Substantia Nigra Ventral Tegmental Area Research Articles

Assessment of cytochrome C oxidase dysfunction in the substantia nigra/ventral tegmental area in schizophrenia.

Perturbations in metabolism are a well-documented but complex facet of schizophrenia pathology. Optimal cellular performance requires the proper functioning of the electron transport chain, which is constituted by four enzymes located within the inner membrane of mitochondria. These enzymes create a proton gradient that is used to power the enzyme ATP synthase, producing ATP, which is crucial for the maintenance of cellular functioning. Anomalies in a single enzyme of the electron transport chain are sufficient to cause disruption of cellular metabolism. The last of these complexes is the cytochrome c oxidase (COX) enzyme, which is composed of thirteen different subunits. COX is a major site for oxidative phosphorylation, and anomalies in this enzyme are one of the most frequent causes of mitochondrial pathology. The objective of the present report was to assess if metabolic anomalies linked to COX dysfunction may contribute to substantia nigra/ventral tegmental area (SN/VTA) pathology in schizophrenia. We tested COX activity in postmortem SN/VTA from schizophrenia and non-psychiatric controls. We also tested the protein expression of key subunits for the assembly and activity of the enzyme, and the effect of antipsychotic medication on subunit expression. COX activity was not significantly different between schizophrenia and non-psychiatric controls. However, we found significant decreases in the expression of subunits II and IV-I of COX in schizophrenia. Interestingly, these decreases were observed in samples containing the entire rostro-caudal extent of the SN/VTA, while no significant differences were observed for samples containing only mid-caudal regions of the SN/VTA. Finally, rats chronically treated with antipsychotic drugs did not show significant changes in COX subunit expression. These findings suggest that COX subunit expression may be compromised in specific sub-regions of the SN/VTA (i.e. rostral regions), which may lead to a faulty assembly of the enzyme and a greater vulnerability to metabolic insult.

Amphetamine sensitisation and memory in healthy human volunteers: A functional magnetic resonance imaging study

Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.

Prior fear conditioning and reward learning interact in fear and reward networks

The ability to flexibly adapt responses to changes in the environment is important for survival. Previous research in humans separately examined the mechanisms underlying acquisition and extinction of aversive and appetitive conditioned responses. It is yet unclear how aversive and appetitive learning interact on a neural level during counterconditioning in humans. This functional magnetic resonance imaging (fMRI) study investigated the interaction of fear conditioning and subsequent reward learning. In the first phase (fear acquisition), images predicted aversive electric shocks or no aversive outcome. In the second phase (counterconditioning), half of the CS+ and CS− were associated with monetary reward in the absence of electric stimulation. The third phase initiated reinstatement of fear through presentation of electric shocks, followed by CS presentation in the absence of shock or reward. Results indicate that participants were impaired at learning the reward contingencies for stimuli previously associated with shock. In the counterconditioning phase, prior fear association interacted with reward representation in the amygdala, where activation was decreased for rewarded compared to unrewarded CS− trials, while there was no reward-related difference in CS+ trials. In the reinstatement phase, an interaction of previous fear association and previous reward status was observed in a reward network consisting of substantia nigra/ventral tegmental area (SN/VTA), striatum and orbitofrontal cortex (OFC), where activation was increased by previous reward association only for CS− but not for CS+ trials. These findings suggest that during counterconditioning, prior fear conditioning interferes with reward learning, subsequently leading to lower activation of the reward network.

Organotypic slice co-culture systems to study axon regeneration in the dopaminergic system ex vivo.

Organotypic slice co-cultures are suitable tools to study axonal regeneration and development (growth or regrowth) of different projection systems of the CNS under ex vivo conditions.In this chapter, we describe in detail the reconstruction of the mesocortical and nigrostriatal dopaminergic projection system culturing tissue slices from the ventral tegmental area/substantia nigra (VTA/SN) with the prefrontal cortex (PFC) or the striatum (STR). The protocol includes the detailed slice preparation and incubation. Moreover, different application possibilities of the ex vivo model are mentioned; as an example, the substance treatment procedure and biocytin tracing are described to reveal the effect of applied substances on fiber outgrowth.

Dopamine Modulates the Excitability of Projection Neurons in the Robust Nucleus of the Arcopallium in Adult Zebra Finches

BackgroundThe nervous system in songbirds is an accessible system for studying vocal learning and memory in vertebrates. In the song system, the anterior forebrain pathway (AFP) is essential for song learning and the vocal motor pathway (VMP) is necessary for song production. The premotor robust nucleus of the arcopallium (RA) located in the VMP receives input from the AFP. The RA receives dopaminergic innervations from the periaqueductal gray and ventral tegmental area–substantia nigra pars compacta, but the physiological functions of this projection remain unclear. In this study, we investigated the effects of dopamine (DA) on the excitability of projection neurons (PNs) in the RA. MethodologyWe recorded the electrophysiological changes from neurons in brain slices of male adult zebra finches using a whole-cell recording technique.Conclusions/SignificanceWe found that DA significantly increased the excitability of RA PNs. Furthermore, a D1-like receptor agonist increased the excitability of RA PNs, and a D1-like receptor antagonist suppressed the excitability induced by DA. However, a D2-like receptor agonist had no effect on the excitability of RA PNs. Moreover, the D2-like receptor agonist did not change the excitability induced by the D1 receptor agonist. These findings suggest that DA can significantly increase the excitability of RA PNs and that D1 receptors play the main role in regulating the excitability of RA PNs in response to DA, thereby providing direct evidence toward understanding the mechanism of DA signal mediation by its receptors to modulate the excitability of RA PNs.

In vivo PET quantification of the dopamine transporter in rat brain with [18F]LBT-999

We examined whether [(18)F]LBT-999 ((E)-N-(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4'-tolyl)nortropane) is an efficient positron emission tomography (PET) tracer for the quantification of the dopamine transporter (DAT) in the healthy rat brain. PET studies were performed using several experimental designs, i.e. test-retest, co-injection with different doses of unlabelled LBT, displacement with GBR12909 and pre-injection of amphetamine. The uptake of [(18)F]LBT-999 confirmed its specific binding to the DAT. The non-displaceable uptake (BP(ND)) in the striatum, between 5.37 and 4.39, was highly reproducible and reliable, and was decreased by 90% by acute injection of GBR12909. In the substantia nigra/ventral tegmental area (SN/VTA), the variability was higher and the reliability was lower. Pre-injection of amphetamine induced decrease of [(18)F]LBT-999 BP(ND) of 50% in the striatum. [(18)F]LBT-999 allows the quantification of the DAT in living rat brain with high reproducibility, sensitivity and specificity. It could be used to quantify the DAT in rodent models, thereby allowing to study neurodegenerative and neuropsychiatric diseases.

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.

Innately low D2 receptor availability is associated with high novelty-seeking and enhanced behavioural sensitization to amphetamine

High novelty-seeking has been related to an increased risk for developing addiction, but the neurobiological mechanism underlying this relationship is unclear. We investigated whether differences in dopamine (DA) D2/3-receptor (D2/3R) function underlie phenotypic divergence in novelty-seeking and vulnerability to addiction. Measures of D2/3R availability using the D2R-preferring antagonist [18F]Fallypride, and the D3R-preferring agonist [3H]-(+)-PHNO and of DA-related gene expression and behaviours were used to characterize DA signalling in Roman high- (RHA) and low-avoidance (RLA) rats, which respectively display high and low behavioural responsiveness both to novelty and psychostimulant exposure. When compared to RLA rats, high novelty-responding RHAs had lower levels of D2R, but not D3R, binding and mRNA in substantia nigra/ventral tegmental area (SN/VTA) and showed behavioural evidence of D2-autoreceptor subsensitivity. RHA rats also showed a higher expression of the tyrosine hydroxylase gene in SN/VTA, higher levels of extracellular DA in striatum and augmentation of the DA-releasing effects of amphetamine (Amph), suggesting hyperfunctioning of midbrain DA neurons. RHA rats also exhibited lower availabilities and functional sensitivity of D2R, but not D3R, in striatum, which were inversely correlated with individual scores of novelty-seeking, which, in turn, predicted the magnitude of Amph-induced behavioural sensitization. These results indicate that innately low levels of D2R in SN/VTA and striatum, whether they are a cause or consequence of the concomitantly observed elevated DA tone, result in a specific pattern of DA signalling that may subserve novelty-seeking and vulnerability to drug use. This suggests that D2R deficits in SN/VTA and striatum could both constitute neurochemical markers of an addiction-prone phenotype.

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.

Neurofeedback-mediated self-regulation of the dopaminergic midbrain

The dopaminergic system is involved in reward encoding and reinforcement learning. Dopaminergic neurons from this system in the substantia nigra/ventral tegmental area complex (SN/VTA) fire in response to unexpected reinforcing cues. The goal of this study was to investigate whether individuals can gain voluntary control of SN/VTA activity, thereby potentially enhancing dopamine release to target brain regions. Neurofeedback and mental imagery were used to self-regulate the SN/VTA. Real-time functional magnetic resonance imaging (rtfMRI) provided abstract visual feedback of the SN/VTA activity while the subject imagined rewarding scenes. Skin conductance response (SCR) was recorded as a measure of emotional arousal. To examine the effect of neurofeedback, subjects were assigned to either receiving feedback directly proportional (n=15, veridical feedback) or inversely proportional (n=17, inverted feedback) to SN/VTA activity. Both groups of subjects were able to up-regulate SN/VTA activity initially without feedback. Veridical feedback improved the ability to up-regulate SN/VTA compared to baseline while inverted feedback did not. Additional dopaminergic regions were activated in both groups. The ability to self-regulate SN/VTA was differentially correlated with SCR depending on the group, suggesting an association between emotional arousal and neurofeedback performance. These findings indicate that SN/VTA can be voluntarily activated by imagery and voluntary activation is further enhanced by neurofeedback. The findings may lead the way towards a non-invasive strategy for endogenous control of dopamine.

Parcellation of the human substantia nigra based on anatomical connectivity to the striatum

Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinson's disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine-grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact.

Synchronized electrical stimulation of the rat medial forebrain bundle and perforant pathway generates an additive BOLD response in the nucleus accumbens and prefrontal cortex

To study how a synchronized activation of two independent pathways affects the fMRI response in a common targeted brain region, blood oxygen dependent (BOLD) signals were measured during electrical stimulation of the right medial forebrain bundle (MFB), the right perforant pathway (PP) and concurrent stimulation of the two fiber systems. Repetitive electrical stimulations of the MFB triggered significant positive BOLD responses in the nucleus accumbens (NAcc), septum, anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), ventral tegmental area/substantia nigra (VTA/SN), right entorhinal cortex (EC) and colliculus superior, which, in general, declined during later stimulation trains. At the same time, negative BOLD responses were observed in the striatum. Thus, the same stimulus caused region-specific hemodynamic responses. An identical electrical stimulation of the PP generated positive BOLD responses in the right dentate gyrus/hippocampus proper/subiculum (DG/HC), the right entorhinal cortex and the left entorhinal cortex, which remained almost stable during consecutive stimulation trains. Co-stimulation of the two fiber systems resulted in an additive activation pattern, i.e., the BOLD responses were stronger during the stimulation of the two pathways than during the stimulation of only one pathway. However, during the simultaneous stimulation of the two pathways, the development of the BOLD responses to consecutive trains changed. The BOLD responses in regions that were predominantly activated by MFB stimulation (i.e., NAcc, septum and ACC/mPFC) did not decline as fast as during pure MFB stimulation, thus an additive BOLD response was only observed during later trains. In contrast, in the brain regions that were predominantly activated by PP stimulation (i.e., right EC, DG/HC), co-stimulation of the MFB only resulted in an additive effect during early trains but not later trains. Consequently, the development of the BOLD responses during consecutive stimulations indicates the presence of an interaction between the two pathways in a target region, whereas the observed averaged BOLD responses do not.

Dopamine restores reward prediction errors in old age

Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. In a human functional magnetic resonance imaging (fMRI) study, we show that healthy older adults have an abnormal signature of expected value resulting in an incomplete reward prediction error signal in the nucleus accumbens, a brain region receiving rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum measured with diffusion tensor imaging (DTI) was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to a level shown by young adults. Critically this drug-effect was linked to restoration of a canonical neural reward prediction error. Thus we identify a neurochemical signature underlying abnormal reward processing in older adults and show this can be modulated by L-DOPA.

Functional Regeneration of the ex-vivo Reconstructed Mesocorticolimbic Dopaminergic System

CNS reparative-medicine therapeutic strategies need answers on the putative recapitulation of the basic rules leading to mammalian CNS development. To achieve this aim, we focus on the regeneration of functional connections in the mesocorticolimbic dopaminergic system. We used organotypic slice cocultures of ventral tegmental area/substantia nigra (VTA/SN) and prefrontal cortex (PFC) on a multielectrode array (MEA) platform to record spikes and local field potentials. The spontaneously growing synaptically based bidirectional bursting activity was followed from 2 to 28 days in vitro (DIV). A statistical analysis of excitatory and inhibitory neurons properties of the physiological firing activity demonstrated a remarkable, exponentially increasing maturation with a time constant of about 5-7 DIV. Immunohistochemistry demonstrated that the ratio of excitatory/inhibitory neurons (3:1) was in line with the functional results obtained. Exemplary pharmacology suggested that GABAA receptors were able to exert phasic and tonic inhibition typical of an adulthood network. Moreover, dopamine D2 receptor inactivation was equally inhibitory both on the spontaneous neuronal activity recorded by MEA and on patch-clamp electrophysiology in PFC pyramidal neurons. These results demonstrate that axon growth cones reach synaptic targets up to full functionality and that organotypic cocultures of the VTA/SN-PFC perfectly model their newly born dopaminergic, glutamatergic and GABAergic neuronal circuitries.

Go and no-go learning in reward and punishment: Interactions between affect and effect

Decision-making invokes two fundamental axes of control: affect or valence, spanning reward and punishment, and effect or action, spanning invigoration and inhibition. We studied the acquisition of instrumental responding in healthy human volunteers in a task in which we orthogonalized action requirements and outcome valence. Subjects were much more successful in learning active choices in rewarded conditions, and passive choices in punished conditions. Using computational reinforcement-learning models, we teased apart contributions from putatively instrumental and Pavlovian components in the generation of the observed asymmetry during learning. Moreover, using model-based fMRI, we showed that BOLD signals in striatum and substantia nigra/ventral tegmental area (SN/VTA) correlated with instrumentally learnt action values, but with opposite signs for go and no-go choices. Finally, we showed that successful instrumental learning depends on engagement of bilateral inferior frontal gyrus. Our behavioral and computational data showed that instrumental learning is contingent on overcoming inherent and plastic Pavlovian biases, while our neuronal data showed this learning is linked to unique patterns of brain activity in regions implicated in action and inhibition respectively.

Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra

Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.

Inhibitors of the phosphodiesterase 2 increased axonal fibre growth in a dopaminergic organotypic ex vivo slice co-culture model

Background Due to the necessity for therapeutic strategies promoting neuro-(re)generation the development of appropriate models appraising the potential of substances for regeneration and repair of neuronal circuits are of great importance. Here we present a procedure for the quantification of fibre outgrowth on the basis of organotypic slice co-cultures of the dopaminergic projection system, appropriate for characterising the effects on axonal growth after treatment with well known controls and growth factors e.g. nerve growth factor (NGF) and new drug candidates. Therefore co-culture preparations were used, consisting of at least two slices of different parts of the brain, namely the ventral tegmental area/substantia nigra (VTA/SN) and the striatum (STR), whereas while incubation fibres projections regenerate and new connections were built, linking the two slices [1,2].

Novelty increases the mesolimbic functional connectivity of the substantia nigra/ventral tegmental area (SN/VTA) during reward anticipation: Evidence from high-resolution fMRI

Reward and novelty are potent learning signals that critically rely on dopaminergic midbrain responses. Recent findings suggest that although reward and novelty are likely to interact, both functions may be subserved by distinct neuronal clusters. We used high-resolution functional magnetic resonance imaging (fMRI) to isolate neural responses to reward and novelty within the human substantia nigra/ventral tegmental area (SN/VTA) complex to investigate the spatial delineation and integration of reward- and novelty-related activity clusters. We demonstrate that distinct clusters within the caudal portion of the medial SN/VTA and the lateral portion of the right SN are predominantly modulated by the anticipation of reward, while a more rostral part of the medial SN/VTA was exclusively modulated by novelty. In addition, the caudal medial SN/VTA cluster embodied an interaction between novelty and reward where novelty selectively increased reward-anticipation responses. This interaction, in turn, was paralleled by differences in the functional-connectivity patterns of these SN/VTA regions. Specifically, novel as compared to familiar reward-predictive stimuli increased the functional connectivity of the medial SN/VTA with mesolimbic regions, including the nucleus accumbens and the hippocampus, as well as with the primary visual cortex. This functional correlation may highlight how afferents of the medial SN/VTA provide integrative information about novelty and reward, or, alternatively, how medial SN/VTA activity may modulate memory processes for novel events associated with rewards.

Action Dominates Valence in Anticipatory Representations in the Human Striatum and Dopaminergic Midbrain

The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However, the separate pathways in the striatum for go and no-go appear to violate this independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action-outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects' requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipated to be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.

Contextual interaction between novelty and reward processing within the mesolimbic system

Medial temporal lobe (MTL) dependent long‐term memory for novel events is modulated by a circuitry that also responds to reward and includes the ventral striatum, dopaminergic midbrain, and medial orbitofrontal cortex (mOFC). This common neural network may reflect a functional link between novelty and reward whereby novelty motivates exploration in the search for rewards; a link also termed novelty “exploration bonus.” We used fMRI in a scene encoding paradigm to investigate the interaction between novelty and reward with a focus on neural signals akin to an exploration bonus. As expected, reward related long‐term memory for the scenes (after 24 hours) strongly correlated with activity of MTL, ventral striatum, and substantia nigra/ventral tegmental area (SN/VTA). Furthermore, the hippocampus showed a main effect of novelty, the striatum showed a main effect of reward, and the mOFC signalled both novelty and reward. An interaction between novelty and reward akin to an exploration bonus was found in the hippocampus. These data suggest that MTL novelty signals are interpreted in terms of their reward‐predicting properties in the mOFC, which biases striatal reward responses. The striatum together with the SN/VTA then regulates MTL‐dependent long‐term memory formation and contextual exploration bonus signals in the hippocampus. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.