The role of the COMT val158met polymorphism in mediating aversive learning in visual cortex
Graphical abstract
Introduction
The catechol-O-methyltransferase (COMT) rs4680 single nucleotide polymorphism (SNP) G > A results in the substitution of valine (Val) to methionine (Met) at codon 158 (Lachman et al., 1996). This polymorphism impacts the effectiveness of COMT, a regulatory enzyme in the metabolic pathways of catecholamines (dopamine, epinephrine and norepinephrine) in the central nervous system and peripherally in red blood cells and liver of both rodents and humans (Weinshilboum and Dunnette, 1981). The amino acid change resulting from the COMT val158met polymorphism alters metabolic activity of the COMT enzyme, where the Val form has a three to four-fold increase in enzymatic activity over the Met form (Weinshilboum et al., 1999). Physiologically, increased COMT activity leads to a more efficient elimination of extracellular dopamine, particularly in prefrontal cortex (PFC) due to a paucity of dopamine transporters in this region (Hirvonen et al., 2010, Slifstein et al., 2008, Yavich et al., 2007). The tonic-phase dopamine hypothesis relates varying COMT enzymatic activity levels to systematic changes in dopamine transmission in ventral striatal and PFC neurons (Bilder et al., 2004). High-activity COMT (Val allele) results in decreased tonic dopamine activity in striatum, therefore lowering the threshold for phasic dopamine through D2 auto-receptors. In PFC on the other hand, high-activity COMT results in lower extracellular dopamine availability. In vivo PET studies however have demonstrated that D2 levels in human cortex and striatum do not differ as a function of COMT genotype (Hirvonen et al., 2010), concluding that the COMT SNP impacts D1 receptors instead.
Given this complexity in fronto-striatal dopamine signaling, it is not surprising that contending hypotheses have been discussed regarding the impact of COMT status on cognitive functioning. Behavioral studies using executive control and working memory paradigms have found that Met allele carriers tend to report task items more accurately compared to Val homozygotes (Barnett et al., 2007, Egan et al., 2001). Opposite findings have been reported for tasks entailing reversal learning, task-switching, and emotional distraction, in which Val homozygotes performed more accurately than individuals carrying at least one Met allele (Bishop et al., 2006, Colzato et al., 2010, Nolan et al., 2004). These findings implicate Met carriers to have an advantage, cognitively, in maintaining task specific demands in the context of working memory, whereas Val carriers appear to display an advantage in updating task demands (Bellander et al., 2015, Rosa et al., 2010). Although this evidence suggests that COMT genotype status may affect behavior, identification of specific neurophysiological mechanisms mediating this link has been difficult. Well-defined experimental protocols that challenge known neurophysiological processes may be a suitable avenue towards this goal. Classical differential conditioning incorporates task demands in the context of changing contingencies and may therefore be ideally suited to extend the COMT literature. The aim of the current study was to examine the extent to which COMT genotype affects aversive learning during classical differential aversive conditioning.
Classical differential aversive conditioning in the laboratory has been extensively studied in both animal and human models, demonstrating the fundamental process of an initially neutral stimulus acquiring an aversive quality through pairing with a noxious stimulus (Miskovic and Keil, 2012). The acquisition of an aversive quality has been shown neurophysiologically to involve learning induced changes in sensory systems, such as retinotopic visual cortex (McTeague et al., 2015, Stolarova et al., 2006), as well as systematic changes in autonomic reflex physiology and behavior (Hamm and Weike, 2005, Hodes et al., 1985). Neuroimaging studies have shown several brain regions to be involved during aversive learning including sensory and motor cortices, as well as limbic structures such as amygdala, insula, striatum and hippocampus (Büchel et al., 1998, LeDoux, 2000). Cortical and subcortical regions are thought to modulate primary sensory cortices through reentrant feedback projections (Amaral et al., 2003), leading to learning induced changes impacting perception (Lamme and Roelfsema, 2000).
Furthermore, stimulus expectancy and anticipation have been theorized to play an essential role in the process of contingency learning (Rescorla and Wagner, 1972), implicating the involvement of anterior brain regions such PFC (Delgado et al., 2006). In a recent study, rapid CS discrimination was found specifically in PFC regions during the acquisition phase of an aversive conditioning paradigm (Rehbein et al., 2014). The PFC may be crucial in aversive learning due to its involvement in attention, associative learning and working memory through top-down modulation of higher-order sensory cortices (Asaad et al., 1998, Barcelo et al., 2000, Desimone, 1996, Miller et al., 2011, Miller et al., 1996, Miller and Cohen, 2001, Rainer and Miller, 2000). The modulatory role of the dopaminergic system has been suggested as one mechanism by which anterior brain regions contribute to the acquisition and extinction of aversive pairings (Abraham et al., 2014, Horvitz, 2000, Wendler et al., 2014).
In summary, these findings imply that fronto-striatal regions may play a modulatory role in aversive learning, potentially reflected in learning-related changes of cognitive processes such as attention, anticipation, and working memory. Previous work partly supports this notion: During viewing of aversive stimuli, as well as during emotional memory tasks, Met carriers tend to show heightened amygdala and hippocampal activation compared to Non-Met carriers (Drabant et al., 2006, Smolka et al., 2007, Smolka et al., 2005, Williams et al., 2010). In terms of autonomic engagement, Met carriers show enhanced startle potentiation during passive viewing of aversive stimuli (Montag et al., 2008). Additionally, Lonsdorf et al. (2009) found Met carriers to have failed startle suppression during the extinction phase of an aversive conditioning paradigm, suggesting that Met carriers may have an increased proneness to anxiety. Although these findings can be taken as evidence for altered emotional reactivity based on COMT genotype, results are mixed when individual differences are taken into account such as psychiatric diagnosis, gender and ethnicity (Domschke et al., 2012, Lee and Prescott, 2014). In addition, Wang et al. (2013) demonstrated that COMT by ethnicity interactions as observed for Caucasians versus Asians (Domschke et al., 2007) may be attributed to altered brain physiology between ethnic groups. The neurophysiological mechanisms that explain the cognitive, autonomic and behavioral differences reported for the COMT val158met polymorphism are scarce in the literature and warrant more systematic investigations that challenge these processes.
An increasingly used neuroimaging tool in the cognitive neurosciences is the steady-state visually evoked potential (ssVEP). In this technique, visual cortical neurons are entrained at a given frequency by an external luminance- or contrast-modulated stimulus, captured as oscillatory scalp voltage changes through electroencephalography (EEG). Recorded activity is thought to reflect the evoked, synchronous activity of large masses of neurons in response to a stimulus. The ssVEP is modulated by experimental manipulations such as selective attention, feature selection, and motivational/affective relevance of the stimulus (Keil et al., 2009, Moratti et al., 2004, Muller et al., 2006, Silberstein et al., 1995, Song and Keil, 2014). The increase of ssVEP amplitude with motivational relevance, especially during aversive engagement, has been attributed to top-down influences on visual cortex exerted by anterior structures involved in the neurocomputation of aversive or appetitive value (Lang and Bradley, 2010).
The aim of the current study was to explore the extent to which COMT genotype status affects defensive reactivity to threat cues during aversive learning. We implemented a differential aversive conditioning paradigm in which a visual stimulus (conditioned stimulus, CS +) attained aversive quality by repeated and consistent pairing with a noxious stimulus (unconditioned stimulus, US), whereas a different visual stimulus (CS −) was never paired with the noxious stimulus. By recording ssVEPs elicited by the visual stimuli (CSs), peripheral physiological measures, and self-report data, we aimed to capture learning-induced perceptual, autonomic and behavioral changes, respectively, in order to assess COMT genotype differences. As aversive learning engages processes underlying both emotional reactivity and cognitive functioning, two alternative hypotheses are plausible in light of the current literature on the COMT val158met polymorphism: Met allele carriers have been shown to exhibit heightened defensive reactivity during passive viewing of aversive stimuli. In the context of aversive learning, this may translate to not only heightened defensive engagement, but also enhanced perceptual processing of the aversively cued stimulus (CS +). On the other hand, as Val/Val homozygotes have been demonstrated to show an advantage in updating task demands, individuals of this genotype may present with more pronounced differential adaptation to the changing contingencies of the differential conditioning paradigm, when comparing the CS + and CS − during habituation, acquisition and extinction.
Section snippets
Participants
Participants were students taking General Psychology courses at the University of Florida who received course credit. A total of 83 participants were originally included in the study. Fourteen individuals were excluded from the analysis due to poor data quality in the electroencephalography (EEG) recording. Poor data quality was determined by excessive loss of trials due to movement artifacts and low signal-to-noise ratio of the steady-state visually evoked potential (ssVEP), measured using the
Occipital electrocortical signals (ssVEP amplitude)
Genotype differences were found for the COMT val158met polymorphism grouped by Met and Non-Met allele carriers. Across conditioning blocks and the first block of extinction, a two-way interaction was found for CS condition × genotype [F(1,61) = 4.73, p < .05], in addition to a three-way interaction of block × CS condition × genotype [F(2,122) = 5.03, p < .05, partial eta squared = .076]. Follow-up ANOVA revealed that during the first block of acquisition, Non-Met allele carriers showed significant
Discussion
The current study sets out to characterize the relation between an individual's COMT val158met polymorphism status and indices of visual processing, reflex physiology and evaluative self-report during aversive conditioning. The conditioning regime reliably prompted defensive responses across COMT genotype groups, shown by a decelerative, orienting response for CS + trials during initial conditioning. Pronounced inter-individual differences were also observed: Across measures, observers
Acknowledgments
This research was funded by the National Institute of Health (MH097320). Thanks to Margaret Bradley for assistance with the peripheral psychophysiological data acquisition and analysis. Thanks also to Gabrielle Gordon for assistance in data collection. The authors declare no competing interests.
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