epigenetics: behavioral influences on gene function, part i. maternal behavior permanently affects...

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Epigenetics: Behavioral Influences on Gene Function,Part I. Maternal Behavior Permanently Affects Adult

Behavior in OffspringMARILEE P. OGREN, PH.D., AND PAUL J. LOMBROSO, M.D.

Our ability to identify both genetic and environmentalmediators of emotional-behavioral disorders in childrenhas increased dramatically in the past decade. Thehuman genome project, completed in 2003, fosteredmany other advances that have allowed us to pursueimportant questions about how the interaction of nature(genes) and nurture (environment) can place children atrisk or protect them from psychiatric illness. During thistime, the Journal published many articles demonstratinghow specific candidate genes are associated with specificdisorders. In addition, a few linkage genetic studies havedemonstrated how multiple genetic loci across thegenome contribute genetic risk to a variety of disorders.Most recently, and perhaps most important to the fieldof child and adolescent psychiatry, several wonderfularticles have been published in our Journal andelsewhere that demonstrate the interaction betweenspecific genes and specific environments in relation topsychiatric disorders. The majority of these articlesemphasized that polymorphic genes (e.g., genes withmore than one nucleotide structure due to mutations ofone type or another) interact differently with differentenvironments. The geneYenvironment interaction find-ings have emphasized the importance of the interactionbetween genetic makeup and the environment ratherthan focusing on the importance of one or the other.

Certainly many future studies will focus on how specificenvironments can be risky for some and other specificenvironments protective for others based on theindividual genotype. Such research will doubtlesschange the way we conceptualize, assess, and treatchildren with psychiatric illness.A less well-known and equally elegant line of genetic

inquiry is now yielding remarkable discoveries for thoseof us who study developmental psychopathology.Rather than aiming to determine whether a specificmutation interacts with a specific environment, the fieldof epigenetics aims to determine how certain environ-ments can turn on or turn off specific genes. This line ofinquiry may be best thought of as the environ-mentYgene interaction approach.We now know that gene function can be altered

without changing the nucleotide sequence itself. Thesechanges are called epigenetic (from the Greek epi-, whichmeans ‘‘on top of ’’ or ‘‘in addition to’’). The emergingfield of epigenetics pursues a novel question: how doesthe environment interact with DNA? This column dis-cusses the relevance of epigenetics to one area in the fieldof child and adolescent psychiatry, the effect of maternalcare on later development and behavior. We havefocused on the work of Michael Meaney, Arie Kaffman,and colleagues (see ‘‘Additional Readings’’ below), whohave turned the usual line of inquiry on its head. Insteadof focusing on how genes can alter behavior, they haveasked how specific behaviors affect genes.When psychiatry became a rigorous field of inquiry, a

debate arose as to whether genes or the environmentwere paramount in the development of psychopathol-ogy. The literature no longer debates this issue, asbecause both nature and nurture are now known to becritical modulators of normal development. Howmutations (nature) can disrupt developmental processes

C L I N I C A L IM P L I C A T I ON S O F B A S I C R E S E A R CH Paul J. Lombroso,M.D.,Marilee P. Ogren, Ph.D.

Accepted October 7, 2007.Dr. Ogren is with the Departments of Biology and Psychology, Boston College,

and Dr. Lombroso is with the Yale Child Study Center.Article Plus (online only) materials for this article appear on the Journal`sWeb

site: www.jaacap.com.Correspondence to Dr. Marilee Ogren, Biology Department, Boston College,

140 Commonwealth Avenue, Boston, MA; e-mail: [email protected]/08/4703-0240�2008 by the American Academy of Child and

Adolescent Psychiatry.DOI: 10.1097/CHI.0b013e3181635e13

Assistant Editors

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is well appreciated. In this first column, we focus on howthe environment (nurture) can affect gene expression.This column summarizes striking findings in rodentsshowing that maternal behavior in the first week of lifepermanently influences the offsprings` response to stressin adulthood as well some of their cognitive andmaternal behaviors. The altered stress response has beenstudied at both the behavioral and molecular levels, andmolecular mechanisms by which behavior can perma-nently alter gene function are known or close at hand. Inother words, gene expression can be turned on and offby certain maternal behaviors through the work ofprecise molecular mechanisms. Perhaps most surprising,these effects are transgenerational; subsequent genera-tions inherit the same behaviors through epigeneticrather than genetic mechanisms. There are no newDNA mutations; instead, certain molecular modifica-tions influence the expression of specific genes or sets ofgenes. Similar effects are evident in nonhuman andhuman primates. This two-part series tells the story ofthese behavioral and molecular events and relates themto similar scenarios in humans. We begin here with thebehavioral events. Part II of this column discusses themolecular events in a subsequent issue of the Journal.

BEHAVIORAL EFFECTS OF MATERNAL NURTURING

Newborn rat pups are pink, hairless, and sightless andhave limited mobility. They are totally dependent onmaternal care for their survival. Crucial maternalbehaviors include nursing and retrieving pups whenthey stray from the nest. Other, more subtle behaviorsare equally important in rodents; these include lickingand grooming (LG) and crouching over the pups tonurse in a posture known as arched-back nursing (ABN;please refer to images available in the Article Plusmaterial available on the Journal Web site, www.jaacap.com). LG constitute important sources of tactile stim-ulation in newborn rat pups. ABN is a posture thatfavors suckling by all pups and the ability for pups tochange nipples because all nipples are exposed at once(compared with dams lying on their sides). Thefrequency of this maternal posture correlates with thefrequency of LG. Together, the frequency of LG-ABNhelps define the overall degree of nurturing by the damand represents an important animal model for theinfluence of maternal behavior on adult behavior inthe offspring.

The use of such animal models of maternal nurturinghas become increasingly important for those studyingthe influences of the human family and early lifeexperiences (particularly adversity) on mental health inadulthood. The ‘‘stress diathesis’’ model suggests thatnervous system development is permanently influencedby adversity in early life. Adversity can take many formsin humans, such as poverty, abuse, and neglect. Recentwork has shown that adversity increases the sensitivity ofdefensive responses during development and that,biologically, this is adaptive because it adjusts organfunction to anticipated levels of environmentaldemands. The price, however, is an increased risk ofseveral types of chronic illness, especially stress-relateddiseases (obesity, metabolic disorders, heart disease,affective disorders, and drug abuse). Two fundamentalideas underlie the stress diathesis model. First, research-ers believe that environmental effects of stress can betransmitted to the developing offspring by variations inparental care. Second, this effect is part of a largerprocess of developmental adaptation to the environ-mentVthe effect can go either way depending on theenvironment into which the animals are born.Some rat mothers naturally display relatively high

levels of nurturing behaviors and others display relativelylow levels. Several studies have shown that the offspringof mothers with high levels of LG-ABN (representinghigh levels of maternal care) are less anxious as adults.This is reflected in less circulating corticotropin(ACTH) and corticosterone in response to stresscompared to the offspring of low LG-ABN mothersthat are relatively less nurturing (Fig. 1). These findingsare consistent with earlier work in rats showing thathandling during the first postnatal week and increasedtactile stimulation by stroking with a paintbrush alsohave lifelong effects on the animals` response to stress.Cognitive and maternal behaviors are also different in

the offspring of high versus low LG-ABN dams.Cognitive differences are related to memory; theoffspring of high LG-ABN mothers do better in spatiallearning and memory tasks than their counterparts, andthey do better at object recognition. The mothersthemselves display differences in stress reactivity; lowLG-ABN mothers are more fearful than their counter-parts. Accordingly, the maternal behavior of the femaleoffspring is also affected by high versus low LG-ABN intheir mothers. Offspring of low LB-ABN mothers arefearful and become low LG-ABN mothers themselves.

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These influences on maternal behavior promote thetransgenerational transmission of individual responses tostress.It is logical to assume that these differences in the

offspring of high versus low LG-ABN mothers arepurely genetic, but ‘‘cross-fostering’’ experiments ruleout this explanation. Pups born to high LG-ABNmothers who are reared by mothers with low LG-ABNare more anxious and circulate more corticosteronethan their counterparts who were born to low LG-ABN mothers but reared by high LG-ABN mothers.No new genetic mutation occurred in the cross-

fostered pups; the difference in the offspring resultsfrom the environmental effects on gene expression.This is what makes the effect epigenetic rather thangenetic in nature.

CRITICAL PERIOD FOR EMOTIONAL, COGNITIVE,AND SOCIAL BEHAVIOR

What is remarkable is that it only takes 1 week toestablish these specific and stable behavioral phenotypesin the rodent offspring. During the first postnatal week,the frequency of tactile stimulation in the form of LG bythe mother has long-term effects on adult behaviors,including the response to stress. Animals that have beenhandled regularly by experimenters or stroked with apaintbrush develop the same behavioral phenotype asthe offspring of high LG-ABN mothers.It is noteworthy that a parallel event is taking place

during this first postnatal week; tactile stimulationinvolving the whiskers is necessary to ensure properdevelopment of the primary somatosensory cortex.Anatomically defined barrel fields are present in thenormal somatosensory cortex of most mammals; theseare aggregates of cortical neurons representing indivi-dual whiskers. If the whiskers are experimentallyremoved during the first week of life, then the barrelfields fail to develop and the circuitry in the so-matosensory cortex is permanently altered. Whiskerremoval after the first postnatal week has no such effect.This work in the somatosensory barrel fields providessome of the most striking evidence of experience-dependent cortical plasticity in mammalian cortex. Thisis a classic example of a ‘‘critical period’’ in whichsensory experience has a permanent effect on corticalorganization and sensory processing. Critical periodsrepresent a specific window of time during earlydevelopment when specific sensory systems are plastic.Each sensory modality has its own critical period. It isnot known how these critical periods in the sensorysystems relate to the work discussed here. However, thestudies involving maternal behavior and the stressresponse are especially remarkable because they repre-sent the first example of an experience-dependentcritical period for emotional behavior. Also, themolecular events that underlie the sensory criticalperiods share some commonalities with those under-lying the emotional critical period discussed here, asdescribed in Part II of this column.

Fig. 1 The quality of maternal nurturing, in terms of tactile stimulation andnursing, affects the stress response in the offspring. Plasma corticotropin(ACTH; top) and corticosterone (bottom) responses to stress are statisticallydifferent (p < .05) in the offspring of high versus low licking and groomingand arched-back nursing (LG-ABN) mothers. The stress response is bluntedin the offspring of high LG-ABNmothers compared with the offspring of lowLB-ABNmothers. Animals (n = 8Y10) were exposed to a 20-minute period ofrestraint (S10 and S20). ACTH and corticosterone levels increased inresponse to stress in both groups, but the offspring of more nurturing mothers(high LG-ABN) were less stressed by both measures than the offspring of lessnurturing mothers (low LG-ABN). From Dong Liu et al. Science,1997;277:1659. Reprinted with permission from the American Associationfor the Advancement of Science, 1200 New York Avenue NW, Washington,DC 20005.

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EFFECTS OF MATERNAL CARE IN PRIMATES

These experiments in rodents are reminiscent of thesurrogate mothers devised by Harry Harlow in the late1950s. Infant monkeys who had been removed fromtheir mothers at birth received nourishment fromsurrogate mothers that were either made of wire orcloth. These animals developed abnormal cognitive,sexual, and maternal behaviors as a consequence.Remarkably, infants given access to a wire motherwho provided nourishment and a cloth mother whoprovided no nourishment spent the majority of theirtime with the cloth surrogate, presumably for the tactilestimulation. These animals fared better on behavioralmeasures than their counterparts who had access only tothe wire mothers.

The benefits of tactile stimulation are evident inpremature human infants as well. In the past, theseinfants had been confined to incubators withoutsufficient tactile stimulation. When regular sessions ofmassage therapy are introduced into their daily routine,these preterm infants show evidence of increased weightgain and longer periods of alertness. Moreover,premature infants who have had the benefit of just1 hour per day of skin-to-skin contact with their mothersshow improved performance on cognitive and motortasks when tested at 6 months.

PHYSIOLOGICAL CHANGES ASSOCIATED WITHTACTILE STIMULATION

It is difficult to imagine how the physical sensationof LG by a dam or, for that matter, handling byexperimenters or being stroked with a paintbrush couldpermanently change the way an animal behavesthroughout its lifetime. The chain of events involvesseveral groups of neurons including those related to thehypothalamic-pituitary axis and specific molecularevents (Fig. 2), which are discussed in more detail inPart II of this column. The molecular changes that makethe changes permanent are an extremely important focusof this work because they provide avenues forpharmacological intervention.

Tactile stimulation, or the lack of it, promotes someimportant physiological responses. As mentioned earlier,rodents with lots of maternal care in the form of tactilestimulation are the least fearful, and secrete the lowestlevels of ACTH and corticosterone in response to stressthroughout their lives (Fig. 1). Rodents with prolonged

separation from their mother, and the resulting loss oftactile stimulation during this period, secrete the highestlevel of corticosterone in response to stress as the resultof an increased release of ACTH.In other words, tactile stimulation reduces the activity

of the hypothalamic-pituitary axis in neonates. This hasthe beneficial effect of protecting well-nurtured neo-nates from the effects of circulating glucocorticoids thatwould otherwise be released from the adrenal gland.Besides the effects on the stress response, this effect isrelated to the increased incidence in chronic diseaseassociated with high stress childhoods. Chronicallyhigh levels of circulating corticosteroids early in lifepredispose human children to chronic disease. Themolecular changes that mediate blunted hypothalamic-pituitary axis reactivity in animals with higher levelsof tactile stimulation during the critical first week oflife is the subject of the next column as is the way inwhich this effect is made permanent (i.e., the epi-genetic effect).These exciting findings in animal models are leading

to epigenetic studies that will shed new light on humanpsychiatric illnesses. Classic genetic inheritance mechan-isms clearly play a role in many psychopathologies suchas depression, anxiety, and some types of schizophrenia.

Fig. 2 The quality of maternal nurturing influences hypothalamic-pituitary-adrenal (HPA) activity in the offspring. The response of the adrenal glands isblunted (right-hand column) in animals with high licking and grooming (LG)and enhanced in animals with low LG. These effects result from changes inhippocampal neurons and their downstream effects on the pituitary andadrenal glands (discussed in Part II of this column). From Kaffman A,Meaney M, Journal of Child Psychology and Psychiatry 2007;48:3/4. Reprintedwith permission from Blackwell Publishing.

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However, these effects are likely to occur together withenvironmentally driven epigenetic mechanisms (i.e.,the interaction of genes and the environment clearlymodifies neurodevelopment). A precise understandingof the environmental contribution will provide us withthe opportunity to intervene in nonpharmacologicalways, such as enhancing parenting skills, to reducepsychopathology and disrupt the transmission of certainpathologies across generations.

Disclosure: The authors report no conflicts of interest.

ADDITIONAL READING

Kaffman A, Meaney M. Neurodevelopmental sequelae of postnatal maternalcare in rodents: clinical and research implications of molecular insights.J Child Psychol Psychiatry. 2007;48:224Y244.

Meaney M. Maternal care, gene expression, and the transmission ofindividual differences in stress reactivity across generations. Annu RevNeurosci. 2001;24:1161Y1192.

Tsankova T, Renthal W, Kuman A, Nestler E. Epigenetic regulation inpsychiatric disorders. Nat Rev. 2007;8:355Y367.

Douglas Mental Health University Institute. Michael Meaney, PhD,C.Q., FRSC. http://www.douglasrecherche.qc.ca/profiles/details.asp?l=e&id=101. Accessed January 3, 2008.

Science and nature: TV & radio follow-up. The ghost in your genes. http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml.Accessed January 3, 2008.

OGREN AND LOMBROSO


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