Serotonergic modulation in executive functioning: Linking genetic variations to working memory performance

Emerging evidence from studies using, for example, acute tryptophan depletion or investigating genetic variation of genes related to the serotonin signaling pathway suggest a role of serotonin in executive functions such as top-down attention, working memory and inhibitory control. In the current study, we aimed at extending this evidence by using the n-back task to examine working memory performance of 130 participants via behavioral and neurophysiological indices and by focusing on variations within genes encoding key regulators of the serotonergic system: the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and a repeat polymorphism in the transcriptional control region of the monoamine-oxidase gene (MAOA-uVNTR). Because serotonin and norepinephrine systems have been shown to be structurally and functionally highly interrelated, we also examined a novel polymorphism in the promoter region of the norepinephrine transporter gene (NET -3081) in anticipation of epistatic effects. We found that carriers of 5-HTTLPR and MAOA-uVNTR alleles recently implicated in executive processing showed a more efficient executive control of working memory-related performance as evidenced by reaction time, error rate as well as N2 and P3b event-related potential measures. This impact was further supported by interactions with the NET polymorphism. Linking serotonergic influence to mechanisms of inhibitory response control implicated in working memory, our results provide further support for and add new evidence concerning the importance of serotonergic neuromodulation in executive functioning.

[1]  Konstantina Zougkou,et al.  The Serotonin Transporter Gene Alters Sensitivity to Attention Bias Modification: Evidence for a Plasticity Gene , 2011, Biological Psychiatry.

[2]  T. Robbins,et al.  Region specific changes in forebrain 5-hydroxytryptamine1a and 5-hydroxytryptamine2a receptors in isolation-reared rats: an in vitro autoradiography study , 2004, Neuroscience.

[3]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[4]  Giuseppe Blasi,et al.  Neural mechanisms of genetic risk for impulsivity and violence in humans. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[5]  I. Lucki,et al.  The spectrum of behaviors influenced by serotonin , 1998, Biological Psychiatry.

[6]  Ahmad R. Hariri,et al.  Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission , 2009, Molecular Psychiatry.

[7]  Martin H. Teicher,et al.  A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder , 2006, Proceedings of the National Academy of Sciences.

[8]  R. Blakely,et al.  Functional Gene Variation in the Human Norepinephrine Transporter , 2008, Annals of the New York Academy of Sciences.

[9]  Christer Halldin,et al.  Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans. , 2009, The international journal of neuropsychopharmacology.

[10]  N. Singewald,et al.  Release of neurotransmitters in the locus coeruleus , 1998, Progress in Neurobiology.

[11]  David Goldman,et al.  Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. , 2006, American journal of human genetics.

[12]  D. Hamer,et al.  A functional polymorphism in the monoamine oxidase A gene promoter , 1998, Human Genetics.

[13]  David Goldman,et al.  The genetics of addictions: uncovering the genes , 2005, Nature Reviews Genetics.

[14]  J. Hohnsbein,et al.  ERP components in Go/Nogo tasks and their relation to inhibition. , 1999, Acta psychologica.

[15]  A. Varghese,et al.  The serotonin transporter: a vehicle to elucidate pulmonary hypertension? , 2004, Circulation research.

[16]  Dennis L. Murphy,et al.  Targeting the murine serotonin transporter: insights into human neurobiology , 2008, Nature Reviews Neuroscience.

[17]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[18]  Ann-Christine Ehlis,et al.  Allelic Variation of Serotonin Transporter Function Modulates the Brain Electrical Response for Error Processing , 2004, Neuropsychopharmacology.

[19]  L. Saksida,et al.  Pharmacological or genetic inactivation of the serotonin transporter improves reversal learning in mice. , 2010, Cerebral cortex.

[20]  Gerome Breen,et al.  Genetic Variation , 2020, Population Genetics with R.

[21]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[22]  J D Brodie,et al.  Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  P. Buckley.  Looking on the Bright Side of Serotonin Transporter Gene Variation , 2012 .

[24]  R Todd Constable,et al.  Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Johannes Müller,et al.  Genetic Variation of Serotonin Function and Cognitive Control , 2007, Journal of Cognitive Neuroscience.

[26]  J. Belsky,et al.  Vulnerability genes or plasticity genes? , 2009, Molecular Psychiatry.

[27]  Ahmad R. Hariri,et al.  Neural mechanisms of genetic risk for impulsivity and violence in humans , 2006 .

[28]  D. Murphy,et al.  Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531 , 2006, Molecular Psychiatry.

[29]  A. J. Bartsch,et al.  Electrophysiological measurements of anterior cingulate function , 2002, Journal of Neural Transmission.

[30]  M. Posner,et al.  Mapping the genetic variation of executive attention onto brain activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Marcus R. Munafò,et al.  Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis , 2008, Biological Psychiatry.

[32]  Arnaud Delorme,et al.  EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis , 2004, Journal of Neuroscience Methods.

[33]  Kathryn M. McMillan,et al.  N‐back working memory paradigm: A meta‐analysis of normative functional neuroimaging studies , 2005, Human brain mapping.

[34]  David Goldman,et al.  The Genetics of Addictions: Uncovering the Genes , 2006 .

[35]  C. Halldin,et al.  Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain , 2004, Human brain mapping.

[36]  C. Berridge,et al.  The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes , 2003, Brain Research Reviews.

[37]  M. Egan,et al.  Serotonin Transporter Genetic Variation and the Response of the Human Amygdala , 2002, Science.

[38]  R. Depue,et al.  Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions. , 1998, Cerebral cortex.

[39]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[40]  M. Posner,et al.  Assessing the molecular genetics of attention networks , 2002, BMC Neuroscience.

[41]  B. O’Donnell,et al.  Active and passive P3 latency and psychometric performance: influence of age and individual differences. , 1992, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[42]  M. Nöthen,et al.  Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. , 1999, Human molecular genetics.

[43]  T. Robbins,et al.  Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting , 2005, The Journal of Neuroscience.

[44]  A. Beauducel,et al.  NEO-Persönlichkeitsinventar nach Costa und McCrae, revidierte Fassung (NEO-PI-R) , 2008 .

[45]  L. Passamonti,et al.  Ventro-lateral prefrontal activity during working memory is modulated by MAO A genetic variation , 2008, Brain Research.

[46]  D. Meyer,et al.  A Neural System for Error Detection and Compensation , 1993 .

[47]  M. Petrides,et al.  Wisconsin Card Sorting Revisited: Distinct Neural Circuits Participating in Different Stages of the Task Identified by Event-Related Functional Magnetic Resonance Imaging , 2001, The Journal of Neuroscience.

[48]  Avshalom Caspi,et al.  Gene–environment interactions in psychiatry: joining forces with neuroscience , 2006, Nature Reviews Neuroscience.

[49]  Jonathan R. Folstein,et al.  Influence of cognitive control and mismatch on the N2 component of the ERP: a review. , 2007, Psychophysiology.

[50]  J. Ballenger.  The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation , 2012 .

[51]  W J Riedel,et al.  Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers , 2000, Journal of psychopharmacology.

[52]  A. Caspi,et al.  Role of Genotype in the Cycle of Violence in Maltreated Children , 2002, Science.

[53]  B. Pennington,et al.  Validity of the Executive Function Theory of Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review , 2005, Biological Psychiatry.

[54]  T. Robbins,et al.  The neuropsychology of ventral prefrontal cortex: Decision-making and reversal learning , 2004, Brain and Cognition.

[55]  Johannes T. Tauscher,et al.  Mapping of the norepinephrine transporter in the human brain using PET with (S,S)-[18F]FMeNER-D2 , 2008, NeuroImage.

[56]  M. D’Esposito.  Working memory. , 2008, Handbook of clinical neurology.

[57]  H. Tanabe,et al.  The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants , 2000, Molecular Psychiatry.

[58]  T. Robbins,et al.  Inhibition and the right inferior frontal cortex , 2004, Trends in Cognitive Sciences.

[59]  T. Robbins.  Arousal systems and attentional processes , 1997, Biological Psychology.

[60]  M. Stein,et al.  Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder , 2009, Neuropharmacology.

[61]  B. Sahakian,et al.  The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention. , 2007, The international journal of neuropsychopharmacology.

[62]  J. Polich.  Updating P300: An integrative theory of P3a and P3b , 2007, Clinical Neurophysiology.

[63]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[64]  John F. G. Atack,et al.  Serotonin Transporter , 2021, Encyclopedia of Evolutionary Psychological Science.

[65]  H. Keselman.  Testing treatment effects in repeated measures designs: an update for psychophysiological researchers. , 1998, Psychophysiology.

[66]  W. Riedel,et al.  Monoamine depletion in psychiatric and healthy populations: review , 2003, Molecular Psychiatry.

[67]  Andreas J. Fallgatter,et al.  Serotonin transporter promoter polymorphism influences topography of inhibitory motor control. , 1999, The international journal of neuropsychopharmacology.

[68]  Alexander Strobel,et al.  On the role of serotonin and effort in voluntary attention: Evidence of genetic variation in N1 modulation , 2011, Behavioural Brain Research.

[69]  I. Waldman,et al.  Candidate gene studies of ADHD: a meta-analytic review , 2009, Human Genetics.

[70]  Graeme N. Smith,et al.  Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas. , 2010, Physiological genomics.

[71]  Edward E. Smith,et al.  Temporal dynamics of brain activation during a working memory task , 1997, Nature.

[72]  R. Uher,et al.  The implications of gene–environment interactions in depression: will cause inform cure? , 2008, Molecular Psychiatry.

[73]  Klaus-Peter Lesch,et al.  Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys , 2005, Biological Psychiatry.

[74]  Francesco Fera,et al.  Genetically dependent modulation of serotonergic inactivation in the human prefrontal cortex , 2008, NeuroImage.