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Effects of PPP1R1B (DARPP-32) Polymorphism on Feedback-Related Brain Potentials Across the Life Span

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Effects of PPP1R1B (DARPP-32) Polymorphism on Feedback-Related Brain Potentials Across the Life Span ORIGINAL RESEARCH ARTICLE published: 04 March 2013 doi: 10.3389/fpsyg.2013.00089 Effects of PPP1R1B (DARPP-32) polymorphism on feedback-related brain potentials across the life span Dorothea Hämmerer 1,2*†, Gudio Biele 3,4,Viktor Müller 1, HolgerThiele 5, Peter Nürnberg 5,6,7, Hauke R. Heekeren1,3 and Shu-Chen Li 1,2*† 1 Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany 2 Department of Psychology, Technische Universität Dresden, Dresden, Germany 3 Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany 4 Institute of Psychology, University of Oslo, Oslo, Norway 5 Cologne Center for Genomics, University of Cologne, Cologne, Germany 6 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 7 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany Edited by: Maximizing gains during probabilistic reinforcement learning requires the updating of Alain Dagher, Montreal Neurological choice – outcome expectations at the time when the feedback about a specific choice Institute and Hospital, Canada or action is given. Extant theories and evidence suggest that dopaminergic modulation Reviewed by: Meghana Bhatt, City of Hope, USA plays a crucial role in reinforcement learning and the updating of choice – outcome expec- James F.Cavanagh, Brown University, tations. Furthermore, recently a positive component of the event-related potential about USA 200 ms (P2) after feedback has been suggested to reflect such updating. The efficacy of *Correspondence: dopaminergic modulation changes across the life span. However, to date investigations Dorothea Hämmerer and Shu-Chen of age-related differences in feedback-related P2 during reinforcement learning are still Li, Department of Psychology, Technische Universität Dresden, scarce. The present study thus aims to investigate whether individual differences in the Zellescher Weg 17, 01062 Dresden, feedback-related P2 would be associated with polymorphic variations in a dopamine rel- Germany. evant gene PPP1R1B (also known as DARPP-32) and whether the genetic effect may e-mail: haemmer@psychologie. differ between age groups. We observed larger P2 amplitudes in individuals carrying the tu-dresden.de; [email protected] genotype associated with higher dopamine receptor efficacy, i.e., a allele homozygotes †Dorothea Hämmerer and Shu-Chen of a single nucleotide polymorphism (rs907094) of the PPP1R1B gene. Moreover, this Li have contributed equally to this effect was more pronounced in children and older adults in comparison to adolescents and work. younger adults.Together, our findings indicate that polymorphic variations in a dopamine rel- evant gene are associated with individual differences in brain-evoked potentials of outcome updating and hint at the possibility that genotype effects on neurocognitive phenotypes may vary as a function of brain maturation and aging. Keywords: PPP1R1B (DARPP-32), dopamine, reward, reinforcement learning, child development, aging INTRODUCTION vein, the P2 amplitude seems to reflect stimulus relevancy for Flexible control of behavior requires the representation, main- context updating in Go-Nogo (Lenartowicz et al., 2010) and tenance, and updating of goal-relevant context information. For task-switching paradigms (Astle et al., 2008). Source estimations instance, in real-life situations of choosing between stocks, even implicate the right dorsolateral prefrontal cortex (DLPFC) in though fluctuations in the markets are highly unpredictable, the the generation of the P2 during context updating (Lenartow- profit histories, and risk profiles of different stocks are common icz et al., 2010). Taken together, extant evidence suggests that context information that are considered when making choices. the feedback-related P2 may reflect flexible updating in changing In laboratories, maximizing gains during probabilistic reinforce- environments. ment learning requires the updating of choice–outcome expec- Very recently, there is also evidence from a functional brain tations at the time when feedback about a specific choice is imaging study, which suggests an involvement of the subcortical given. Studies using electroencephalography (EEG) have iden- dopaminergic system in modulating prefrontally based updat- tified event-related potentials that are related to reinforcement ing processes. Specifically, D’Ardenne et al. (2012) observed an learning (see Nieuwenhuis et al., 2004 for a review). Of spe- increased response in the ventral tegmental area (VTA) as well cific interest here is a positive frontal-centrally distributed com- as in the DLPFC during context updating when the participants ponent about 200 ms after the feedback for an action or a performed a Go-Nogo task. Moreover, applying TMS over the choice, called feedback-related P2; the amplitude of this compo- right DLPFC increased reaction times especially during condi- nent can be modulated by expectancy. For instance, the ampli- tions requiring context updating, confirming the relevance of the tude of the P2 was found to be larger for unexpected than right DLPFC for updating (D’Ardenne et al., 2012). Together, for expected (cued) stimuli (JieMin et al., 2010). In a related these findings indicate that subcortical dopaminergic structures www.frontiersin.org March 2013 | Volume 4 | Article 89 | 1 Hämmerer et al. PPP1R1B polymorphism, age, and outcome updating may contribute to DLPFC’s context updating function via a BOLD signal in the striatum, greater frontal-striatal connectivity frontal-striatal pathway. during cognitive performance, as well as better cognitive perfor- mance on executive functions (Meyer-Lindenberg et al., 2007). LIFESPAN DIFFERENCES IN DOPAMINERGIC MODULATION We thus hypothesized that the amplitude of the feedback-related The dopaminergic systems undergo maturation and senescence P2 would be larger in the A homozygotes of the PPP1R1B gene across the lifespan. Dopamine modulation in the prefrontal cortex than in any G carriers. To address the second question, we com- (PFC) as well as subcortical and midbrain regions is less effective pare this effect in four age groups, sampled across the lifespan. We during childhood and old age in comparison to other life periods. expected the potential effect of the PPP1R1B polymorphism on the For instance, there is ample evidence for aging-related declines P2 amplitude to be larger in age groups with reduced dopamin- of pre- and postsynaptic markers of the dopamine system (see ergic modulation, that is, in children and older adults. Such a Bäckman et al., 2006; Li et al., 2010; Li, 2012 for reviews). Based result would be in line with previous findings of larger effects of on cross-sectional estimates, the aging-related decline progresses individual differences in genetic variations in populations with with a rate of about 10% per decade starting in the third decade of suboptimal neuromodulation (e.g., Nagel et al., 2008; Li et al., life and affects midbrain (Bannon and Whitty, 1997; Reeves et al., 2013). 2002), subcortical (Seeman et al., 1987; Rinne et al., 1990; see also Severson et al., 1982) as well as frontal, cingulate, temporal, pari- MATERIALS AND METHODS etal, and occipital cortical areas (Kaasinen et al., 2000; Inoue et al., SAMPLE 2001). With respect to child development, the evidence is much Only male subjects were included in the present analyses given scarcer due to obvious reservations of applying invasive meth- that endogenous fluctuations in estradiol during the menstrual ods, such as PET receptor imaging, in these age groups. However, cycle alter dopamine synthesis (Jacobs and D’Esposito, 2011). increasing dopamine and dopamine transporter levels in the dor- Our sample included 20 children (9–11 years), 23 teenagers (13– sal striatum have been reported until the age of 9, by which point 14 years), 22 younger adults (20–30 years), and 21 older adults adult levels are reached (Haycock et al., 2003, see also Seeman et al., (65–75) recruited from the participant pools of the Center for 1987). In contrast to the relatively early maturation of the sub- Lifespan Psychology, Max Planck Institute for Human Develop- cortical dopaminergic system, D1 receptor function in the lateral ment (for a previous report on parts of this dataset, see Hämmerer PFC develops much more gradually and only reaches maturation et al., 2011). All participants were residents of Berlin, Germany. around adulthood (Rothmond et al., 2012). Given lifespan age None reported a history of medical, neurological, psychiatric dis- differences in brain development in general and in dopamine func- ease, or head injury. All participants or parents of the participants tions in specific, lifespan age differences in evoked brain potentials gave informed consent, and the study was approved by the local relevant for reinforcement learning and outcome updating may be ethics board. Participants were paid for their participation in the expected. Whereas lifespan age differences in the feedback-related study (10C for the first, and 7C for every following hour of the negativity have been observed in a few studies (see Eppinger et al., experiment). 2011; Hämmerer and Eppinger, 2012 for reviews), developmental and aging-related effects on the feedback-related P2 component GENOTYPING have not been investigated systematically. Saliva was collected from the participants using the Oragene® DNA sample collection kit (ON, Canada). DNA was extracted STUDY AIMS from
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