VU Research Portal Genetic architecture and behavioral analysis of attention and impulsivity Loos, M. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Loos, M. (2012). Genetic architecture and behavioral analysis of attention and impulsivity. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 28. Sep. 2021 Genetic architecture and behavioral analysis of attention and impulsivity Maarten Loos 1 About the thesis The work described in this thesis was performed at the Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. This work was in part funded by the Dutch Neuro-Bsik Mouse Phenomics consortium. The Neuro-Bsik Mouse Phenomics consortium was supported by grant BSIK 03053 from SenterNovem (The Netherlands). Publication of this thesis was financially supported by: Vrije Universiteit Amsterdam, The Netherlands Sylics, services in mouse phenomics, cellomics and bioinformatics. Trade name of Synaptologics B.V., Amsterdam, The Netherlands About the cover The cover illustrates the emergence of complex phenomena from simple rules. The image was adapted from a painting of an unknown artist exhibited in Centre national d'art et de culture Georges-Pompidou, Paris, France in August 2008. 2 VRIJE UNIVERSITEIT Genetic architecture and behavioral analysis of attention and impulsivity ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Aard- en Levenswetenschappen op donderdag 10 mei 2012 om 15.45 uur in het auditorium van de universiteit, De Boelelaan 1105 door Maarten Loos geboren te Roosendaal promotor: prof.dr. A.B. Smit copromotoren: prof.dr. S. Spijker dr. T. Pattij leescommissie: dr. A. Palmer dr. M.M. van Gaalen prof.dr. C.M.A. Pennartz dr. M.J.H. Kas prof.dr. E.J. de Geus dr. L. Diergaarde dr. R.O. Stiedl Voor mijn ouders Contents Chapter 1 General introduction 9 Chapter 2 Dopamine receptor D1/D5 gene expression in the medial 21 prefrontal cortex predicts impulsive choice in rats Chapter 3 Inhibitory control and response latency differences between 37 C57BL/6J and DBA/2J mice in a Go/No-Go and 5-choice serial reaction time task and strain-specific responsivity to amphetamine Chapter 4 Activity and impulsive action are controlled by different 59 genetic and environmental factors Chapter 5 Independent genetic loci for sensorimotor gating and 87 attentional performance in BXD recombinant inbred strains Chapter 6 Insights in the genetic architecture of impulsivity in mice 111 Chapter 7 Enhanced alcohol self-administration and relapse in a highly 127 impulsive inbred mouse strain Chapter 8 General discussion 143 References 151 Nederlandse samenvatting 169 Dankwoord 175 Curriculum Vitae 178 Peer-reviewed publications 179 7 8 Chapter 1 General Introduction 9 10 Introduction Complex genetic traits With his laws of inheritance presented in 1865, Gregor Mendel explained how biological characteristics, such as pea shape and flower color, were inherited (Mendel, 1866). The presence of only one genetic factor appeared to be necessary and sufficient to determine flower color, and the inheritance of this genetic trait therefore could be explained in simple terms. In the same year Sir Francis Galton, a biometrician devoted to quantifying human characteristics such as reaction time, described that many characteristics do not follow a dichotomous distribution but appear in several intermediate quantifiable flavors (Galton, 1865). He compared biological characteristics of parents and children, and established the degree of correlation between relatives as index of the heritability. The rivalry between the schools of dichotomous Mendelian geneticists and the quantitative biometricians was resolved in the 1918 by Sir Ronald Fisher. He statistically demonstrated that continuous characters as measured by biometricians could be governed by the action of a large number of Mendelian factors (Fisher, 1918), and the ‘complex genetic trait’ was born. The molecular inheritance of these factors and a functional mechanism by which they were transmitted to the offspring were not defined until 1953, when James Watson and Francis Crick published and discussed the structure of DNA (Watson & Crick, 1953) and suggested a DNA replication mechanism. Over the years, variation in most human characteristics (even traits such as IQ) has turned out to be, albeit to different extent, genetic in origin and complex in nature. Many genes underlie human behavior and their unique combinatorial inheritance includes the risk to develop various prevalent psychiatric and neurological diseases, such as attention deficit hyperactivity disorder (ADHD), schizophrenia and drug addiction (Faraone & Biederman, 1998; Greenwood et al., 2007; Kreek et al., 2005). By identifying genetic variants in the human population that predispose individuals to disease, quantitative genetics can yield insights into the contribution of multiple genes to complex disease traits. This is of great importance given the fact that the molecular basis of most psychiatric and neurological diseases is at best poorly understood. Dissecting complex traits into core elements will facilitate gene finding In genetic linkage studies and genome wide association studies, the aim is to relate the presence of a specific genetic variant to the observation of a specific phenotype. Over the last decade it has become clear that for prevalent human psychiatric and neurologic diseases, with overall substantial heritability, it is difficult to identify the causal genetic variants. To date, association studies have cumulated evidence for a limited number of genes associated with the clinical diagnosis of psychiatric disease, e.g. ADHD (DRD4, DRD5, SLC6A3, SNAP-25 and HTR1B; Faraone & Mick, 2010) and Schizophrenia (NRG1 and DTNBP1; Munafo et al., 2006 and Riley & Kendler, 2006). Together these risk alleles explain only a fraction of total risk contributed by genetic factors to these 11 Chapter 1 diseases despite tremendous advances in SNP genotyping technology and increases in samples sizes owing to large collaborative projects. Two explanations for this ‘missing heritability’ are being discussed at the moment. First, many genetic variants may act together, each with a small effect (< 1.0 %) that can barely be detected in even the largest collaborative studies. Secondly, each affected person may carry a different variant with a modest effect size that would go unnoticed in current genotyping assays focusing on common genetic variants and would not be picked up by genetic linkage studies due to too low effect size. Most psychiatric diseases are heterogeneous in nature and patients may have varying degrees of severity of each of the identified symptoms. For instance, in ADHD three subtypes are being recognized, characterized by symptoms of inattention, of hyperactivity/impulsivity, and a combined subtype. In fact, it is under debate whether symptoms of hyperactivity/impulsivity and inattention in ADHD reflect the same or separate disorders (Derefinko et al., 2008; Diamond, 2005; Milich et al., 2001). It is conceivable that quantitative genetic studies are facilitated when the disease phenotype is partitioned better into its core elements, to each of which a limited number of genetic variants contribute (Fig. 1; de Geus, 2002; Kas & Van Ree, 2004). Figure 1 | The genetic architecture of complex traits. (a) Many genetic polymorphisms on the genome contribute to higher (+) or lower (-) phenotypic values of brain phenotypes (b; grey ovals) and behavioral phenotypes (c; white rectangles). These phenotypes are core elements that are intermediate to genome and disease (d; grey rectangles). They are genetically less complex than the disease itself and are therefore a suitable starting point for a genetic mapping study to identify disease-contributing genes. Schematic modified after De Geus (2002). 12 Introduction Translation of psychiatric disease symptoms into rodent paradigms Executive functions are a diverse collection of cognitive processes such as rule acquisition, inhibiting inappropriate actions, planning, cognitive flexibility and selective attention. These executive functions have in common that they require an intact prefrontal cortex. Because these functions are highly demanding, they are sensitive to deterioration by e.g. ageing, chronic stress and occur under certain neurological conditions, such as in Alzheimer’s and Parkinson’s disease