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      Dissociable Catecholaminergic Modulation of Visual Attention: Differential Effects of Catechol-O-Methyltransferase and Dopamine Beta-Hydroxylase Genes on Visual Attention

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          Abstract

          Visual attention enables us to prioritise behaviourally relevant visual information while ignoring distraction. The neural networks supporting attention are modulated by two catecholamines, dopamine and noradrenaline. The current study investigated the effects of single nucleotide polymorphisms in two catecholaminergic genes – COMT (Val 158Met) and DBH (444 G/A) – on individual differences in attention functions. Participants ( n = 125) were recruited from the Oxford Biobank by genotype-based recall. They were tested on a continuous performance task (sustained attention), a Go/No-Go task (response inhibition), and a task assessing attentional selection in accordance with the Theory of Visual Attention (TVA). We found a significant effect of DBH genotype status on the capacity to maintain attention over time (sustained attention) as measured by the continuous performance task. Furthermore, we demonstrated a significant association between COMT genotype status and effective threshold of visual perception in attentional selection as estimated based on the TVA task performance. No other group differences in attention function were found with respect to the studied genotypes. Overall, our findings provide novel experimental evidence that: (i) dopaminergic and noradrenergic genotypes have dissociable effects on visual attention; (ii) either insufficient or excessive catecholaminergic activity may have equally detrimental effects on sustained attention.

          Highlights

          • Catecholaminergic genotypes have dissociative cognitive effects on visual attention.

          • DBH (444 G/A) polymorphism affects sustained attention.

          • COMT Val 158Met polymorphism affects perceptual threshold in visual attention.

          • Both too little and too much catecholamines may detrimentally impact sustained attention.

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          Most cited references79

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          The attention system of the human brain.

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            Inverted-U-shaped dopamine actions on human working memory and cognitive control.

            Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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              Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

              Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
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                Author and article information

                Contributors
                Journal
                Neuroscience
                Neuroscience
                Neuroscience
                Elsevier Science
                0306-4522
                1873-7544
                01 August 2019
                01 August 2019
                : 412
                : 175-189
                Affiliations
                [a ]Department of Experimental Psychology, University of Oxford, Oxford, UK
                [b ]Oxford Centre for Human Brain Activity, University of Oxford, Oxford, UK
                [c ]Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK
                [d ]Department of Psychology, Center for Visual Cognition, University of Copenhagen, Copenhagen, Denmark
                [e ]Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
                [f ]Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
                [g ]Department of Psychiatry, University of Oxford, Oxford, UK
                [h ]Oxford Health NHS Foundation Trust, Oxford, UK
                [i ]Centre for Human Brain Health, University of Birmingham, Birmingham, UK
                [j ]School of Psychology, University of Birmingham, Birmingham, UK
                [k ]Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, USA
                Author notes
                [* ]Corresponding author at: Centre for Human Brain Health, University of Birmingham, Birmingham, B15 2TT, United Kingdom. m.chechlacz.1@ 123456bham.ac.uk
                Article
                S0306-4522(19)30399-9
                10.1016/j.neuroscience.2019.05.068
                6645579
                31195057
                83c7adf0-544a-424c-820c-da1b63acab36
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 January 2019
                : 31 May 2019
                Categories
                Article

                Neurosciences
                attentional selection,sustained attention,comt,dbh,individual differences,catecholamines
                Neurosciences
                attentional selection, sustained attention, comt, dbh, individual differences, catecholamines

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