Elsevier

NeuroImage

Volume 84, 1 January 2014, Pages 922-931
NeuroImage

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

https://doi.org/10.1016/j.neuroimage.2013.09.065Get rights and content

Highlights

  • Dopamine critical for enhanced memory for novelty, yet mechanism in humans unknown

  • C allele of human DRD4 promoter SNP augments perceptual oddball memory enhancement

  • Memory effects parallel C allele-dependent striatal, SN/VTA, hippocampal activation

  • Memory increase and neuronal responses are dynamic showing adaptation in C carriers

Abstract

Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the − 521C>T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic–hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

Introduction

Dopamine activity signals unexpected, salient, motivationally-relevant information (Berridge, 2007, Horvitz, 2000, Ljungberg et al., 1992, Redgrave et al., 1999, Ungless, 2004). Enhanced memory for novel, or salient, stimuli is thought to be mediated by dopamine via hippocampal inputs from the dopaminergic midbrain (Lisman and Grace, 2005), which comprises the substantia nigra and ventral tegmental area (SN/VTA) (Duzel et al., 2009). In humans, processing of unexpected, salient stimuli can be studied using “oddball” paradigms, in which the oddball stimulus deviates from its prevailing context along a particular dimension. Long-term human memory for these contextually novel stimuli is enhanced (Ranganath and Rainer, 2003), an effect abolished by hippocampal damage (Kishiyama et al., 2004). A role for dopamine in contextual novelty detection is suggested by human functional magnetic resonance imaging (fMRI) studies demonstrating activation in dopaminergic areas in response to novel oddball stimuli (Bunzeck and Duzel, 2006, Duzel et al., 2009).

Both animal and human data point towards a critical role for the dopamine 4 (D4) receptor in novelty processing. Drd4 gene knockout mice show decreased exploration in response to novel stimuli (Dulawa et al., 1999, Rubinstein et al., 1997), whereas a selective D4 receptor agonist increases novel object exploration in mice (Powell et al., 2003). The D4 receptor is preferentially expressed in limbic regions, including the hippocampus (Mrzljak et al., 1996), prefrontal cortex (Ariano et al., 1997, Defagot et al., 1997, Matsumoto et al., 1995), and globus pallidus (Mrzljak et al., 1996). Although D4 receptor expression has been shown in primate SN, this is in SN pars reticulata (Mrzljak et al., 1996) and not the SN pars compacta or VTA, which contain the majority of dopaminergic neurones in the SN/VTA (Duzel et al., 2009). D4 receptor expression in SN pars compacta has, however, been shown in rodents (Defagot et al., 1997). In humans, the rather small (3.5 kb) DRD4 gene has generated much interest due to a high degree of functional variability, and an observed association between functional DRD4 polymorphisms and attention deficit/hyperactivity disorder (ADHD) (Franke et al., 2011), substance abuse (Li et al., 2011) and the personality trait of novelty seeking (NS) (Munafo et al., 2008b), which is considered a characteristic feature of both disorders.

Human NS is characterized by impulsivity, exploratory drive and excitability, and has been proposed to reflect individual differences in dopamine system sensitivity (Cloninger et al., 1993). Although initial evidence suggested an association between NS and a variable number tandem repeat (VNTR) polymorphism in exon III of DRD4 (Benjamin et al., 1996, Ebstein et al., 1996), a recent meta-analysis (Munafo et al., 2008b) refutes this, but demonstrates strong evidence for an association between NS and a cytosine to thymine polymorphism in the DRD4 promoter region (− 521C>T single nucleotide polymorphism, SNP). For this promoter polymorphism, which is in linkage disequilibrium with the exon III VNTR (Ekelund et al., 2001, Strobel et al., 2002), the C allele is associated with increased transcription levels of up to 40% compared with the T allele in vitro (Okuyama et al., 1999). However, in human post-mortem brain the − 521C>T SNP was not found to significantly affect DRD4 mRNA expression levels (Simpson et al., 2010), thus whether this SNP is functional is currently not clear.

In animal models of novelty seeking, both striatal dopamine (Blanchard et al., 2009) and the hippocampus (Blanchard et al., 2009, Kabbaj et al., 2000) are implicated in behavioral responses to novelty. Thus, given the overlap in brain areas involved in both enhanced memory for novel stimuli and novelty seeking, and the common proposed role for dopamine in these processes, we hypothesized that memory for contextually novel stimuli in humans is modulated by DRD4 promoter polymorphism. We tested this hypothesis in healthy human subjects, pre-selected on the basis of DRD4 genotype. Although our experiments address the role of the promoter − 521C>T SNP in novelty-evoked memory enhancement, in view of the (albeit less consistent) evidence for an association between DRD4 exon III VNTR and NS (Munafo et al., 2008b) subjects were also stratified on the basis of this polymorphism to enable the VNTR to be included as a covariate in our statistical model.

Subjects encoded lists of neutral nouns during fMRI scanning (Fig. 1a). The critical manipulation was the presentation of a perceptual (P) oddball (a noun presented in a novel font) and an emotional (E) oddball (aversive noun) in each list. After encoding each list, subjects performed a distractor task followed by free recall. Both recall performance, and evoked neuronal responses, for oddball nouns were compared to neutral control nouns randomly selected from the same list. We demonstrate that the DRD4 promoter polymorphism significantly modulates memory for perceptual oddballs in an allele dose-dependent manner, with C/C homozygotes showing approximately twice the memory advantage for these stimuli than T/T subjects. This effect is observed again in a larger, independent sample of individuals completing the same behavioral task outside of fMRI scanning. In the scanned group, this memory enhancement is associated with a C allele-dependent enhanced activation of dopaminergic areas and hippocampus during successful encoding of perceptual oddballs.

Section snippets

Samples

Sample sizes are in accord with power considerations for determining genetic contributions to episodic memory in humans (Rasch et al., 2010a).

Perceptual oddball memory

In the scanned sample, which included only male subjects, − 521C>T DRD4 promoter polymorphism does not affect memory for control nouns (Fig. 1b; one-way ANOVA for control noun recall across genotype F2,44 = 0.542 P = 0.585). All − 521C>T genotypes show memory enhancement for P oddballs (Fig. 1c). Critically, and according to our prediction, the DRD4 promoter polymorphism significantly modulates enhanced memory for P oddballs. For the 34 lists viewed by the scanned sample (Fig. 1c), we observe a

Discussion

Animal data support a model of novelty-evoked memory enhancement that is mediated by reciprocal interactions between the hippocampus and dopaminergic structures in midbrain and ventral striatum (Lisman and Grace, 2005). Our data demonstrate engagement of all these brain areas during successful encoding of contextually novel, perceptual oddballs. Critically, these effects are only observed in subjects carrying the C allele of the − 521C>T DRD4 promoter polymorphism, which is mirrored by an

Conclusion

Our experiment was predicated on a strong hypothesis that the dopamine system mediates enhanced memory for novel stimuli, based on animal data (Lisman and Grace, 2005) and reports of novelty-evoked activation of human dopaminergic brain areas (Bunzeck and Duzel, 2006, Duzel et al., 2009). A separate line of investigation has shown a consistent association between the − 521C>T DRD4 polymorphism and differential sensitivity to novelty in humans, i.e., NS personality trait (Munafo et al., 2008b).

Acknowledgments

This work was supported by the Federal Ministry of Education and Research, Deutsche Forschungsgemeinschaft (DFG KA1623/3-1 for NG, JB, RK, TRR 58 B3 for CB and Z02 to AR) and the EU (LSHM-CT-2007-037286 and ERC-20IO-AdG 20100407 for CB). BS is supported by a Marie Curie Career Integration grant (FP7-PEOPLE-2011-CIG 304248) and grant SAF2011-27766 from the Spanish Ministry of Science and Innovation. We thank Nicole Döring and Frauke Fassbinder for excellent technical assistance as well as the

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