Epigenetics of the Developing Brain Frances A. Champagne|Psychology

Epigenetics of the Developing Brain Frances A. Champagne|Psychology

understanding of the dynamic molecular interplay between DNA and its surrounding proteins suggest that epigenetic mechanisms are a critical link between early life experiences (e.g., prenatal stress, parent-offspring interactions) and long-term changes in brain and behavior. Although much of this evidence comes from animal studies, there is increasing converging evidence of these epigenetic processes in humans. These new insights into epigenetic pathways highlight the integration of nature and nurture during development and the potential for heritable changes that persist across generations.

E arly experiences create the foundations of individualdifferences and how each person interacts with the world. Though debate about the relative contributions of nature versus nurture to personality, behavior, and risk of disease has dominated discussions within psychology, biology, and neurosci­ ence, the science is now poised to move beyond this dichotomy. Advances in molecular biology have provided insights into both nature and nurture and suggest that development is a process involving complex interactions between these two inseparable factors. This newfound understanding of gene-environment interplay has significant implications for conceptualizations of the developing brain. Even before birth, brains are chang­ ing and refining in response to experiences. At first, these are shared experiences between the mother and fetus, and there is a growing sense that what a mother eats, drinks, or breathes and certainly how she feels during pregnancy can affect the fetus. This sensitivity to the environment continues from birth into childhood and beyond. Both the sensory and the social world around a developing child can have a lasting impact on the brain. The question raised by this phenomenon of developmen­ tal and neural plasticity is regarding mechanism: How does this dynamic process take place? Answering this question unites both the classic notions of nature versus nurture with the new and emerging science of epigenetics.

From Genetics to Epigenetics Each human’s genetic make-up is predictive of both physical and psychological characteristics, and the current ability to sequence genomes and provide individuals with a detailed description of their DNA is truly astounding. In experimental studies in animals, manipulating DNA, even a single gene, can

have profound consequences. However, exclusive focus on genetic make-up as an account of an individual’s identity has always been at odds with the sense that environments, particularly those experienced during childhood, shape development. Moreover, decades of research has confirmed that “nurture” in the very broad sense, consisting of sensory, social, nutritional, and toxicological experiences, has a profound effect on brain function and behavior. This uncomfortable dichotomy between the role of DNA and the role of the environment as developmental influences may be resolved by taking a closer look at DNA.

Within the DNA sequence is encoded the instructions for creating the building blocks of human anatomy, hence often earning the description “the book of life” However, like all books, the biological book of life must be read for the knowledge within to be realized. This reading is an active process involving the collective efforts of numerous proteins and enzymes that either interact directly with DNA or with the proteins around which DNA is wrapped (Peterson & Laniel, 2004; Razin, 1998). The dilemma of biology is in the compact storage of sufficient DNA to encode all the information needed to create a complex organism; which in the case of humans involves over 20,000 protein-encoding genes and more than 3 billion nucleotide base pairs (adenine, thymine, cytosine, guanine). This is ultimately a space issue. In order to fit this much biological material into each cell, a compact structure is imposed on DNA consisting of a network of histone proteins (see Figure 1). Much like the towering apartment complexes in Manhattan that permit a population density of 70,000 people per square mile, these histones interact directly with the DNA and allow for the dense packaging observed in the nucleus of cells (Peterson & Laniel, 2004; Razin, 1998). However, solving this space issue creates a

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FIGURE 1 Schematic Illustration of Epigenetic Mechanisms

DNA is wrapped around clusters of histone proteins to promote compact storage of the genome. (A) The DNA can become methylated, by addition of a methyl chemical directly to the DNA sequence. This epigenetic modification typically reduces gene activity. (B)The histones can also be chemically modified, with consequences for gene activity.

Collectively, these epigenetic marks influence the accessibility of DNA to transcription.

second problem. The readability of DNA is entirely dependent on the accessibility of DNA. When DNA is compactly stored it is not readable; much like a book located far from reach or obscured by an adjacent bookshelf. Thus, gene activation, the transcription of DNA, involves significant rearrangements in the architecture of DNA and its surrounding histone proteins (see Figure 1). Once DNA is unwrapped from histones and associated chemicals and proteins, the reading can commence and a chain of events is initiated that can lead to biological changes in the organism. The chemicals and proteins that control gene activity without altering the DNA sequence are collectively referred to as epigenetic. These factors can promote both gene expression and gene silencing, with both of these processes being essential for normal development (Taylor & Jones, 1985).

Epigenetic factors create a secondary layer of information within the genome. The elegant DNA sequence provides the instructions of “what” to make, while epigenetics instructs as to the “when” and “how much.” Both layers of information are needed for normal development to proceed. Epigenetics also accounts for the diversity of cells that emerge in an organism. Within an individual, each cell has a specific role to play, and there are multiple cell types (e.g., muscle, blood, neurons) that have distinct physical and functional characteristics. However, each of these cells has the same DNA sequence. The unique characteristics of cells are generated from their unique epigenetic patterns (Taylor & Jones, 1985). Thus, in neurons, genes that are needed in muscle cells may be epigenetically silenced and genes that promote neuronal function are epigenetically active. It is important to note that these epigenetic patterns can be highly stable. Cells must “remember” and maintain their characteristics over the lifespan.

Understanding of the importance of epigenetics in controlling the activity of genes emerged in the 1980s, and these molecular mechanisms have been studied extensively within certain disease states, particularly cancer (Jones & Laird, 1999). The new perspective that has emerged in the past decade is regarding

the role of these mechanisms in gene-environment interplay. Epigenetic factors, particularly chemical modifications directly to the DNA itself, were initially thought to be resistant to change beyond early embryogenesis. However, in the past 10 years, evidence has emerged supporting the malleability of epigenetic variation in response to a diverse range of experiences occurring across the lifespan. These experiences include classic biological exposures, such as food, toxins, and hormones as well as the quality of the socio-emotional environment, conveyed primarily through parent-infant interactions (Champagne, 2010). Environmentally induced epigenetic variation may be a common mechanism for all aspects of environmental experience to shape and control the genome. The implications of this perspective are profound. While DNA sequence is the result of a slow and methodical evolution, the capacity of the environment to create epigenetic variation suggests that dynamic functional consequences for the genome can arise during development and dramatically alter the characteristics of an individual. Moreover, this epigenetic plasticity may be particularly evident in response to experiences occurring during sensitive periods (i.e., prenatal through to childhood).

Prenatal Programming During fetal development, the rapid pace of biological change creates a window of vulnerability to developmental disruption. Prenatal exposure to famine is associated with increased met­ abolic dysfunction, neurodevelopmental disorder, and schizo­ phrenia in adulthood (Susser, Hoek, & Brown, 1998). Mothers exposed to stress during pregnancy are more likely to experience birth complications and pre-term birth (Coussons-Read et al., 2012). Stress programming is also observed—where the stress response of offspring is heightened when the mother is prena- tally stressed (Glover, O’Connor, & O’Donnell, 2010). These correlational findings are complemented by studies examining

The current ability to sequence genomes and provide individuals with a detailed description of their DNA is truly astounding.

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Prenatal exposure may directly impact fetal tissues through physiological changes in the mother during pregnancy.

childhood outcomes following in vitro fertilization where the fetus is genetically related or unrelated to the mother. This study design suggests that there are unique developmental outcomes associated with genetic risk and the environmental risk conferred by maternal prenatal distress. For example, reduced birth weight, reduced gestational length, and antisocial behavior emerge as out­ comes of prenatal stress even when there is no genetic relatedness between mother and child (Rice et al., 2009).

An increasing appreciation of the plasticity of epigenetic factors in response to the environment has led to a particular focus on these mechanisms in the context of prenatal adversity. In longitudinal studies of the impact of famine, individuals exposed during the earliest stages of fetal development carry a lasting epigenetic signature. In particular, there is altered DNA methylation—an epigenetic modification directly to DNA that is associated with gene silencing (see Figure 1)—in genes controlling growth and metabolism among individuals exposed in utero to famine (Heijmans et al., 2008). Although famine involves nutritional restriction, this exposure is also a significant physiological and emotional stressor, and there is increasing evidence of epigenetic outcomes as a consequence of prenatal stress. In a recent study, more than 900 genes were found to be altered in their DNA methylation levels in children born to prenatally stressed mothers, with many of these genes being involved in immune function (Cao-Lei et al., 2014). One gene that has emerged in many studies of prenatal stress and distress encodes for the glucocorticoid receptor (Nr3cl)—a protein that plays a role in the stress response system. Epigenetic variation that reduces the activity of the glucocorticoid receptor gene can render individuals hypersensitive to stressors and puts them at risk of numerous neurodevelopmental and physical disorders (Champagne, 2013). Maternal depression and anxiety during pregnancy and exposure to stress are associated with epigenetic suppression of Nr3cl in infants and children with some indication that these epigenetic shifts are programming the stress response of affected infants (Hompes et al., 2013; Oberlander et al., 2008).

Human studies of prenatal programming are compelling but are necessarily correlational. However, experiments in animals have been used to establish “cause and effect” to examine the impact of prenatal adversity on the brain, and provide support for an epigenetic hypothesis. In mice, offspring of prenatally stressed mothers manifest behavioral, physiological, and neurobiological changes consistent with heightened stress reactivity and anxiety. Within the hippocampus, a brain structure implicated in both the neuroendocrine response to stress and with learning and memory, this early life stress results in decreased expression of glucocorticoid receptors (reduced gene activity) and elevations in DNA methylation within the Nr3cl gene (Mueller & Bale, 2008). The observation that these epigenetic changes associated with prenatal experiences are sustained into adulthood speaks to the enduring nature of these biological mechanisms. This sustained molecular impact is likewise observed following prenatal exposure to dietary manipulations and exposure to toxins (Champagne, 2010).

A critical question that remains is how these epigenetic marks are triggered. What is it about these prenatal experiences that are capable of inducing an epigenetic change? There are at least three possible routes to consider, which may work in combi­ nation to achieve these effects (Monk, Spicer, & Champagne, 2012). First, the prenatal exposure may directly impact fetal tissues through physiological changes in the mother during pregnancy. In the case of prenatal stress, it is hypothesized that the stress the mother experiences increases her release of stress hormones (glucocorticoids) and these hormones either directly or indirectly (i.e., through other physiological pathways like the immune system) act at a molecular level to alter epigenetic pat­ terns within the genome. This explanation certainly makes intu­ itive sense and there are studies that (a) confirm that increases in maternal glucocorticoids are associated with increases in the levels of these hormones in amniotic fluids, (b) illustrate the epigenetic variation induced by glucocorticoids, and (c) illus­ trate that maternal glucocorticoid levels are predictive of stress responses in offspring. A second pathway involves prenatal epi­ genetic disruption to the placenta. The placenta is the interface between the mother and fetus during pregnancy and is essential to growth and development during this period. Epigenetic dis­ ruption in the placenta is associated with birth complications and neurodevelopmental problems, and maternal exposure to stress, nutritional variation, and toxins is associated with altered DNA methylation levels in the placenta. Finally, the impact of prenatal environmental conditions may be achieved through alterations in the quality of postnatal mother-infant interactions. For example, stress can trigger depressed mood and reduce the amount of positive affect and physical contact that mothers engage in with the newborn (Monk et al., 2012). Disruptions to the mother-infant relationship as a consequence of prenatal stress have been observed in both humans and animals and may set the stage for long-term developmental disruption in infants. The quality of this relationship can also moderate the impact of prenatal stress. For example, although high maternal glucocorticoid levels during pregnancy can predict deficits in cognitive ability among infants, this effect

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is attenuated when there is a secure mother-infant attachment (Bergman, Sarkar, Glover, & O’Connor, 2010).

Mothering the Newborn Brain The newborn brain is a biologically sensitive structure that is rapidly changing and refining in response to the sights, sounds, and feelings of the surrounding world. In mammals, this world is dominated by interactions with parents, particularly mothers. Although it is generally accepted that the quality of the mother-infant relationship can exert a profound influence on development, much of the direct evidence confirming this influence comes from animal studies. Classic studies in monkeys conducted by Harry Harlow in the 1950s and 1960s demonstrated that infants deprived of maternal contact during infancy had a heightened reactivity to stress and were impaired in social behavior in later life (Harlow, Dodsworth, 8t Harlow, 1965). More recent applications of this experimental design indicated that these long-term effects are associated with neurobiological and molecular changes, including decreased brain serotonin neurotransmitter receptors and enlargement in the volume of stress-sensitive brain regions (Spinelli et ah, 2010; Spinelli et al., 2009). These detrimental effects of parental deprivation are similarly observed in humans, such as when infants are reared in orphanages and have limited physical or social interactions with caregivers. This form of institutional rearing leads to social and emotional problems in childhood and adolescence, cognitive impairment, decreased total brain volume, and increases in the volume of the amygdala (Hostinar, Stellern, Schaefer, Carlson, & Gunnar, 2012; O’Connor, Rutter, Beckett, Keaveney, & Kreppner, 2000; Tottenham et ah, 2010). The amygdala is involved in the processing of fearful stimuli, and enlargement in the size of the amygdala likely contributes to the increased activation of this brain region in response to threat cues that has been observed in institutional-reared children. The serotonin system, which is altered in response to maternal deprivation in primates, may also moderate the effects of maternal deprivation in humans. Among adolescents with a genetic variant of the serotonin transporter, there is a heightened level of emotional impairment observed following institutional rearing, particularly amongst those individuals who experience subsequent stressful life experiences (Kumsta et al., 2010). These gene-environment interactions play a critical role in the development of psychiatric outcomes in response to early life adversity.

Laboratory rodents can also be used to illustrate the effect of maternal deprivation, prolonged separation, and disruption to the quality of mother-infant interactions. These models confirm and expand on what has been learned from humans and non-human primates. Heightened neuroendocrine response to stress, disruptions to the serotonin system, and alterations in brain architecture are all hallmarks of the experience during neonatal development of reduced maternal care (Curley, Jensen, Mashoodh, & Champagne, 2011). However, one does not have to invoke these extreme forms of early life experience to observe neurobiological and behavioral consequences. In all species, there are naturally occurring variations in parental care. In humans,

The impact of prenatal environmental conditions may be achieved through alterations in the quality of postnatal mother-infant interactions.

variation exists in how sensitive and responsive mothers are to infant cues of distress (Hane 8c Fox, 2006). In non-human primates, mothers differ in the frequency with which they hold infants (Fairbanks 8c McGuire, 1988). Even in laboratory rodents, mothers display significant variation in the frequency with which they provide physical contact to offspring. A particular form of contact that is characteristic of maternal rodents is pup licking and grooming. This behavior serves, as the name implies, to groom and clean the pups and is also a source of sensory experience that shapes the developing brain. Offspring that receive more of this form of maternal care during the first week of life are less stress sensitive and perform better on cognitive tasks, and these functional consequences are associated with morphological and molecular changes in the brain that can be observed into adulthood (Meaney, 2001). It is the lasting nature of these changes that suggested the possible involvement of epigenetic variation.

The early assumption that epigenetic variation could be induced only during embryogenesis hindered the application of epigenetic analyses to studies of postnatal environmental influence. However, there is now strong support for the involvement of epigenetic pathways in explaining the long-term impact of maternal care. In rodents, high levels of maternal care lead to decreased DNA methylation within the Nr3cl gene during infancy and, due to the lasting nature of this chemical mark, reduced Nr3cl DNA methylation is sustained in these offspring across the lifespan (Weaver et al., 2004). Consequent to these epigenetic changes, offspring that receive high levels of maternal care during infancy have increased levels of glucocorticoid receptors in the hippocampus and are better able to reduce their physiological and behavioral response to stress. Cross-fostering studies, where offspring are transferred from a high or low maternal care biological mother to a high or low maternal care rearing environment confirm that these epigenetic, neuroendocrine, and behavioral effects of maternal care are attributed to the experiences offspring have during development

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The newborn brain is a biologically sensitive structure that is rapidly changing and refining in response to the sights, sounds, and feelings of the surrounding world.

(Weaver et al., 2004). Moreover, these epigenetic changes are reversible in adulthood using pharmacological treatments that target DNA methylation (Weaver et al., 2004; Weaver et al., 2005). Because the experience of high versus low levels of maternal

Learn M o re

Psychobiology, Epigenetics, and Neuroscience Lab http://champagnelab.psych.columbia.edu

This website provides links to ongoing research publications focused on basic and translational research on the biological impact of early life experiences.

Columbia Center for Children’s Environmental Health http://ccceh.org

This website provides information for researchers, health professionals, communities, and families on the impact of environmental exposures during development.

Brain Facts w w w .bra in facts.org

The Brain Facts website is a public information initiative developed by global nonprofit organizations working to advance brain research.This site includes descriptions of researchers’ current understanding of brain development and epigenetics.

Ghost in Your Genes www.pbs.org/wgbh/nova/genes/

NOVA documentary describing key findings that have contributed to researchers’ understanding of the role of epigenetics in gene-environment interplay.

Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life

E. Jablonka and M. J. Lamb (2005). Cambridge, MA: MIT Press

Nature Via Nurture: Genes, Experience, and What Makes Us Human

M. Ridley (2003). NewYork, NY: Harper.

care lead to changes in the transcription of hundreds of genes within the brain, it is likely that early rearing experiences lead to significant shifts in the epigenetic profile of the entire genome— the epigenome.

Evidence for the involvement of epigenetic pathways in the effects of naturally occurring variations in maternal care in rodents has been complemented by many subsequent studies exploring these mechanisms in response to disruptions to mother-infant interactions. Prolonged periods of maternal separation in rodents induces epigenetic variation in the brain of offspring, particularly in genes in involved in the stress response, such as vasopressin, corticotrophin releasing factor receptor (Crfr2), and Nr3cl (Franklin et al., 2010; Kundakovic, Lim, Gudsnuk, & Champagne, 2013; Murgatroyd et al., 2009). Rodents can also engage in abusive caregiving behavior, and the experience of these interactions during postnatal development can lead to epigenetic changes within the brain-derived neurotrophic factor (Bdnf) gene (Roth, Lubin, Funk, & Sweatt, 2009). Epigenetic silencing of Bdnf can impair neural plasticity and may lead to an increased risk of mood disorder in adulthood. In primates that are deprived of maternal care, epigenetic disruption is observed in both the brain and the blood, suggesting that the blood may carry an epigenetic signature of this early life adversity (Provencal et al., 2012). The translation of animal studies to humans is highly dependent on researchers’ ability to measure experience- dependent epigenetic changes in the blood, saliva, or buccal cells. In humans, postmortem brain analyses suggest that increased Nr3cl DNA methylation is observed in individuals with a history of childhood abuse (McGowan et al., 2009) and this epigenetic shift can similarly be observed in the blood (Perroud et al., 2014). However, it is important to note that genome-wide epigenetic shifts are likely occurring in response to disruption to the quality of the early life social environment, and it is unclear what the brain-blood relationship will be for all genes.

From One Generation to the Next The lasting epigenetic impact of mother-infant interactions that occur prenatally or postnatally may account for the emergence of neurobiological and behavioral disruption that has been observed consequent to early life adversity. A question that has emerged is whether these changes could persist to subsequent generations. It is well-established in both humans and animals that patterns of maternal care can be transmitted from mother to daughter and from fathers to sons (in species where males participate in caregiving). In rodents, the experience of high levels of maternal care by female offspring leads to shifts in the developing neuroendocrine circuits that regulated maternal care itself. Consequently, if a rat pup has received high levels of maternal care, it will bestow high levels of maternal care toward its own offspring. This transmission of maternal behavior is associated with epigenetic changes within the gene encoding the estrogen receptor (Esrl; Champagne, 2008). High maternal care leads to decreased DNA methylation and other changes to the histones surrounding the Esrl gene. These effects emerge during postnatal development and persist into adulthood (Pena,

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Neugut, & Champagne, 2013). A similar epigenetic transmission is observed following the experience of abusive caregiving. Rat pups that have experienced abuse are more likely to engage in abusive caregiving themselves, and this shift in behavior is accompanied by epigenetic changes in the Bdnf gene (Roth et al., 2009). These examples provide support for the role of epigenetic mechanisms in the experience-dependent transmission of variation in behavior across generations that may account for the transgenerational impact of abuse, attachment security, and parental care in humans.

Classic views of inheritance focus on the transmission of genetic information—variation in DNA. Thus, increasing evidence of a behavioral transmission of epigenetic variation via parental care is typically viewed as an example of developmental plasticity rather than of inheritance. However, epigenetic variation may also be inherited in a similar way to the inheritance of DNA—through the germline. The sperm and oocyte are the carriers of an individual’s genetic make-up to its descendants. Although these cells can be damaged or the DNA mutated following exposure to radiation or toxins, it has been assumed that these cells otherwise do not carry a lifetime accumulation of “baggage” to the next generation. At the time of conception, there is significant epigenetic reprogramming that occurs. During this time, the epigenome is reset (Feng, Jacobsen, & Reik, 2010). However, there is emerging evidence that this biological “clean slate” retains some remnants from its ancestors. Parental exposure to toxins, dietary extremes, and stress can leave an epigenetic mark within the germline that is inherited by offspring. For example, altered DNA methylation in the Crfr2 gene is observed in the sperm of male mice that experience maternal separation during the postnatal period. This same epigenetic mark is present in the brains of offspring of these males (Franklin et al., 2010). The observation of this inheritance through males is important mechanistically, because male mice do not have any contact with offspring. Although researchers still have much to learn about the mechanisms that account for paternal epigenetic inheritance, this is certainly a phenomenon

that challenges current views on the origins of an individual’s unique characteristics.

Future Directions

Epigenetics is in its infancy and will certainly grow and develop as the field moves forward. There are critical questions that have yet to be addressed regarding the process by which the qualities of the environment become encoded into the epigenome and the degree of stability versus plasticity that can be expected from this molecular partner to DNA. However, regardless of where the pursuit of these questions leads, epigenetics has created a new way of thinking. Rather than being constrained by the conventions of nature versus nurture, questions of development and inheritance can be addressed from a truly integrative perspective. The developing brain is the product of this integration, responding and changing in response to variation in DNA sequence, inherited molecular marks, and epigenetic variation that arises through life experience. It is important to note that experience can also be viewed in an integrated way through the lens of epigenetics. What individuals eat, drink, breathe, and how they feel can impact their biology through the same mechanism. The social environments to which individuals are exposed, and perhaps even those of their parents, can shift the readability of their DNA just as profoundly as exposure to drugs, toxins, and pollutants. The implications for policy and practice of the elucidation of these biological pathways may be significant, particularly when considering the potential heritability of environmentally induced epigenetic change. When adults nurture the developing brain they are nurturing the DNA of generations to come—a realization that conjures a growing sense of responsibility and hope.

Frances A. Champagne, PhD, is cu rren tly an associa te pro fessor in th e D epartm ent o f Psychology a t Columbia University. Her research and teach ing focus on the neurobio log ica l and ep igene tic im pact o f early life experiences and the c ritica l ro le o f m others and fa the rs in shaping deve lopm enta l outcom es.

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8 Zero tv Three • January 2015

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