Epistasis between Dopamine Regulating Genes Identifies a Nonlinear Response of the Human Hippocampus During Memory Tasks

Bertolino, Alessandro; Giorgio, Annabella Di; Blasi, Giuseppe; Sambataro, Fabio; Caforio, Grazia; Sinibaldi, Lorenzo; Latorre, Valeria; Rampino, Antonio; Taurisano, Paolo; Fazio, Leonardo; Romano, Raffaella; Douzgou, Sofia; Popolizio, Teresa; Kolachana, Bhaskar; Nardini, Marcello; Weinberger, Daniel R.; Dallapiccola, Bruno

doi:10.1016/j.biopsych.2008.02.001

Cited by 79 publications

(97 citation statements)

References 73 publications

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“…Given the lack of behavioural differences between groups, we consider the greater PFC recruitment by the VV homozygous group to represent a form of compensatory mechanism, enabling them to resolve interference appropriately and in a proactive manner; this interpretation is congruent with the DMC model. Interestingly, the left-lateralized regions observed to be more activated in VV individuals in the proactive condition are close to those previously reported (in the same population) during tasks involving updating processes (Bertolino et al, 2008;Caldu et al, 2007;Egan et al, 2001;Mattay et al, 2003), suggesting that these studies may have tapped into common processes. Indeed, Miyake et al (2000), using variable latent analyses, showed that even though the executive functions of inhibition, updating and flexibility can be considered as independent constructs, the cognitive processes engaged by these three functions share some common features.…”

Section: Impact Of Comt Val 158 Met Polymorphism On Neural Substratessupporting

confidence: 87%

“…Indeed, independently of any genetic considerations, the interfering component of the Sternberg probe recency task (Sternberg, 1966) was previously found to be associated with left PFC activity (mainly in the left IFG; Badre & Wagner, 2005;Burgess & Braver, 2010;D'Esposito et al, 1999;Jonides et al, 1998;Mecklinger et al, 2003;Nelson et al, 2003;Postle & Brush, 2004). Activation in a similar region was also observed in studies considering the impact of COMT genotype on updating and inhibitory functions, with Met allele carriers showing lesser recruitment of the left prefrontal cortex for the same level of performance (Bertolino et al, 2008;Caldu et al, 2007;Egan et al, 2001;Jaspar et al, 2014a;Jaspar et al, 2014b;Mattay et al, 2003). Together, these elements led us to hypothesize that VV homozygous people should recruit the bilateral PFC more extensively in response to interference during the probe recency task.…”

Section: Aim Of the Study And A Priori Hypothesesmentioning

confidence: 75%

“…First, from a behavioural point of view, we did not expect any genotype-related differences. Indeed, even though COMT genotype effects have been shown in different multi-compound executive tasks (Barnett et al, 2007;Bruder et al, 2005;Caldu et al, 2007;Egan et al, 2001;Malhotra et al, 2002;Minzenberg et al, 2006;Rosa et al, 2004;Roussos et al, 2008), the advantage of Met allele carriers reported in these studies is no longer observed when tasks involve more specific cognitive processes (for example, in WM tasks such as the n-back task) (Bertolino et al, 2008;Caldu et al, 2007;Egan et al, 2001;Mattay et al, 2003). If, as expected, we observed an absence of behavioural differences between genotypes, the observation of increases of PFC activity in one group will be considered as the reflection of compensatory mechanisms set up to perform the task in the most efficient way possible.…”

Section: Aim Of the Study And A Priori Hypothesesmentioning

confidence: 84%

“…Similarly, Mattay et al (2003) found more activity in the left middle frontal gyrus (MFG) in VV individuals (compared to MM individuals) when they had to perform 2-back and 3-back tasks. Finally, Bertolino et al (2008) showed a negative relationship between the number of Met alleles and right DLPFC activity during a 1-back task. These results strongly suggest that COMT Val 158 Met polymorphism impacts DLPFC responses during updating.…”

Section: Introductionmentioning

confidence: 94%

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Modulating effect of COMT Val158Met polymorphism on interference resolution during a working memory task

Jaspar

Dideberg

Maquet

et al. 2015

Brain and Cognition

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Jaspar M., Dideberg V., Bours V. Maquet P., Collette F. (2015). Modulating Effect of COMT Val 158 Met Polymorphism on Interference Resolution during a Working Memory Task. Brain and Cognition (In press)2 Abstract Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15 years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val 158 Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus.Keywords: COMT gene -Working memory -fMRI -Cognitive control 3 IntroductionIn the last two decades, several lines of evidence have suggested that the neurotransmitter dopamine (DA) plays an important role in cognitive functions associated with prefrontal activity (Braver & Cohen, 1999;Cropley et al., 2006;Mattay et al., 2002). The study of the influence of DA on cognition in healthy populations appears particularly relevant given the long hypothesized role of DA in schizophrenia (Carlsson et al., 2000), a pathology that is well known to be associated with cognitive impairments (in particular in the executive domain). In that general context, genetic variability related to the catechol-Omethyltransferase (COMT) gene has received increasing attention as a potential modulator of executive functioning (Witte & Flöel, 2012). The human COMT gene codes for the major enzyme involved in the metabolic degradation of released DA. This gene, located on the lon...

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Section: Impact Of Comt Val 158 Met Polymorphism On Neural Substratessupporting

confidence: 87%

Section: Aim Of the Study And A Priori Hypothesesmentioning

confidence: 75%

Section: Aim Of the Study And A Priori Hypothesesmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

Modulating effect of COMT Val158Met polymorphism on interference resolution during a working memory task

Jaspar

Dideberg

Maquet

et al. 2015

Brain and Cognition

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show abstract

“…Studies with humans also showed less DRD2 availability in the hippocampus during a working memory task, suggesting that dopamine release therein might play a specific role in WM (Aalto et al, 2005). A recent imaging genetics study found that the catechol-O-methyltransferase (COMT) gene, a DA-related gene, was correlated with activations in the hippocampus elicited by a working memory task (Bertolino et al, 2008). In sum, there appears to be a hippocampal dopaminergic network that is functionally involved in WM processing.…”

Section: Introductionmentioning

confidence: 99%

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

Jin¹,

Lei²,

Wang³

et al. 2013

NeuroImage

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The genetic and neural basis of working memory (WM) has been extensively studied. Many dopamine (DA) related genes, including the NTSR1 gene (a DA modulator gene), have been reported to be associated with WM performance. The NTSR1 protein is predominantly expressed in the cerebral cortex and the hippocampus, the latter of which is closely involved in WM processing based on both lesion and fMRI studies. Thus far, however, no study has examined the joint effects of NTSR1 gene polymorphism and hippocampal morphology on WM performance. Participants of the current study were 330 healthy Chinese college students. WM performance was measured with a 2-back WM paradigm. Structural MRI data were acquired and then analyzed using an automated procedure with atlas-based FreeSurfer segmentation software (v 4.5.0) package. Linear regression analyses were conducted with a NTSR1 C/T polymorphism which was previously reported to be associated with WM (rs4334545), hippocampal volume, and their interaction as predictors of WM performance, with gender and intracranial volume (ICV) as covariates. Results showed a significant interaction between NTSR1 genotype and hippocampal volume (p b .05 for both the left and right hippocampi). Further analysis showed that the correlation between hippocampal volume and WM scores was significant for carriers of the NTSR1 T-allele (p b .05 for both hippocampi), but not for CC homozygotes. These results indicate that the association between hippocampal structure and WM performance was modulated by variation in the NTSR1 gene, and suggest that further studies of brain-behavior associations should take genetic background information into account.

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Altered Effect of Dopamine Transporter 3′UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia

Prata¹,

Mechelli²,

Picchioni³

et al. 2009

Arch Gen Psychiatry

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Epistasis between Dopamine Regulating Genes Identifies a Nonlinear Response of the Human Hippocampus During Memory Tasks

Cited by 79 publications

References 73 publications

Modulating effect of COMT Val158Met polymorphism on interference resolution during a working memory task

Modulating effect of COMT Val158Met polymorphism on interference resolution during a working memory task

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

Altered Effect of Dopamine Transporter 3′UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia

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