Linking Emotion to Social Brain

7/21/2019 Linking Emotion to Social Brain

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EMBOreports VOL 8 | SPECIAL ISSUE | 2007 2007 EUROPEAN MOLECULAR BIOLOGY ORGANIZATIONS24

science & societyscience & society

Linking emotion to the social brainThe role of the serotonin transporter in human social behaviour

Klaus-Peter Lesch

In 2006, research on the neurotransmit-ter serotonin and its transporter protein

(5-HTT) in the synaptic gap celebrated aseries of anniversaries. Forty-five years ear-lier, presynaptic neurotransmitter uptakewas discovered (Hertting & Axelrod, 1961).Two decades later, 5-HTT was first linked todepression (Langer et al, 1981), shortly afterits identification as a target of antidepressantdrugs (Raisman et al, 1979). The sequence ofthe transporter gene from rats was published10 years after that (Blakely et al, 1991),which initiated an avalanche of moleculargenetic studies on the regulation of emotion-ality. This research culminated in two reportsrevealing an association between variationsof the 5-HTTgene (5-HTT andSLC6A4) andanxiety-related traits as well as depression(Collier et al, 1996; Lesch et al, 1996).

Since then, clinical studies have fur-ther supported the link between variantsof 5-HTTand disorders in the regulation ofemotion. Although modest effect sizestypical of non-Mendelian traitspoly-genic patterns of inheritance, epistatic andepigenetic interactions, and heterogeneitybetween studies confounded the results,5-HTT comprises a model molecule forstudying geneenvironment interactions in

cognitive and psychiatric neuroscience.The demonstration in rhesus macaques

that stress early in life uniquely reinforceslinks between variations of 5-HTT, behav-iour and psychopathology seems to her-ald in a new era of behavioural genetics.Moreover, the discovery that 5-HTT is asusceptibility gene for depression is a firststep towards explaining the moleculardimensions of personality and behaviour,identifying physiological pathways thatlead to other disorders of cognitive functionand emotion, and analysing the interactive

effects of genes and environment in thedevelopment of disease.

On the heels of these results from behav-

ioural genetics, novel approaches includ-ing neurophysiology, neuropsychology andfunctional neuroimaging, as well as theinclusion of other phenotypes (such as highercognitive functions, communication skills,social competence and longevity), have fur-ther strengthened the connection between5-HTT, cognition and emotionality, andcontribute to a more profound understand-ing of how genetic variations modulatebehaviour (Fig 1). Similarly, studies in trans-genic mice have underscored the centralrole of serotonin and its fine-tuning by the

transporter protein in embryonic brain dev-elopment and synaptic plasticity, particu-larly in brain areas related to cognitive and

emotional processes.The potential relevance of this research

for social cognitionthe neurobiologicalprocesses that are used to conform withsocial norms and procedurestranscendsthe boundaries of behavioural geneticsto embrace biosocial science. Steeringresearch in this new direction raises itto the next level of complexity, with theaim of understanding the nature of thesegenetic variations in humans, as well astheir influence on individual differencesand social competence and behaviour.

BEHAVIOUR

Complex

functional

interactions

and

psychological

dimensions

GENE PROTEIN NEURON CIRCUIT

Multiple

alleles

with small

effects

Change

in levels

or conformation

Subtle

structural

and functional

alterations

Response to

environmental

cues:

endophenotypes

Gene gene interaction

Gene environment interaction

Developmental and adult plasticity

Fig 1| Different levels of complexity: how genes influence behaviour and psychopathological dimensions.


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2007 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION EMBO reports VOL 8 | SPECIAL ISSUE | 2007 S2

science & societyspecia l issue

Individual differences in behaviouralpredisposition, which are commonlyreferred to as personality traits, are rel-

atively enduring, continuously distributedand substantially inheritable. Although per-sonality results from a complex interplayof genetic and environmental factors, theirrelative influence is the subject of one of thelongest and most contentious controversiesin scientific history (McGue & Bouchard,1998). There is now considerable evidencethat personality traits (such as fearfulness,negative emotionality and stress reactiv-ity) and environmental factors increase therisk of depressionan aetiologically hetero-geneous group of brain disorders that reflectalterations in cognitive, psychomotor andemotional processes (Fig 2). Because themode of inheritance of depression is com-

plex, it is increasingly accepted that suscep-tibility is due to several genes in associationwith each other and in conjunction withepigenetic programming. Genes implicatedin the control of cognition, emotionalityand despair, and with a role in monoamineneurotransmission, such as the serotoninsystem, have been a rational starting pointfor understanding the molecular basis ofthis disorder.

Serotonin is a phylogenetically ancientsignalling molecule. It is the most widelydistributed neurotransmitter in the brainand is implicated in the regulation ofemotions. The neurological circuitry ofemotionality involves numerous brainstructures, including the anterior cingulatecortex, amygdala, hippocampus, ventralstriatum, hypothalamus and several otherinterconnected structures. The amygdala isthe central unit where cognition, emotionand learning are processed, and it associ-ates such stimuli with events that are eitherpunishing or rewarding (Phelps, 2006).Serotonergic signalling pathways integratenot only basic physiological functions, butalso elementary tasks of sensory process-

ing, cognition, emotion regulation andmotor activity.

Moreover, serotonin is an important regu-lator of early brain development and adultneuroplasticity, including cell proliferation,migration, differentiation and synaptogenesis(Di Pino et al, 2004). As it shapes variousbrain systems during development, it setsthe stage for functions that regulate emotionsthroughout life. It is also a crucial modula-tor of emotional behaviour including anxietyand stress responses, impulsivity and aggres-sion. The diversity of these functions is due

to the capacity of serotonin to orchestratethe activity and interaction of several otherneurotransmitter systems. It can therefore beviewed as a team player within this highlycomplex system of neural communication,which is mediated by 14 receptor subtypes.

The action of serotonin as a messengerin the brain is regulated tightly by its syn-thesizing and metabolizing enzymes, and,more directly, by 5-HTT, which regulatesthe concentration of serotonin in the syn-aptic gap and therefore its effect on thereceiving neuron. It is likely that variationsin the transporter protein itself have a pro-found effect on the role of serotonin as amoderator of cognition and emotionality.

The transcriptional activity of human5-HTT is modulated by a repetitivesequence, which has a short (s) and a long(l) variant (Fig 3). This sequence is uniqueto humans and simian primates; hence, thedifferent activity of the two variants in rhe-sus macaques provides a unique model tostudy the relative contribution of genes andenvironmental factors to the function of

serotonin, personality traits and disordersof emotion regulation. Initial reports asso-ciated the low-expressing s-variant withsignificantly greater levels of neuroticism

a trait related to anxiety, depression andstress reactivity (Lesch et al, 1996). The roleof the s-variant in personality traits of nega-tive emotionality was finally confirmed bymeta-analyses of the published data.

An association between 5-HTT anddepression was first reported byCollier and co-workers (1996), and

was subsequently confirmed by other stud-ies. Similarly, the s-variant and l-variantof 5-HTTseem to have a role in a range ofdisorders related to regulation of emotion.Of particular interest is the role of 5-HTTin autism, which comprises a spectrumof deficits in language development andsocial cognition, repetitive and restrictedbehaviours or interests, and resistance tochange. The most promising findings so far,however, indicate an association betweenboth variants of 5-HTT and responsive-ness to antidepressant treatments (Lesch &Gutknecht, 2005).

Biology has had an increasing influenceon the social sciences, and biosocial con-

cepts have paved the way for investigatinghuman personality from an evolutionaryperspective (Buss, 1991). Personalitydimensions define the ability of an individ-ual to adapt to other people in a given socialcontext, which is crucial for long-termreproductive success. Extraversion andagreeableness allow higher mammals toform social structures ranging from pairbonds to coalitions of groups; emotionalstability and conscientiousness are crucialfor the maintenance of these structures,whereas openness might reflect a capacity

ENVIRONMENT

DEPRESSION

Perinatal

trauma

Adverse

life events

Loss

Psychosocial

stress

GENETIC

SUSCEPTIBILITY

Anxiety-related

traits

Negative emotionality

Stress reactivity

Variation in

gene structure

or expression

Genetic

background

Anxiety disorders

Alcohol

dependence

Fig 2| Vulnerability and co-morbidity of depression: neither genes nor environment act alone.

Although personality resultsfrom a complex interplay ofgenetic and environmentalfactors, their relative influenceis the subject of one of thelongest and most contentiouscontroversies in scientific history


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for innovation. From an evolutionary psy-chology perspective, anxiety is a pervasiveand innately driven form of distress thatarises in response to actual or threatenedexclusion from social groups (Baumeister& Tice, 1990). On the basis of this idea,Nakamura and colleagues (1997) discus-sed the higher prevalence of the anxiety-associated s-variant of 5-HTT among theJapanese population as a possible popula-tion-typical adaptation to prevent socialexclusion in a society that is characterizedby extraordinary emotional restraint andinterpersonal sensitivity.

Because the genetic basis of personalityand behavioural traits exists in mammalsranging from rodents to nonhuman primates,research efforts have recently focused on thelatter, especially rhesus macaque monkeys.

Using this model, environmental influencescan be more easily controlled, and are there-fore less likely to confound associationsbetween genes and behaviour.

The stressful experience of maternalseparation has robust and long-termconsequences for the serotonin sys-

tem in rhesus monkeys, as indicated by lowcerebrospinal fluid (CSF) concentrationsof 5-hydroxyindoleacetic acid (5-HIAA),which is the main metabolite of serotonin.This early-life trauma also causes anxiety-related and depression-related behavioursassociated with deficient social adaptationand interaction throughout life. Given thatrhesus monkeys also have s-variants andl-variants of 5-HTT, which is called rh5-HTT(Lesch et al, 1997), they were tested for asso-ciations between early-life stress, serotoninfunction and rh5-HTTgenotype.

The low-activity s-variant of rh5-HTTis,indeed, predictive of CSF 5-HIAA concen-trations, but early-life experiences also influ-ence the serotonin system (Fig 4; Bennettet al, 2002). In the neonatal periodbetween 7 and 30 days after birthwhen

environmental influences are modest andleast likely to confound genebehaviourassociations, infants carrying the s-variantof rh5-HTTdisplayed higher stress-reactivitythan l-variant homozygotes (Champoux et al,2002). The effects were more pronouncedfor monkeys raised in a neonatal nurserythan for those reared by their mothers, whichconfirmed the role of the environment.

Beyond the neonatal period, particu-larly during adolescence, further evidencefor a complex interplay between the sero-tonin system and social success has been

5-HTTLPRmRNA

Promoter

Variants of regulation

Exon

I

II III

VII

XIV

XII

AAA

AAA

AAA

AAA

Chromosome 17

GENOTYPE

l/l

l/s

s/s

32%

49%

19%

FREQUENCY

S

L

Depression

Bipolar disorder

Anxious-avoidant

personality disorder

Alcohol

dependence

Anxiety-related

personality traits

Na+ 5-HT

MAO

Serotoninreceptor

Storagevesicle

Serotonintransporter

Fig 3| Allelic variation of serotonin transporter function in anxiety-related personality disorders,

depression and other disorders of the regulation of emotion. LPR, linked polymorphic region; MAO,

monoamine oxidase.

PSYCHOSOCIALDEVELOPMENT

Peer-reared

Maternal

separationADULTS

Stress reactivity

Alcohol consumption

NEONATES

Negative emotionality

Activity

ADOLESCENTS

Social competence

Aggression

Altered

brain serotonin

function

AAA

N

C

rh5-HTTLPR

S

Fig 4| Effects of maternal separation and rh5-HTTgenotype on psychosocial development, including

brain serotonin function, regulation of emotion, social competence, stress reactivity, behaviour and

psychopathology.


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accrued. Impaired serotonin signalling isassociated with lower rank within a socialgroup, less competent social behaviour andgreater impulsive aggression. Although sub-jects with low CSF 5-HIAA concentrationsare no more likely to engage in competi-tive aggression than other monkeys, theiraggressive behaviour frequently escalatesto violent and hazardous intensity.

Social interaction and competition-elic-ited aggression are moderated by an inter-active effect of the rh5-HTTgenotype andthe rearing environment (Barr et al, 2003).Infants that are homozygous for the l-variantare more likely to engage in rough playthan carriers of the s-variant. Peer-reareds-variant carriers play less with their peersthan those that are homozygous for thel-allele, whereas the rh5-HTTgenotype has

no effect on the incidence of social playamong mother-reared monkeys. Sociallydominant mother-reared l-variant carriersare more likely than their peer-reared coun-terparts to engage in aggression duringadolescence, whereas peer-reared, butnot mother-reared, monkeys carrying thes-variant show more aggressive behavioursthan their homozygous l-variant counter-parts. These findings indicate that peer-reared subjects with the s-variant, althoughunlikely to win in a competitive encounter,are more inclined to persist in aggressiononce it begins.

For macaques, similar to humans, sur-vival depends on effective social func-tioning. Social skills facilitate access

to food, protection and mates. Sociallyadept individuals tend to be healthier andlive longer. Rhesus macaques also exhibita variation of aggression-related behaviourthat is unequalled in other primate spe-cies. On the basis of assumptions that thestructure of macaque social organizationis influenced more by phylogeny than byenvironment, and that polymorphisms in

genes of the serotonin signalling pathwaycontribute to the variability of species-characteristic social behaviour, the variationof genes involved in the serotonin signallingpathway was determined in seven macaquespecies representing the entire spectrum ofdifferent social organization grades (Fig 5;Wendland et al, 2006). Macaque specieswith tolerant societies, relaxed dominanceand high levels of conciliation were mono-morphic for the rh5-HTTgene. By contrast,species that are known to have intolerant,hierarchical and nepotistic societies were

polymorphic at one or more loci. The rhe-sus macaque, which is the most intolerantand hierarchical species, showed the great-est degree of allelic variation. These findingssuggest that genetic variation of serotoninneurotransmission affects key elements ofmacaque social behaviour, particularly theexceptional level of interspecies variationin aggression.

Taken together, the research onmacaques provides evidence of an envi-ronment-dependent association betweenallelic variation of rh5-HTTexpression and

central serotonin function, and illustrateshow this specific genetic variation moder-ates behaviour and psychosocial develop-ment (Fig 4). Because rhesus monkeysshow personality and behavioural traits

that parallel anxiety, depression andaggression associated with the low-activitys-variant of the human 5-HTT gene, thisprimate model facilitates the search forgenetic mechanisms of individual differ-

ences. Indeed, the corollary of deleteriousearly experiences, such as inadequatematernal care in humans, seems consistentwith the idea that 5-HTT influences therisk of disorders of social cognition andemotion regulation. Analogous to the find-ings in primates, humans with one or twolow-activity s-variants of the 5-HTT geneare more likely to become depressed afteradverse life events (Caspi et al, 2003).Moreover, childhood maltreatment of indi-viduals carrying the s-allele increases therisk of depression later in life.

tonkeanasylvanus

thibetanaarctoides

fascicularisnemestrina

mulatta

Tolerant

1

2

3

1

2

3

1

2

4

3

5-HTTLPR

MAOALPR

Socialorganization

category

IntolerantHierachicalNepotistic

Macaque species

Numberofalleles

Fig 5| Degree of variation in two genes of the serotonin signalling pathway (the serotonin transporter and

monoamine oxidase A), aggression and social organization in seven macaque species. This four-grade

classification of social organization across several species of the genusMacacais based on the extent and

asymmetry of aggression-related behaviour within particular species (Thierry, 2000). Grade 1 species

have hierarchical and nepotistic societies, as well as low levels of conciliation, whereas grade 4 species

can be considered as more tolerant, displaying relaxed dominance, open relationships and high levels of

conciliatory behaviour. For example, the risk of a retaliatory attack from a subordinate after an initial attack

by a dominant is much higher in grade 4 species than in grade 1 species, although the retaliatory attack will

probably be less severe. LPR, linked polymorphic region; MAOA, monoamine oxidase.

Serotonergic signalling pathwaysintegrate not only basicphysiological functions, butalso elementary tasks of sensoryprocessing, cognition, emotionregulation and motor activity

Biology has had an increasinginfluence on the social sciences,and biosocial concepts pavedthe way for investigating humanpersonality from an evolutionaryperspective


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During the past few years, imagingtechniques have become increas-ingly sophisticated (Fig 1), leading

to the first report of an association between5-HTT genotype and excitability of theprefrontal cortex, which implies a relation-ship between cognitive processing and5-HTTfunction in humans (Fallgatter et al,1999). Using functional magnetic reso-nance imaging (fMRI), Hariri and co-workersobserved that carriers of the s-variant havegreater neuronal activity of the amygdalain response to fearful stimuli (Hariri et al,2002). Subsequent investigations focusedon the modifying impact of the anteriorcingulate cortex in the context of the roleof 5-HTTin depression, but did not questionthe assumption that the neutral baseline

used as the control did not itself producechanges in activation as a function of5-HTTgenotype.

In tackling this problem, Canli andco-workers showed that allelic variationsof 5-HTT are associated with differentialactivation in response to negative, positiveand neutral stimuli in limbic, striatal andcortical regions (Canli et al, 2005).Although they confirmed greater amygdalaactivation to negative stimuli as comparedwith neutral stimuli in carriers of the s-variantof 5-HTT, this was due to decreased

activation in response to neutral stimulirather than increased activation in responseto negative stimuli. These findings are con-sistent with the idea that the anterior cingu-late cortex has an integral role in bothemotional and non-emotional cognitiveprocesses, and implies a role of serotonintransport efficiency in a wide-ranging spec-trum of brain processes that control affec-tive, cognitive and motor processes (Fig 6;Canli et al, 2006).

Although 5-HTT influences the impact ofpsychosocial stress on depression risk, theneural mechanisms underlying this mod-erator effect are still poorly understood. Asa first step towards identifying these mecha-nisms, individuals with self-reported lifestress but no history of psychopathology

were investigated using multimodal fMRI.On the basis of these and other data, Canliand co-workers suggested a model in whichlife stress interacts with the 5-HTTgenotypeto influence amygdala and hippocampalresting activation, which might provokea chronic state of negative cognitive bias(Canli et al, 2006). Although these interac-tions might constitute a neural mechanismfor epigenetic vulnerability to depression,additional studies revealed other brainregions that are moderated by an interactionof 5-HTTgenotype and life stress.

Intriguingly, these regions belong to cir-cuits that integrate imitation-relatedbehaviour, from which social cognition

and behaviour have evolved (Iacoboni,2005). Social cognition comprises repre-sentations of internal somatic states, inter-personal knowledge and motivations, andprocedures used to decode and encodeones self in relation to other people. Thiscomplex set of processes, which must becarefully orchestrated to enable social func-tioning and communication-facilitated net-working, has recently been associated withdistinct neurocircuits in the brain. Thesefindings might imply that social compe-tence is subject to an interaction between5-HTT genotype and psychosocial stress;dysfunction is thought to cause social andcommunication disabilities associated with

autistic syndromes.A mouse model with an inactivated

5-HTT geneand consequently a dis-turbed serotonin systemhas consider-ably advanced our understanding of theneurobiological basis of anxiety-related anddepression-related behaviour (Bengel etal, 1998; Lesch & Mssner, 2006). In addi-tion, the 5-HTT-knockout mouse provides amodel to study the impact of genetic mech-anisms on the development and plasticity ofthe brain, including regionalization of thecortex and its connectivity to subcorticalstructures (Di Pino et al, 2004). However,our knowledge of the machinery involvedin these fine-tuning processes remains frag-mentary. Finally, epigenetic programming ofemotionality by maternal behaviour under-scores the view that environmental influ-ences can persistently remodel neuronalunits during early development.

We are clearly a long way from fullyunderstanding the evolutionary and neuralmechanisms of social cognitive phenomenaand social functioning. But the potentialimpact of 5-HTTvariation on social cogni-tion transcends the boundaries of behav-ioural genetics to embrace biosocialscience and create a new social neuro-genetics of behaviour. It has transformed

Activity

Altered intrinsicbaseline activityof neural networks

Enhancedactivation ofeffector systemsrelated to regulationof emotion

+

MEDIALPREFRONTAL

CORTEX

Sensory stimuliwith emotional impact

AMYGDALA

Reducedinhibitoryfeedback

Hyperactivation

+

NEURAL CIRCUITRYOF SOCIAL COGNITION

Low 5-HTT function

Stress/life events

Fig 6| Influence of the interaction between the 5-HTTgene and the environment on neural networks of

social cognition and emotion regulation.

the potential impact of 5-HTTvariation on social cognitiontranscends the boundaries ofbehavioural genetics to embrace

biosocial science and create a newsocial neurogenetics of behaviour


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Wendland JR, Lesch KP, Newman TK, Timme A,Gachot-Neveu H, Thierry B, Suomi SJ (2006)Differential functional variability of serotonintransporter and monoamine oxidase A genes inmacaque species displaying contrasting levelsof aggression-related behavior. Behav Genet36:163172

Klaus-Peter Lesch is at the Departmentof Psychiatry and Psychotherapy, Molecularand Clinical Psychobiology at the Universityof Wrzburg, Germany.E-mail: [email protected]

doi:10.1038/sj.embor.7401008

biosocial science with respect to ourunderstanding of gender-specific behav-iour, marriage and the family as social insti-tutions, freedom of will and legalresponsibility, and the natural history ofmoral obligation (Butz & Torrey, 2006).Biosocial genomics now allows us toexplore the nature of genetic variationbetween humans and its influence on indi-vidual differences, as well as the relativeimpact of genetic and environmental fac-tors on cognition, emotion and behaviour.Its integration in behavioural genetics willeventually tear down some long-standingmyths about the uniqueness of humanbehaviour. Although the impact of neuro-genetics on social sciences has long beenanticipated and represents an inevitablealbeit welcomedevelopment, the transi-

tion from complicated correlations touseful predictions will be a challenge.

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