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1.  Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2 
“Schizotypy” is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [123I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
PMCID: PMC4089730  PMID: 25071490
schizotypy; dopamine; DRD2; fMRI; SPECT
2.  DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding 
Schizophrenia Bulletin  2011;39(1):206-216.
The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.
PMCID: PMC3523900  PMID: 21976709
DRD2; dopamine; default mode network; functional magnetic resonance imaging; single-photon emission computerized tomography
3.  DRD2/CHRNA5 Interaction on Prefrontal Biology and Physiology during Working Memory 
PLoS ONE  2014;9(5):e95997.
Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume.
A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI.
We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups.
The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.
PMCID: PMC4018353  PMID: 24819610
4.  Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans 
Dopamine modulation of neuronal activity during memory tasks identifies a non-linear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2 receptors (encoded by DRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D2 proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD2 polymorphism (rs1076560) causing reduced presynaptic D2 receptor expression and the DAT 3’-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing BOLD - fMRI during memory tasks and structural MRI. Results indicated a significant DRD2/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD2 allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a non-linear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2 knock-out animals (D2R−/−) indicate that DAT and D2 proteins interact in vivo. Taken together, our results demonstrate that the interaction between genetic variants in DRD2 and DAT critically modulates the non-linear relationship between dopamine and neuronal activity during memory processing.
PMCID: PMC2686116  PMID: 19176830
working memory; Recognition Memory; FMRI; Dopamine; Transport; D2; Receptor
5.  Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia 
Brain  2008;132(2):417-425.
Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case–control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.
PMCID: PMC2640212  PMID: 18829695
dopamine; D2 receptor; working memory; prefrontal cortex; striatum
6.  Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment 
Brain  2012;135(5):1436-1445.
Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical–subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti-dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and cortical–subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti-dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n = 46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal–parietal and prefrontal–striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal–striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose-response effects of anti-psychotic drugs on cognition in schizophrenia (n = 111). Thus, we suggest that genetic modulation of DRD2–AKT1-related prefrontal–subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment.
PMCID: PMC3338927  PMID: 22525159
antipsychotics; functional MRI; prefrontal cortex; schizophrenia; striatum
7.  Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans 
Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine - G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced ‘emotion control’ compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
PMCID: PMC2834475  PMID: 19940176
amygdala; DRD2; dopamine; emotion; fMRI; prefrontal cortex
8.  Hyperstimulation of striatal D2 receptors with sleep deprivation: Implications for cognitive impairment 
NeuroImage  2009;45(4):1232-1240.
Sleep deprivation interferes with cognitive performance but the mechanisms are poorly understood. We recently reported that one night of sleep deprivation increased dopamine in striatum (measured with [11C] raclopride, a PET radiotracer that competes with endogenous dopamine for binding to D2 receptors) and that these increases were associated with impaired performance in a visual attention task. To better understand this association here we evaluate the relationship between changes in striatal dopamine (measured as changes in D2 receptor availability using PET and [11C]raclopride) and changes in brain activation to a visual attention task (measured with BOLD and fMRI) when performed during sleep deprivation versus during rested wakefulness. We find that sleep induced changes in striatal dopamine were associated with changes in cortical brain regions modulated by dopamine (attenuated deactivation of anterior cingulate gyrus and insula) but also in regions that are not recognized targets of dopaminergic modulation (attenuated activation of inferior occipital cortex and cerebellum). Moreover, the increases in striatal dopamine as well as its associated regional activation and deactivation patterns correlated negatively with performance accuracy. These findings therefore suggest that hyperstimulation of D2 receptors in striatum may contribute to the impairment in visual attention during sleep deprivation. Thus, while dopamine increases in prefrontal regions (including stimulation of D1 receptors) may facilitate attention our findings suggest that hyperstimulation of D2 receptors in striatum may impair it. Alternatively, these associations may reflect a compensatory striatal dopamine response (to maintain arousal) that is superimposed on a larger response to sleep deprivation.
PMCID: PMC2714585  PMID: 19349237
Dopamine D2 receptors; Raclopride; Visual attention; PET; fMRI; Default network; Thalamus
9.  Intronic Polymorphisms Affecting Alternative Splicing of Human Dopamine D2 Receptor Are Associated with Cocaine Abuse 
Neuropsychopharmacology  2010;36(4):753-762.
The dopamine receptor D2 (encoded by DRD2) is implicated in susceptibility to mental disorders and cocaine abuse, but mechanisms responsible for this relationship remain uncertain. DRD2 mRNA exists in two main splice isoforms with distinct functions: D2 long (D2L) and D2 short (D2S, lacking exon 6), expressed mainly postsynaptically and presynaptically, respectively. Two intronic single-nucleotide polymorphisms (SNPs rs2283265 (intron 5) and rs1076560 (intron 6)) in high linkage disequilibrium (LD) with each other have been reported to alter D2S/D2L splicing and several behavioral traits in human subjects, such as memory processing. To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls). Robust effects of rs2283265 and rs1076560 on reducing formation of D2S relative to D2L were confirmed. The minor alleles of rs2283265/rs1076560 were considerably more frequent in Caucasians (18%) compared with African Americans (7%). Also, in Caucasians, rs2283265/rs1076560 minor alleles were significantly overrepresented in cocaine abusers compared with controls (rs2283265: 25 to 9%, respectively; p=0.001; OR=3.4 (1.7–7.1)). Several SNPs previously implicated in diverse clinical association studies are in high LD with rs2283265/rs1076560 and could have served as surrogate markers. Our results confirm the role of rs2283265/rs1076560 in D2 alternative splicing and support a strong role in susceptibility to cocaine abuse.
PMCID: PMC3055737  PMID: 21150907
alternative splicing; cocaine; dopamine; DRD2; D2S; human; addiction and substance abuse; dopamine; neurogenetics; psychostimulants; drd2; d2s; human; alternative splicing; cocaine
10.  The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory 
Psychopharmacology  2009;207(1):35-45.
Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear.
The present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory.
Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation.
Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex.
These results support models of dopamine function that posit a ‘gating’ function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.
PMCID: PMC2764850  PMID: 19672580
Dopamine; fMRI; Working memory; Executive function; Striatum
11.  Increased dopamine release in the right anterior cingulate cortex during the performance of a sorting task: A [11C]FLB 457 PET study 
NeuroImage  2009;46(2):516-521.
There is clear evidence that the prefrontal cortex is strongly involved in executive processes and that dopamine can influence performance on working memory tasks. Although, some studies have emphasized the role of striatal dopamine in executive functions, the role played by prefrontal dopamine during executive tasks is unknown. In order to investigate cortical dopamine transmission during executive function, we used D2-dopamine receptor ligand [11C]FLB 457 PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). During the retrieval with shift task of the MCST, the subjects had to match each test card to one of the reference cards based on a classification rule (color, shape or number) determined by comparing the previously viewed cue card and the current test card. A reduction in [11C]FLB 457 binding potential in the right dorsal anterior cingulate cortex (ACC) was observed when subjects performed the active task compared to the control task. These findings may suggest that right dorsal ACC dopamine neurotransmission increases significantly during the performance of certain executive processes, e.g., conflict monitoring, in keeping with previous evidence from fMRI studies showing ACC activation during similar tasks. These results may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease and schizophrenia.
PMCID: PMC2972252  PMID: 19264140 CAMSID: cams1532
FLB 457; Positron emission tomography; Executive function; Anterior cingulate cortex; Dopamine; Conflict monitoring
12.  Increased Orbitofrontal Brain Activation after Administration of a Selective Adenosine A2A Antagonist in Cocaine Dependent Subjects 
Background: Positron Emission Tomography imaging studies provide evidence of reduced dopamine function in cocaine dependent subjects in the striatum, which is correlated with prefrontal cortical glucose metabolism, particularly in the orbitofrontal cortex. However, whether enhancement of dopamine in the striatum in cocaine dependent subjects would be associated with changes in prefrontal cortical brain activation is unknown. One novel class of medications that enhance dopamine function via heteromer formation with dopamine receptors in the striatum is the selective adenosine A2A receptor antagonists. This study sought to determine the effects administration of the selective adenosine A2A receptor antagonist SYN115 on brain function in cocaine dependent subjects. Methodology/Principle Findings: Twelve cocaine dependent subjects underwent two fMRI scans (one after a dose of placebo and one after a dose of 100 mg of SYN115) while performing a working memory task with three levels of difficulty (3, 5, and 7 digits). fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L) lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole. Conclusion/Significance: These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of adenosine A2A receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A2A receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.
PMCID: PMC3361057  PMID: 22654774
cocaine; fMRI; adenosine A2A; orbitofrontal cortex; working memory
13.  Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive vs. motor flexibility 
Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional MRI study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double-blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated BOLD signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensori-motor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs. motor) are affected differently by increased dopaminergic stimulation.
PMCID: PMC3795948  PMID: 23660437
bromocriptine; psychopharmacology; intentional flexibility; functional magnetic resonance imaging (fMRI)
14.  Dopamine and fronto-striatal networks in cognitive aging 
Neurobiology of Aging  2011;33(3):623.e15-623.e24.
Recent studies have linked dopamine to differences in behavior and brain activity in normal individuals. We explored these relationships in older and younger adults by investigating how functional connectivity between the striatum and prefrontal cortex is related to caudate dopamine and verbal working memory task performance. We studied 12 young and 18 older participants with functional magnetic resonance imaging (fMRI) during this task, and used positron emission tomography with the tracer 6-[18F]-fluoro-L-m-tyrosine (FMT) to assess dopamine synthesis capacity. Younger adults had a greater extent of frontal-caudate functional connectivity during the load-dependent delay period of the working memory task than the older participants. Across all subjects, the extent of this functional connectivity was negatively correlated with dopamine synthesis capacity, such that participants with the greatest connectivity had the lowest caudate FMT signal. Additionally, the extent of functional connectivity was positively correlated with working memory performance. Overall these data suggest interdependencies exist between fronto-striatal functional connectivity, dopamine, and working memory performance and that this system is functioning suboptimally in normal aging.
PMCID: PMC3245323  PMID: 21511369
aging; working memory; dopamine; functional connectivity; FMT
15.  Motivational salience and genetic variability of dopamine D2 receptor expression interact in the modulation of interference processing 
Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497) has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. Forty-six young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI). Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both). Reaction times (RTs) were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent vs. congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward (REW) and punishment trials (PUN). In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction.
PMCID: PMC3672681  PMID: 23760450
DRD2; TaqIA; dopamine; genetic; motivation; interference processing; flanker; fMRI
16.  Linguistic Grammar Learning and DRD2-TAQ-IA Polymorphism 
PLoS ONE  2013;8(5):e64983.
As research into the neurobiology of language has focused primarily on the systems level, fewer studies have examined the link between molecular genetics and normal variations in language functions. Because the ability to learn a language varies in adults and our genetic codes also vary, research linking the two provides a unique window into the molecular neurobiology of language. We consider a candidate association between the dopamine receptor D2 gene (DRD2) and linguistic grammar learning. DRD2-TAQ-IA polymorphism (rs1800497) is associated with dopamine receptor D2 distribution and dopamine impact in the human striatum, such that A1 allele carriers show reduction in D2 receptor binding relative to carriers who are homozygous for the A2 allele. The individual differences in grammatical rule learning that are particularly prevalent in adulthood are also associated with striatal function and its role in domain-general procedural memory. Therefore, we reasoned that procedurally-based grammar learning could be associated with DRD2-TAQ-IA polymorphism. Here, English-speaking adults learned artificial concatenative and analogical grammars, which have been respectively associated with procedural and declarative memory. Language learning capabilities were tested while learners’ neural hemodynamic responses were simultaneously measured by fMRI. Behavioral learning and brain activation data were subsequently compared with the learners’ DRD2 (rs1800497) genotype. Learners who were homozygous for the A2 allele were better at concatenative (but not analogical) grammar learning and had higher striatal responses relative to those who have at least one A1 allele. These results provide preliminary evidence for the neurogenetic basis of normal variations in linguistic grammar learning and its link to domain-general functions.
PMCID: PMC3669058  PMID: 23741438
17.  Transient Calcium and Dopamine Increase PKA Activity and DARPP-32 Phosphorylation 
PLoS Computational Biology  2006;2(9):e119.
Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.
Reinforcement learning, based on the association of a stimulus-triggered movement with a reward, involves changes in connection strength between neurons. Memory storage occurs in the striatum, the input stage of the basal ganglia, when a stimulus or movement signal originating from the cortex and a reward signal originating from the midbrain reach the target striatal cells together. Repetitive pairing of these two signals strengthens the connection between cortical and striatal cells. The strengthening of the connections is caused by activation of biochemical signalling pathways inside the striatal cells. These intracellular signalling pathways are explored in a quantitative computational model describing the biochemical pathways important for reinforcement learning. Lindskog et al.'s study shows that when brief reward and stimuli signals are paired, a stronger response in the intracellular signalling occurs compared with the situation when each signal is given alone. This result illustrates mechanisms whereby paired stimuli, but not unpaired stimuli, can cause learning. Furthermore, the model predicts that the biochemical responses are different after brief stimulation as compared with prolonged stimulation. This result highlights the difficulties in predicting the nonlinear interactions within signalling cascades based on prolonged stimulations, which often are used in biochemical experiments.
PMCID: PMC1562452  PMID: 16965177
18.  An fMRI investigation of the fronto-striatal learning system in women who exhibit eating disorder behaviors 
NeuroImage  2011;56(3):10.1016/j.neuroimage.2011.03.026.
In the present study, we sought to examine whether the fronto-striatal learning system, which has been implicated in bulimia nervosa, would demonstrate altered BOLD activity during probabilistic category learning in women who met subthreshold criteria for bulimia nervosa (Sub-BN). Sub-BN, which falls within the clinical category of Eating Disorder Not Otherwise Specified (EDNOS), is comprised of individuals who demonstrate recurrent binge eating, efforts to minimize their caloric intake and caloric retention, and elevated levels of concern about shape, weight, and/or eating, but just fail to meet the diagnostic threshold for bulimia nervosa (BN). fMRI data were collected from eighteen women with subthreshold-BN (Sub-BN) and nineteen healthy control women group-matched for age, education and body mass index (MC) during the weather prediction task. Sub-BN participants demonstrated increased caudate nucleus and dorsolateral prefrontal cortex (DLPFC) activation during the learning of probabilistic categories. Though the two subject groups did not differ in behavioral performance, over the course of learning, Sub-BN participants showed a dynamic pattern of brain activity differences when compared to matched control participants. Regions implicated in episodic memory, including the medial temporal lobe (MTL), retrosplenial cortex, middle frontal gyrus, and anterior and posterior cingulate cortex showed decreased activity in the Sub-BN participants compared to MCs during early learning which was followed by increased involvement of the DLPFC during later learning. These findings demonstrate that women with Sub-BN demonstrate differences in fronto-striatal learning system activity, as well as a distinct functional pattern between fronto-striatal and MTL learning systems during the course of implicit probabilistic category learning.
PMCID: PMC3860103  PMID: 21419229
Eating disorders; fMRI; Fronto-striatal system; Weather prediction task; Bulimia nervosa; Memory system interactions
19.  COMT and ANKK1-Taq-Ia Genetic Polymorphisms Influence Visual Working Memory 
PLoS ONE  2013;8(1):e55862.
Complex cognitive tasks such as visual working memory (WM) involve networks of interacting brain regions. Several neurotransmitters, including an appropriate dopamine concentration, are important for WM performance. A number of gene polymorphisms are associated with individual differences in cognitive task performance. COMT, for example, encodes catechol-o-methyl transferase the enzyme primarily responsible for catabolizing dopamine in the prefrontal cortex. Striatal dopamine function, linked with cognitive tasks as well as habit learning, is influenced by the Taq-Ia polymorphism of the DRD2/ANKK1 gene complex; this gene influences the density of dopamine receptors in the striatum. Here, we investigated the effects of these polymorphisms on a WM task requiring the maintenance of 4 or 6 items over delay durations of 1 or 5 seconds. We explored main effects and interactions between the COMT and DRD2/ANKK1-Taq-Ia polymorphisms on WM performance. Participants were genotyped for COMT (Val158Met) and DRD2/ANKK1-Taq-Ia (A1+, A1−) polymorphisms. There was a significant main effect of both polymorphisms. Participants' WM reaction times slowed with increased Val loading such that the Val/Val homozygotes made the slowest responses and the Met/Met homozygotes were the fastest. Similarly, WM reaction times were slower and more variable for the DRD2/ANKK1-Taq-Ia A1+ group than the A1− group. The main effect of COMT was only apparent in the DRD2/ANKK1-Taq-Ia A1− group. These findings link WM performance with slower dopaminergic metabolism in the prefrontal cortex as well as a greater density of dopamine receptors in the striatum.
PMCID: PMC3561341  PMID: 23383291
20.  Abnormalities of Dorsolateral Prefrontal Function in Women With Premenstrual Dysphoric Disorder: A Multimodal Neuroimaging Study 
The American journal of psychiatry  2013;170(3):305-314.
To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol.
PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol.
In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms.
Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.
PMCID: PMC3968942  PMID: 23361612
21.  Neurotransmitter Roles in Synaptic Modulation, Plasticity and Learning in the Dorsal Striatum 
Neuropharmacology  2010;58(7):951-961.
The dorsal striatum is a large forebrain region involved in action initiation, timing, control, learning and memory. Learning and remembering skilled movement sequences requires the dorsal striatum, and striatal subregions participate in both goal-directed (action-outcome) and habitual (stimulus-response) learning. Modulation of synaptic transmission plays a large part in controlling input to as well as the output from striatal medium spiny projection neurons (MSNs). Synapses in this brain region are subject to short-term modulation, including allosteric alterations in ion channel function and prominent presynaptic inhibition. Two forms of long-term synaptic plasticity have also been observed in striatum, long-term potentiation (LTP) and long-term depression (LTD). LTP at glutamatergic synapses onto MSNs involves activation of NMDA-type glutamate receptors and D1 dopamine or A2A adenosine receptors. Expression of LTP appears to involve postsynaptic mechanisms. LTD at glutamatergic synapses involves retrograde endocannabinoid signaling stimulated by activation of metabotropic glutamate receptors (mGluRs) and D2 dopamine receptors. While postsynaptic mechanisms participate in LTD induction, maintained expression involves presynaptic mechanisms. A similar form of LTD has also been observed at GABAergic synapses onto MSNs. Studies have just begun to examine the roles of synaptic plasticity in striatal-based learning. Findings to date indicate that molecules implicated in induction of plasticity participate in these forms of learning. Neurotransmitter receptors involved in LTP induction are necessary for proper skill and goal-directed instrumental learning. Interestingly, receptors involved in LTP and LTD at glutamatergic synapses onto MSNs of the “indirect pathway” appear to have important roles in habit learning. More work is needed to reveal if and when synaptic plasticity occurs during learning and if so what molecules and cellular processes, both short- and long-term, contribute to this plasticity.
PMCID: PMC2849868  PMID: 20096294
Long-term plasticity; Dopamine; Glutamate; Endocannabinoid; Instrumental learning; Skill Learning
22.  A New Framework for Cortico-Striatal Plasticity: Behavioural Theory Meets In Vitro Data at the Reinforcement-Action Interface 
PLoS Biology  2015;13(1):e1002034.
A computational model yields new insights into the bewildering complexity of cortico-striatal plasticity and its rationale for supporting operant learning.
Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem—action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and behaviour, our model shows how striatum acts as the action-reinforcement interface.
Author Summary
A key component of survival is the ability to learn which actions, in what contexts, yield useful and rewarding outcomes. Actions are encoded in the brain in the cortex but, as many actions are possible at any one time, there needs to be a mechanism to select which one is to be performed. This problem of action selection is mediated by a set of nuclei known as the basal ganglia, which receive convergent “action requests” from all over the cortex and select the one that is currently most important. Working out which is most important is determined by the strength of the input from each action request: the stronger the connection, the more important that action. Understanding learning thus requires understanding how that strength is changed by the outcome of each action. We built a computational model that demonstrates how the brain's internal signal for outcome (carried by the neurotransmitter dopamine) changes the strength of these cortical connections to learn the selection of rewarded actions, and the suppression of unrewarded ones. Our model shows how several known signals in the brain work together to shape the influence of cortical inputs to the basal ganglia at the interface between our actions and their outcomes.
PMCID: PMC4285402  PMID: 25562526
23.  Dopamine-transporter levels drive striatal responses to apomorphine in Parkinson's disease 
Brain and Behavior  2013;3(3):249-262.
Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.
PMCID: PMC3683285  PMID: 23785657
Cognition; DAT; dopamine-agonist; fMRI; Parkinson's disease; working memory
24.  Striatal Dopamine and Working Memory 
Cerebral Cortex (New York, NY)  2008;19(2):445-454.
Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.
PMCID: PMC2733326  PMID: 18550595
aging; caudate; fMRI; maintenance; PET; putamen
25.  Impaired prefrontostriatonigral functional connectivity and substantia nigra hyperactivity in schizophrenia 
Biological psychiatry  2013;74(2):122-129.
The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine (DA) has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related fMRI study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with DA regulating regions of the basal ganglia.
18 individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related fMRI during working memory. We conducted between-group contrasts of task-evoked, univariate, activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present.
We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis.
These results suggest that functional impairments of the prefrontostriatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.
PMCID: PMC3620727  PMID: 23290498
schizophrenia; psychosis; fMRI; substantia nigra; prefrontal cortex; basal ganglia

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