Preliminary investigation of the influence of dopamine regulating genes on social working memory

Working memory (WM) refers to mental processes that enable temporary retention and manipulation of information, including information about other people (“social working memory”). Previous studies have demonstrated that nonsocial WM is supported by dopamine neurotransmission. Here, we investigated in 131 healthy adults whether dopamine is similarly involved in social WM by testing whether social and nonsocial WM are influenced by genetic variants in three genes coding for molecules regulating the availability of dopamine in the brain: catechol-O-methyltransferase (COMT), dopamine active transporter (DAT), and monoamine-oxidase A (MAOA). An advantage for the Met allele of COMT was observed in the two standard WM tasks and in the social WM task. However, the influence of COMT on social WM performance was not accounted for by its influence on either standard WM paradigms. There was no main effect of DAT1 or MAOA, but a significant COMT x DAT1 interaction on social WM performance. This study provides novel preliminary evidence of effects of genetic variants of the dopamine neurotransmitter system on social cognition. The results further suggest that the effects observed on standard WM do not explain the genetic effects on effortful social cognition

Genetic influences on emotion/cognition interactions : from synaptic regulation to individual differences in working memory for emotional faces

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Probing and pushing potential genetics, development and training of cognitive functions

Capacities of cognitive functions increase considerably during childhood and adolescence. This development is of importance as poor development can predict lower performance on academic skills. Furthermore, severe impairment is related to symptoms of many neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD). These observations have lead to a great interest within the research community to understand 1) underlying mechanisms that influence cognitive development, and 2) factors that can improve cognitive capacity. This thesis aims to increase understanding of these topics, focusing on two specific cognitive functions: working memory (WM) and non-verbal reasoning (NVR). Study I investigated the effects of polymorphisms within certain candidate genes on WM performance and also brain function and structure in a sample of typically developing children and adolescents. We found that a polymorphism within the SNAP25 gene was significantly associated with WM capacity, ADHD symptoms in males as well as activity and grey matter density within the posterior cingulate cortex. This brain activity in turn correlated with degree of ADHD symptoms. Brain activity significantly predicted ADHD symptoms two years later. Studies II and III investigated how reasoning ability and WM can be improved with training. Study II assessed a newly developed NVR training programme in combination with a previously studied WM training programme in a sample of typically developing 4-year-old children. Training NVR resulted in significant improvements in performance on a measure of fluid reasoning and training of WM significantly improved performance on WM measures. There was limited transfer between the two different functions. Study III assessed the same training programme in children with intellectual disability. In this group, there was a large variance in progress observed during training and we found that this variance was important for predicting improvements following training. Baseline capacities, gender, and co-morbidity with additional diagnoses predicted the degree to which the children with intellectual disability improved during training. The study findings highlight the importance of inter-individual differences for understanding the effects of cognitive training. Finally, Study IV showed that variations within a gene coding for dopamine transporters is associated with inter-individual differences in the degree of improvements observed after cognitive training. Together, these studies illustrate that the genetic variants we are born with influence the development of our brains and cognitive abilities, and that this development can be influenced by environment and experience such as cognitive training. Importantly, genes and environment interact, with our pre-determined genetic setup influencing our susceptibility to environmental influence

Neurobiological Foundations Of Stability And Flexibility

In order to adapt to changing and uncertain environments, humans and other organisms must balance stability and flexibility in learning and behavior. Stability is necessary to learn environmental regularities and support ongoing behavior, while flexibility is necessary when beliefs need to be revised or behavioral strategies need to be changed. Adjusting the balance between stability and flexibility must often be based on endogenously generated decisions that are informed by information from the environment but not dictated explicitly. This dissertation examines the neurobiological bases of such endogenous flexibility, focusing in particular on the role of prefrontally-mediated cognitive control processes and the neuromodulatory actions of dopaminergic and noradrenergic systems. In the first study (Chapter 2), we examined the role of frontostriatal circuits in instructed reinforcement learning. In this paradigm, inaccurate instructions are given prior to trial-and-error learning, leading to bias in learning and choice. Abandoning the instructions thus necessitates flexibility. We utilized transcranial direct current stimulation over dorsolateral prefrontal cortex to try to establish a causal role for this area in this bias. We also assayed two genes, the COMT Val158Met genetic polymorphism and the DAT1/SLC6A3 variable number tandem repeat, which affect prefrontal and striatal dopamine, respectively. The results support the role of prefrontal cortex in biasing learning, and provide further evidence that individual differences in the balance between prefrontal and striatal dopamine may be particularly important in the tradeoff between stability and flexibility. In the second study (Chapter 3), we assess the neurobiological mechanisms of stability and flexibility in the context of exploration, utilizing fMRI to examine dynamic changes in functional brain networks associated with exploratory choices. We then relate those changes to changes in norepinephrine activity, as measured indirectly via pupil diameter. We find tentative support for the hypothesis that increased norepinephrine activity around exploration facilitates the reorganization of functional brain networks, potentially providing a substrate for flexible exploratory states. Together, this work provides further support for the framework that stability and flexibility entail both costs and benefits, and that optimizing the balance between the two involves interactions of learning and cognitive control systems under the influence of catecholamines

Moderator Effects of Working Memory on Symptom Stability in Attention-Deficit/Hyperactivity Disorder by Dopamine D1 and D2 Receptor Polymorphisms During Development

Background: Developmental changes in dopaminergic pathways in the prefrontal cortex (PFC) that are important for working memory have been hypothesized to play a central role in the trajectory of attention-deficit/hyperactivity disorder (ADHD), but not the initial onset of the disorder. This dissertation research examines whether dopamine receptor D1 (DRD1) and dopamine receptor D2 (DRD2) gene polymorphisms moderate the association between improvements in working memory and declines in attention problems in ADHD from childhood to adolescence/young adulthood. Methods: Participants were 76 racially/ethnically diverse youth diagnosed with ADHD in childhood and followed prospectively for almost 10 years. Stability of ADHD symptomatology was measured as a quantitative trait using the Attention Problems scale from the Child Behavior Checklist collected both in childhood and adolescence/young adulthood. Digit Span Forward and Digit Span Backward were administered at both time points to assess working memory maintenance and manipulation, respectively. Genotype and age were moderator variables. Results: DRD1 and DRD2 polymorphisms were associated with the stability of attention problems in adolescence/young adulthood, but not childhood. DRD1 polymorphisms, but not DRD2, significantly moderated the association between working memory and attention problems, with the strongest effects evidenced during adolescence/young adulthood. Notably, DRD1 moderation of working memory on attention problems was specific to manipulation performance. Conclusions: Attention problems decreased over the course of almost 10 years if manipulation concomitantly improved during this period of development in a subgroup of individuals with childhood-diagnosed ADHD depending on their genetic makeup

COMT and DRD2/ANKK-1 gene-gene interaction account for resetting of gamma neural oscillations to auditory stimulus-driven attention

Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture

Development of dopaminergic genetic associations with visuospatial, verbal and social working memory

Dopamine transmission in the prefrontal cortex (PFC) supports working memory (WM), the temporary holding, processing and manipulation of information in one’s mind. The gene coding the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine, in particular in the PFC, has a common single nucleotide polymorphism leading to two versions of the COMT enzyme which vary in their enzymatic activity. The methionine (Met) allele has been associated with higher WM performance and lower activation of the PFC in executive function tasks than the valine (Val) allele. In a previous study, COMT genotype was associated with performance on verbal and visuospatial WM tasks in adults, as well as with performance on a novel social WM paradigm that requires participants to maintain and manipulate information about the traits of their friends or family over a delay. Here, data collected in children and adolescents (N=202) were compared to data from the adult sample (N=131) to investigate possible age differences in genetic associations. Our results replicate and extend previous work showing that the pattern of superior WM performance observed in Met/Met adults emerges during development. These findings are consistent with a decrease in prefrontal dopamine levels during adolescence. Developmentally moderated genetic effects were observed for both visuospatial and social WM, even when controlling for non-social WM performance, suggesting that the maintenance and manipulation of social information may also recruit the dopamine neurotransmitter system. These findings show that development should be considered when trying to understand the impact of genetic polymorphisms on cognitive function

The interplay between a dietary preference for fat and sugar, gene expression in the dopaminergic system and executive cognition in humans

Obesity is a health issue of both individual and global importance. Evidence from rodent literature suggests that dietary preferences for fat and sugar might influence dopaminergic signaling in the brain and thus executive cognition. These diet-related changes could provide a mechanistic basis potentially explaining obesity-promoting behaviour. However, valid evidence for this link in humans is still scarce. This thesis aimed to add to this gap by studying dopamine-related gene expression profiles in peripheral cells and executive cognition in a human sample (n = 75). The results provide indications for an association between dietary preference and alterations in dopamingeric sigaling on a peripheral gene expression level even though the group differences were not statistically significant. A link to cognition could not be established with the methods applied. Yet, several targets for future research are suggested to further explore this interplay