Research and Quality
.
Medical Expenditure Panel Survey
.
Rockville, MD
:
US Department of Health and Human Services
;
2018
87
Takesian
AE
,
Hensch
TK
.
Balancing plasticity/stability across brain development
.
Prog Brain Res
.
2013
;
207
:
3
34
88
GTEx Consortium
.
The Genotype-Tissue Expression (GTEx) project
.
Nat Genet
.
2013
;
45
(
6
):
580
585
89
Alberts
B
,
Johnson
A
,
Lewis
J
, et al
.
Molecular Biology of the Cell
, Sixth Edition.
New York, NY
:
WW Norton & Company
;
2014
90
Armutcu
F
.
Organ crosstalk: the potent roles of inflammation and fibrotic changes in the course of organ interactions
.
Inflamm Res
.
2019
;
68
(
10
):
825
839
91
Vollmer
J
,
Casares
F
,
Iber
D
.
Growth and size control during development
.
Open Biol
.
2017
;
7
(
11
):
170190
92
Snell-Rood
EC
.
Selective processes in development: implications for the costs and benefits of phenotypic plasticity
.
Integr Comp Biol
.
2012
;
52
(
1
):
31
42
93
Du Toit
G
,
Roberts
G
,
Sayre
PH
, et al.;
LEAP Study Team
.
Randomized trial of peanut consumption in infants at risk for peanut allergy. [published correction appears in N Engl J Med. 2016;375(4):398]
.
N Engl J Med
.
2015
;
372
(
9
):
803
813
94
Best
JR
,
Miller
PH
,
Naglieri
JA
.
Relations between executive function and academic achievement from ages 5 to 17 in a large, representative national sample
.
Learn Individ Differ
.
2011
;
21
(
4
):
327
336
95
Blakemore
SJ
,
Choudhury
S
.
Development of the adolescent brain: implications for executive function and social cognition
.
J Child Psychol Psychiatry
.
2006
;
47
(
3–4
):
296
312
96
Card
JP
,
Levitt
P
,
Gluhovsky
M
,
Rinaman
L
.
Early experience modifies the postnatal assembly of autonomic emotional motor circuits in rats
.
J Neurosci
.
2005
;
25
(
40
):
9102
9111
97
Lynch
SV
,
Pedersen
O
.
The human intestinal microbiome in health and disease
.
N Engl J Med
.
2016
;
375
(
24
):
2369
2379
98
Dorrestein
PC
,
Mazmanian
SK
,
Knight
R
.
Finding the missing links among metabolites, microbes, and the host
.
Immunity
.
2014
;
40
(
6
):
824
832
99
Baffy
G
,
Loscalzo
J
.
Complexity and network dynamics in physiological adaptation: an integrated view
.
Physiol Behav
.
2014
;
131
:
49
56
100
Nelson
CA
,
Fox
NA
,
Zeanah
C
.
Romania’s Abandoned Children
.
Cambridge, MA
:
Harvard University Press
;
2014
101
Nelson
CA
 III
,
Gabard-Durnam
LJ
.
Early adversity and critical periods: neurodevelopmental consequences of violating the expectable environment
.
Trends Neurosci
.
2020
;
43
(
3
):
133
143
102
Sullivan
RM
,
Holman
PJ
.
Transitions in sensitive period attachment learning in infancy: the role of corticosterone
.
Neurosci Biobehav Rev
.
2010
;
34
(
6
):
835
844
103
Hensch
TK
,
Bilimoria
PM
.
Re-opening windows: manipulating critical periods for brain development
.
Cerebrum
.
2012
;
2012
:
11
104
Chen
K
,
Ma
X
,
Nehme
A
, et al
.
Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity [published online ahead of print January 3, 2020]
.
Mol Psychiatry
. doi:
105
Lewis
DA
.
Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia
.
Curr Opin Neurobiol
.
2014
;
26
:
22
26
106
Bath
KG
,
Manzano-Nieves
G
,
Goodwill
H
.
Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice
.
Horm Behav
.
2016
;
82
:
64
71
107
Heun-Johnson
H
,
Levitt
P
.
Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice
.
Neurobiol Stress
.
2017
;
8
:
10
20
108
Morishita
H
,
Cabungcal
JH
,
Chen
Y
,
Do
KQ
,
Hensch
TK
.
Prolonged period of cortical plasticity upon redox dysregulation in fast-spiking interneurons
.
Biol Psychiatry
.
2015
;
78
(
6
):
396
402
109
McEwen
BS
.
Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling
.
Ann N Y Acad Sci
.
2010
;
1204
(
suppl
):
E38
E59
110
Gervain
J
,
Vines
BW
,
Chen
LM
, et al
.
Valproate reopens critical-period learning of absolute pitch
.
Front Syst Neurosci
.
2013
;
7
:
102
111
Hensch
TK
,
Quinlan
EM
.
Critical periods in amblyopia. [published correction appears in Vis Neurosci. 2018;35:E024]
.
Vis Neurosci
.
2018
;
35
:
E014
112
Žiak
P
,
Holm
A
,
Halička
J
,
Mojžiš
P
,
Piñero
DP
.
Amblyopia treatment of adults with dichoptic training using the virtual reality oculus rift head mounted display: preliminary results
.
BMC Ophthalmol
.
2017
;
17
(
1
):
105
113
Jobin
C
.
Precision medicine using microbiota
.
Science
.
2018
;
359
(
6371
):
32
34
114
Callaghan
BL
,
Richardson
R
.
The effect of adverse rearing environments on persistent memories in young rats: removing the brakes on infant fear memories
.
Transl Psychiatry
.
2012
;
2
(
7
):
e138

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.