Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission

Jedema, Hank P.; Gianaros, Peter J.; Greer, Phil J.; Kerr, Dustin D.; Liu, Shijing; Higley, J. Dee; Suomi, Stephen J.; Olsen, Adam S.; Porter, Jessica; Lopresti, Brian J.; Hariri, Ahmad R.; Bradberry, Charles W.

doi:10.1038/mp.2009.90

Cited by 122 publications

(132 citation statements)

References 57 publications

(99 reference statements)

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“…When incongruent, it modulates the activity of downstream brain areas that are involved in response selection and action, such as the amygdala and striatum. In that way, increased OFC activity may allow short-allele carriers to flexibly adapt behaviour when a mismatch is detected between the expected and actual outcome of behaviour, for instance during reversal learning in rhesus macaques (Jedema et al 2009). …”

Section: Neural Mechanisms Of Epigenetic Programmingmentioning

confidence: 98%

“…The cognitive enhancement is also consistent with the observation that short-allele carriers show increased processing of negative feedback (Althaus et al 2009). In rhesus monkeys, the short-allele of the rh5-HTTLPR was associated with superior performance on an array of cognitive tasks: the probability discounting task, the delay discounting task, the reversal learning task and the delayed match-to-sample task (Jedema et al 2009). The better performance in the probability discounting task is consistent with the increased attention to high and low probabilities in the risky decision-making task in humans carrying the short 5-HTTLPR variant (Roiser et al 2006) and may be explained by augmented cortico-limbic activation (Fallgatter et al 1999(Fallgatter et al , 2004 and superior ability to integrate feedback information over time to guide behaviour on subsequent choices (Althaus et al 2009).…”

Section: Neural Mechanisms Of Epigenetic Programmingmentioning

confidence: 99%

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When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

Lesch

2011

Current Topics in Behavioral Neurosciences

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Although converging epidemiological evidence links exposure to stressful life events with increased risk for affective spectrum disorders, there is extraordinary interindividual variability in vulnerability to adversity. The environmentally moderated penetrance of genetic variation is thought to play a major role in determining who will either develop disease or remain resilient. Research on genetic factors in the aetiology of disorders of emotion regulation has, nevertheless, been complicated by a mysterious discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations. One explanation for this incongruity is that at least some specific gene effects are conditional on environmental cues, i.e. gene-by-environment interaction (G × E) is present. For example, a remarkable number of studies reported an association of variation in the human serotonin (5-HT) transporter gene (SLC6A4, 5-HTT, SERT) with emotional and cognitive traits as well as increased risk for depression in interaction with psychosocial adversity. The results from investigations in non-human primate and mouse support the occurrence of G × E interaction by showing that variation of 5-HTT function is associated with a vulnerability to adversity across the lifespan leading to unfavourable outcomes resembling various neuropsychiatric disorders. The neural and molecular mechanisms by which environmental adversity in early life increases disease risk in adulthood are not known but may include epigenetic programming of gene expression during development. Epigenetic mechanisms, such as DNA methylation and chromatin modification, are dynamic and reversible and may also provide targets for intervention strategies (see Bountra et al., Curr Top Behav Neurosci, 2011). Animal models amenable to genetic manipulation are useful in the identification of molecular mechanisms underlying epigenetic programming by adverse environments and individual differences in resilience to stress. Therefore, deeper insight into the role of epigenetic regulation in the process of neurodevelopmental programmes is likely to result in early diagnosis of affective spectrum disorders and will contribute to the design of innovative treatments targeting neural pathways that foster resilience.

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Section: Neural Mechanisms Of Epigenetic Programmingmentioning

confidence: 98%

Section: Neural Mechanisms Of Epigenetic Programmingmentioning

confidence: 99%

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

Lesch

2011

Current Topics in Behavioral Neurosciences

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“…Genetic studies have tied this neuromodulatory pathway to social behavior in humans and other primates, with variants of two serotonergic genes having been examined in particular depth: a variable insertion in the gene encoding tryptophan hydroxylase (TPH2), the rate limiting enzyme in serotonin synthesis, and the 5HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism within the promoter region of the serotonin transporter gene (SLC6A4, solute carrier family 6 member 4). Both variants have orthologs in humans and rhesus macaques, have been associated with altered development of several brain regions (135,136), and may influence the intensity and duration of signaling at serotonergic synapses (135,137).…”

Section: Genetic Regulation Of Social Behaviormentioning

confidence: 99%

Neuroethology of primate social behavior

Chang¹,

Brent²,

Adams³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

107

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A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology.decision | evolution | reward | serotonin | oxytocin S ensitivity and responsiveness to information about others is critical for human health (1, 2), survival (3), and even financial success (4). To navigate our social worlds, we track the behavior of others and form models of their intentions and emotional states, we actively seek out and exchange information about others, and we flexibly alter our behavior in response to what we know about others. These faculties are so important to human behavior that their disruption constitutes psychopathology (5, 6). These specializations for social behavior reflect a rich evolutionary heritage of adaptation to group life (7-9). Like humans, many nonhuman primates also live in large groups characterized by patterns of social behaviors like grooming, imitative and cooperative foraging, differentiated affiliative relationships, ritualized courtship and mating behavior, and competitive interactions structured by social dominance (10, 11). Not surprisingly, the ability to deftly navigate the social environment has observable consequences for reproductive success in some nonhuman primates (12). Evolutionary Perspective on Social BehaviorSocial behavior places strong and unique demands on the nervous system. Across primate species, group size (a potential proxy of social complexity) is correlated with forebrain volume, after correcting for body size (9). Additional brain tissue beyond that required to maintain a body of a particular size is costly, in both developmental complexity and metabolic demands (7, 13-15). Indeed, social complexity and the elaboration of neural mechanisms to support it are associated with diets high in dependa...

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“…2 In addition, rhesus macaque models have also shown that brain morphology varies more by SERT variation than does in vivo SERT or serotonin concentration. 3 Thus, SERT gene alleles have been reported to be involved in phenotypes, endophenotypes and anatomical structure. Serotonin balance at the synaptic cleft is modulated by the serotonin transporter encoded by the serotonin transporter gene commonly known as HTT, SLC6A4 or SERT (herein referred to as SERT).…”

Section: Introductionmentioning

confidence: 99%

Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region

Ehli

Lengyel-Nelson

et al. 2011

Mol Psychiatry

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A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL 17 (17r) allele and the L A (16r) allele. The XS 11 (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L A (16r) allele compared with the L G (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases.

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Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission

Cited by 122 publications

References 57 publications

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

Neuroethology of primate social behavior

Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region

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