DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus.     

Reprint of: DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus.     

Neural mechanisms of reward processing associated with depression-related personality traits

Objective

Although impaired reward processing in depression has been well-documented, the exact nature of that deficit remains poorly understood. To investigate the link between depression and the neural mechanisms of reward processing, we examined individual differences in personality.

Developmental changes in the reward positivity: An electrophysiological trajectory of reward processing

Children and adolescents learn to regulate their behavior by utilizing feedback from the environment but exactly how this ability develops remains unclear. To investigate this question, we recorded the event-related brain potential (ERP) from children (8–13 years), adolescents (14–17 years) and young adults (18–23 years) while they navigated a “virtual maze” in pursuit of monetary rewards. The amplitude of the reward positivity, an ERP component elicited by feedback stimuli, was evaluated for each age group. A current theory suggests the reward positivity is produced by the impact of reinforcement learning signals carried by the midbrain dopamine system on anterior cingulate cortex, which utilizes the signals to learn and execute extended behaviors. We found that the three groups produced a reward positivity of comparable size despite relatively longer ERP component latencies for the children, suggesting that the reward processing system reaches maturity early in development. We propose that early development of the midbrain dopamine system facilitates the development of extended goal-directed behaviors in anterior cingulate cortex.     

Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals

Adolescence is an evolutionarily conserved developmental period, with neural circuits and behaviors contributing to the detection, procurement, and receipt of rewards bearing similarity across species. Studies with laboratory animals suggest that adolescence is typified by a “reward-centric” phenotype—an increased sensitivity to rewards relative to adults. In contrast, adolescent rodents are reportedly less sensitive to the aversive properties of many drugs and naturally aversive stimuli. Alterations within the mesocorticolimbic dopamine and endocannabinoid systems likely contribute to an adolescent reward-sensitive, yet aversion-resistant, phenotype. Although early hypotheses postulated that developmental changes in dopaminergic circuitry would result in a “reward deficiency” syndrome, evidence now suggests the opposite: that adolescents are uniquely poised to seek out hedonic stimuli, experience greater “pleasure” from rewards, and consume rewarding stimuli in excess. Future studies that more clearly define the role of specific brain regions and neurotransmitter systems in the expression of behaviors toward reward- and aversive-related cues and stimuli are necessary to more fully understand an adolescent-proclivity for and vulnerability to rewards and drugs of potential abuse.     

Effects of stress-induced inflammation on reward processing in healthy young women

BackgroundAnhedonia, or loss of interest or pleasure, is a feature of depression and transdiagnostic construct in psychopathology. Theory and compelling evidence from preclinical models implicates stress-induced inflammation as a psychobiological pathway to anhedonic behavior; however, this pathway has not been tested in human models. Further, although anhedonia may reflect dysregulation in multiple dimensions of reward, the extent to which stress-induced inflammation alters these dimensions is unclear. Thus, the current experimental study used a standardized laboratory stressor task to elicit an inflammatory response and evaluate effects of stress-induced inflammation on multiple behavioral indices of reward processing.MethodsHealthy young women (age 18–25) completed behavioral reward tasks assessing reward learning, motivation, and sensitivity and were randomized to undergo an acute psychosocial stressor (n = 37) or a no-stress active control (n = 17). Tasks were re-administered 90–120 min post-stress to coincide with the peak of the stress-induced inflammatory response. Blood samples were collected for assessment of the pro-inflammatory cytokine interleukin-6 (IL-6) at baseline and 90 and 120 min post stressor.ResultsStress-induced IL-6 was associated with increased response bias during reward learning and increased motivation when probability of receiving a reward was low. Sensitivity to reward in the context of a motivation task was not altered in association with stress-induced IL-6.ConclusionsContrary to hypotheses, mild increases in IL-6 following acute stress were associated with increased reward responsiveness during reward learning and selective increases in motivation. Results contribute to an emerging and nuanced literature linking inflammation to reward processing, and demonstrate that behavioral effects of stress-induced inflammation may be detected in the laboratory setting.Clinical trial registration: NCT03828604.     

Neural activation to loss and reward among alcohol naive adolescents who later initiate alcohol use

Adolescent alcohol use is associated with adverse psychosocial outcomes, including an increased risk of alcohol use disorder in adulthood. It is therefore important to identify risk factors of alcohol initiation in adolescence. Research to date has shown that altered neural activation to reward is associated with alcohol use in adolescence; however, few studies have focused on neural activation to loss and alcohol use. The current study examined neural activation to loss and reward among 64 alcohol naive 12−14 year olds that did (n = 20) and did not initiate alcohol use by a three year follow-up period. Results showed that compared to adolescents that did not initiate alcohol use, adolescents that did initiate alcohol use by the three year follow-up period had increased activation to loss in the left striatum (i.e., putamen), right precuneus, and the brainstem/pons when they were alcohol naive at baseline. By contrast, alcohol initiation was not associated with neural activation to winning a reward. These results suggest that increased activation in brain regions implicated in salience, error detection/self-referential processing, and sensorimotor function, especially to negative outcomes, may represent an initial vulnerability factor for alcohol use in adolescence.     

Individual associations of adolescent alcohol use disorder versus cannabis use disorder symptoms in neural prediction error signaling and the response to novelty

Two of the most commonly used illegal substances by adolescents are alcohol and cannabis. Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with poorer decision-making in adolescents. In adolescents, level of AUD symptomatology has been negatively associated with striatal reward responsivity. However, little work has explored the relationship with striatal reward prediction error (RPE) representation and the extent to which any augmentation of RPE by novel stimuli is impacted. One-hundred fifty-one adolescents participated in the Novelty Task while undergoing functional magnetic resonance imaging (fMRI). In this task, participants learn to choose novel or non-novel stimuli to gain monetary reward. Level of AUD symptomatology was negatively associated with both optimal decision-making and BOLD response modulation by RPE within striatum and regions of prefrontal cortex. The neural alterations in RPE representation were particularly pronounced when participants were exploring novel stimuli. Level of CUD symptomatology moderated the relationship between novelty propensity and RPE representation within inferior parietal lobule and dorsomedial prefrontal cortex. These data expand on an emerging literature investigating individual associations of AUD symptomatology levels versus CUD symptomatology levels and RPE representation during reinforcement processing and provide insight on the role of neuro-computational processes underlying reinforcement learning/decision-making in adolescents.     

Distinct linear and non-linear trajectories of reward and punishment reversal learning during development: relevance for dopamine's role in adolescent decision making

Abnormalities in value-based decision making during adolescence have often been attributed to non-linear, inverted-U shaped development of reward-related processes. This hypothesis is strengthened by functional imaging work revealing an inverted-U shaped relationship between age and reward-related activity in the striatum. However, behavioural studies have mostly reported linear rather than non-linear increases in reward-related performance. In the present study, we investigated the mechanisms underlying the development of reward- and punishment-related processing across four age groups using a reversal learning task previously shown to depend on striatal dopamine. We demonstrate both linear and non-linear age effects on distinct components of reversal learning. Specifically, results revealed a linear shift with age in terms of valence-dependent reversal learning, with children exhibiting better punishment than reward reversal learning, adults exhibiting better reward than punishment reversal learning and adolescents exhibiting an intermediate performance pattern. In addition, we also observed a non-linear, inverted-U shaped relationship between age and valence-independent reversal learning, which was due to aberrant ability of adolescents to update behaviour in response to negative performance feedback. These findings indicate that the (linear or nonlinear) nature of the relationship between age and reward learning depends on the type of reward learning under study.     

Effects of dopamine depletion on the spontaneous activity of type I striatal neurons: relation to local dopamine concentration and motor behavior

The relation between the electrophysiological activity of Type I striatal neurons, local dopamine (DA) concentration, and motor behavior in rats was investigated using intraventricular administration of the neurotoxin 6-hydroxydopamine (6-HDA) and extracellular single-unit recording. Results are compared with findings of past experiments in which the activity of Type II striatal neurons was examined after comparable 6-HDA-induced lesions. Several differences between the present observations and the earlier results were found. First, although large depletions (greater than 50%) of DA local to the site of the recording were required before the spontaneous firing rate of either cell type was increased, the levels necessary for this effect were found to be less for Type I cells than for Type II neurons. Second, although DA depletions of greater than 50% always were associated with increased Type I cell activity, depletions of greater than 95% resulted in spontaneous firing rates that were lower than those observed after depletions of approximately 90%. Thus, the relation between extent of dopaminergic depletion and Type I cell firing rate was biphasic, whereas that relation previously was found to be monophasic for Type II neurons. Finally, whereas increased Type I cell activity in the lateral striatum was associated with the aphagia, adipsia, and akinesia induced by large DA-depleting brain lesions, increased Type II cell activity in the medial striatum was found to be associated with these impairments. Because accumulating evidence suggests that the functioning of the lateral striatum is more critical for these behaviors, however, it is proposed that the substrate of the behavioral dysfunctions resulting from DA depletion is the Type I cell population in lateral striatum.     

Influence of reward motivation on human declarative memory

Motivational relevance can prioritize information for memory encoding and consolidation based on reward value. In this review, we pinpoint the possible psychological and neural mechanisms by which reward promotes learning, from guiding attention to enhancing memory consolidation. We then discuss how reward value can spill-over from one conditioned stimulus to a non-conditioned stimulus. Such generalization can occur across perceptually similar items or through more complex relations, such as associative or logical inferences. Existing evidence suggests that the neurotransmitter dopamine boosts the formation of declarative memory for rewarded information and may also control the generalization of reward values. In particular, temporally-correlated activity in the hippocampus and in regions of the dopaminergic circuit may mediate value-based decisions and facilitate cross-item integration. Given the importance of generalization in learning, our review points to the need to study not only how reward affects later memory but how learned reward values may generalize to related representations and ultimately alter memory structure.     

Mesolimbic interaction of emotional valence and reward improves memory formation

Animal studies suggest that dopaminergic neuromodulation is critical for hippocampal memory formation. Compatible with this notion, recent functional imaging evidence in humans showed that reward modulates the hippocampus-dependent formation of episodic memories through activation of areas belonging to the mesolimbic dopaminergic system, including the ventral striatum and substantia nigra/ventral tegmental area (SN/VTA). However, the amygdala is also closely embedded within this mesolimbic circuitry with reciprocal connections to the SN/VTA, raising the possibility that emotionally valenced stimuli might also interact with hippocampal encoding through dopaminergic neuromodulation. By the same token, emotional processing in the amygdala might be affected by reward-related processing in the mesolimbic system. In an event-related functional magnetic resonance imaging study, reward-related activity in the ventral striatum was enhanced by the concurrent presentation of emotionally positive but not emotionally negative stimuli. Emotional processing in the amygdala, on the other hand, was not affected by reward. One day after study, recollection of the positive stimuli was better when they were associated with reward at encoding as compared with unrewarded positive stimuli. The findings are compatible with the notion that the output of the reward system and memory formation in the hippocampus is influenced by positive emotional valence and suggest that the ventral striatum is a key structure for this modulation.     

Different developmental trajectories for anticipation and receipt of reward during adolescence

Typical adolescent behaviour such as increased risk-taking and novelty-seeking is probably related to developmental changes in the brain reward system. This functional MRI study investigated how brain activation related to two components of reward processing (Reward Anticipation and Reward Outcome) changes with age in a sample of 39 children, adolescents and young adults aged 10–25. Our data revealed age-related changes in brain activity during both components of reward processing. Activation related to Reward Anticipation increased with age, while activation related to Reward Outcome decreased in various regions of the reward network. This shift from outcome to anticipation was confirmed by subsequent analyses showing positive correlations between age and the difference in activation between Reward Anticipation and Reward Outcome. The shift was predominantly present in striatal regions and was accompanied by a significant effect of age on behaviour, with older participants showing more response speeding on potentially rewarding trials than younger participants. This study provides evidence for functional changes in the reward system which may underlie typical adolescent behaviour.     

Neural processes of reward and punishment processing in childhood and adolescence: An event-related potential study on age differences

Reward and punishment processing are subject to substantial developmental changes during youth. However, little is known about the neurophysiological correlates that are associated with these developmental changes, particularly with regard to both anticipatory and outcome processing stages. Thus, the aim of this study was to address this research gap in a sample of typically developing children and adolescents.Fifty-four children and adolescents (8–18 years) performed a Monetary Incentive Delay Task comprising a monetary reward and punishment condition. Using event-related brain potential recordings, the cue-P3 and the stimulus-preceding negativity (SPN) were analyzed during the anticipation phase, while the Reward Positivity and the feedback-P3 were analyzed during the outcome phase.When anticipating monetary loss or no gain, SPN amplitude in the right hemisphere decreased with age. Moreover, exploratory analyses revealed a decrease in feedback-P3 amplitudes in response to monetary loss with increasing age. No other group differences were observed.Age-related changes in the SPN and fP3 component suggest that sensitivity to negative outcomes decreases from childhood to late adolescence, supporting the notion that adolescence is associated with reduced harm-avoidance. Longitudinal research including young adults is needed to substantiate our findings and its clinical implications regarding disturbed developmental trajectories in psychiatric populations.     

Acupuncture treatment modulates the corticostriatal reward circuitry in major depressive disorder

Major depressive disorder (MDD) is a common disorder with a high prevalence and significant social and economic impacts. Nevertheless, the treatment of MDD is far from satisfactory. Acupuncture treatment has emerged as a promising method for treating MDD. However, the neural mechanism by which acupuncture reduces depressive symptoms is not fully understood. Studies have shown that the corticostriatal reward circuitry is associated with the pathophysiology of MDD; thus, we investigated the corticostriatal resting-state functional connectivity (rsFC) before and after real and sham acupuncture treatments combined with the antidepressant fluoxetine. Forty-six female major depressive patients were assigned to either verum acupuncture plus fluoxetine (n = 22) or sham acupuncture plus fluoxetine (n = 24) treatment for 8 weeks, and resting state functional magnetic resonance imaging (fMRI) data were collected before the first and after the last treatment sessions. The results showed that compared with sham acupuncture, the verum acupuncture group showed: (1) significantly increased rsFC between inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/parahippocampus, as well as dorsal caudate and middle temporal gyrus; (2) significantly decreased rsFC between right ventral rostral putamen and right dorsolateral prefrontal cortex, and right dorsal caudate and bilateral cerebellar tonsil. The increased rsFC between the inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/parahippocampus were significantly positively associated with decreased clinical scores (Montgomery–Åsberg Depression Rating Scale and Self-Rating Depression Scale scores) at the end of the eight-week treatment. Our findings suggest that acupuncture may achieve treatment effects by modulating the corticostriatal reward/motivation circuitry in MDD patients.     

Differential reward processing in subtypes of adult attention deficit hyperactivity disorder

Objectives

Abnormalities in reward processing have been found in adolescents and adults with ADHD using the ‘Monetary Incentive Delay’ (MID) task. However, ADHD groups in previous studies were heterogeneous regarding ADHD subtype, gender and, in part, drug treatment status.This study sought to compare neural activations in the ventral striatum (VS) and prefrontal regions during reward processing in homogenous ADHD subtype groups and healthy adults, using the MID task.

Methods

In total, 24 drug-naïve, right-handed male adults with ADHD (12 subjects with combined type (ADHD-ct) and 12 subjects with predominantly inattentive (ADHD-it) type ADHD), and twelve healthy right-handed male control subjects were included.

Results

Compared to ADHD-ct and healthy subjects, ADHD-it subjects showed a bilateral ventral striatal deficit during reward anticipation. In contrast, ADHD-ct subjects showed orbitofrontal hyporesponsiveness to reward feedback when compared with ADHD-it and healthy subjects.

Conclusions

This is the first fMRI study that delineates dysfunctional and subtype-divergent neural and behavioural reward processing in adults with ADHD.     

Neural correlates of reward and attention in macaque area LIP

Saccade reaction times decrease and the frequency of target choices increases with the size of rewards delivered for orienting to a particular visual target. Similarly, increasing rewards for orienting to a visual target enhances neuronal responses in the macaque lateral intraparietal area (LIP), as well as other brain areas. These observations raise several questions. First, are reward-related modulations in neuronal activity in LIP, as well as other areas, spatially specific or more global in nature? Second, to what extent does reward modulation of neuronal activity in area LIP reflect changes in visual rather than motor processing? And third, to what degree are reward-related modulations in LIP activity independent of performance-related modulations thought to reflect changes in attention? Here we show that increasing the size of fluid rewards in blocks reduced saccade reaction times and improved performance in monkeys performing a peripherally-cued saccade task. LIP neurons responded to visual cues spatially segregated from the saccade target, and for many neurons visual responses were systematically modulated by expected reward size. Neuronal responses also were positively correlated with reaction times independent of reward size, consistent with re-orienting of attention to the saccade target. These observations suggest that motivation and attention independently contribute to the strength of sustained visual responses in LIP. Our data thus implicate LIP in the integration of the sensory, motor, and motivational variables that guide orienting.     

Prenatal haloperidol exposure: Effects on brain weights and caudate neurotransmitter levels in rats

Monoamines may exert a trophic effect on early brain development. To assess the role of dopamine in prenatal neurological development of the rat, haloperidol (HAL) was given in daily 2.5 or 5 mg/kg SC doses to dams over gestational days 6 to 20. This treatment regime did not enhance fetal mortality, but did produce reliable, if modest, stunting of the body and brain weight of offspring. The 5 mg/kg HAL dose consistently reduced offspring brain weight to roughly 90% of controls. This effect was probably permanent, in that it was seen throughout maturation and in adults as late as 140 days of postnatal age. Appropriate controls showed that this effect was not due to drug-induced reductions in food intake, to the presence of HAL in maternal milk, or to behavioral abnormalities in HAL-exposed dams. These effects had, at best, modest regional specificity, in that most brain regions were affected, independently of degree of dopaminergic innervation. Closer investigation of HAL effects on the striatum suggested that this permanent weight reduction was not accompanied by alterations in striatal concentrations of monoamines, monoamine metabolites, amino acids, choline, acetylcholine, DNA, protein, or water. It is concluded that prenatal HAL does stunt growth, but that this effect may not involve a direct drug influence restricted to the fetal dopamine system in the brain.     

Multiple single-unit recordings in the striatum of freely moving animals: effects of apomorphine and -amphetamine in normal and unilateral 6-hydroxydopamine-lesioned rats

Ensembles of striatal neurons were recorded in freely moving normal and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats using chronically implanted electrode arrays. Animals received bilateral striatal implants of two 16-microwire arrays 1 week before recordings. Identified striatal neurons were categorized as medium spiny-like and large aspiny-like based on a combination of their activity autocorrelations and firing rates. Baseline firing rates of medium spiny-like neurons in the 6-OHDA-lesioned striata were significantly faster than were firing rates of the same neurons in the intact hemispheres of 6-OHDA-lesioned rats or normal animals. However, firing rates of large aspiny-like neurons were faster in both hemispheres of the 6-OHDA-lesioned rats as compared to normal animals. Interestingly, firing rates of neurons in all groups decreased by fivefold or greater under urethane anesthesia, although the relative firing rates between hemispheres were unchanged. -Amphetamine (5.0 mg/kg, s.c.) increased the firing rates of both types of striatal neurons by twofold or greater in normal rats and in the intact hemispheres of 6-OHDA-lesioned animals. By contrast, this treatment did not alter neuron firing in the 6-OHDA-lesioned striata. Apomorphine (0.05 mg/kg, s.c.) did not affect neuronal firing rates either in normal rat striatum or in the unlesioned hemispheres of 6-OHDA-lesioned animals. However, it did significantly increase the firing rate of the medium spiny-like neurons in 6-OHDA-lesioned striata. These results demonstrate that the dopaminergic innervation of the striatum differentially influences two electrophysiologically distinct sets of striatal neurons in freely moving rats.