Neural mechanisms underlying the reward‐related enhancement of motivation when remembering episodic memories with high difficulty

The motivation to receive rewards enhances episodic memories, and the motivation is modulated by task difficulty. In episodic retrieval, however, functional neuroimaging evidence regarding the motivation that mediates interactions between reward and task difficulty is scarce. The present fMRI study investigated this issue. During encoding performed without fMRI, participants encoded Japanese words using either deep or shallow strategies, which led to variation in difficulty level during subsequent retrieval. During retrieval with fMRI, participants recognized the target words in either high or low monetary reward conditions. In the behavioral results, a reward‐related enhancement of memory was found only when the memory retrieval was difficult, and the rewarding effect on subjective motivation was greater in the retrieval of memories with high difficulty than those with low difficulty. The fMRI data showed that reward‐related increases in the activation of the substantia nigra/ventral tegmental area (SN/VTA), medial temporal lobe (MTL), dorsomedial prefrontal cortex (dmPFC), and dorsolateral prefrontal cortex (dlPFC) were greater during the retrieval of memories with high difficulty than those with low difficulty. Furthermore, reward‐related enhancement of functional connectivity between the SN/VTA and MTL and between the SN/VTA and dmPFC during the retrieval of memories with high difficulty was significantly correlated with reward‐related increases of retrieval accuracy and subjective motivation. The reward‐related enhancement of episodic retrieval and retrieval‐related motivation could be most effective when the level of retrieval difficulty is optimized. Such reward‐related enhancement of memory and motivation could be modulated by a network including the reward‐related SN/VTA, motivation‐related dmPFC, and memory‐related MTL. Hum Brain Mapp 38:3428–3443, 2017. © 2017 Wiley Periodicals, Inc.     

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.     

Amygdala and ventral tegmental area differentially interact with hippocampus and cortical medial temporal lobe during rest in humans

Neuromodulatory regions that detect salience, such as amygdala and ventral tegmental area (VTA), have distinct effects on memory. Yet, questions remain about how these modulatory regions target subregions across the hippocampus and medial temporal lobe (MTL) cortex. Here, we sought to characterize how VTA and amygdala subregions (i.e., basolateral amygdala and central‐medial amygdala) interact with hippocampus head, body, and tail, as well as cortical MTL areas of perirhinal cortex and parahippocampal cortex in a task‐free state. To quantify these interactions, we used high‐resolution resting state fMRI and characterized pair‐wise, partial correlations across regions‐of‐interest. We found that basolateral amygdala showed greater functional coupling with hippocampus head, hippocampus tail, and perirhinal cortex when compared to either VTA or central‐medial amygdala. Furthermore, the VTA showed greater functional coupling with hippocampus tail when compared to central‐medial amygdala. There were no significant differences in functional coupling with hippocampus body and parahippocampal cortex. These results support a framework by which neuromodulatory regions do not indiscriminately influence all MTL subregions equally, but rather bias information processing to discrete MTL targets. These findings provide a more specified model of the intrinsic properties of systems underlying MTL neuromodulation. This emphasizes the need to consider heterogeneity both across and within neuromodulatory systems to better understand affective memory.     

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.     

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.     

Signed Reward Prediction Errors in the Ventral Striatum Drive Episodic Memory

Recent behavioral evidence implicates reward prediction errors (RPEs) as a key factor in the acquisition of episodic memory. Yet, important neural predictions related to the role of RPEs in episodic memory acquisition remain to be tested. Humans (both sexes) performed a novel variable-choice task where we experimentally manipulated RPEs and found support for key neural predictions with fMRI. Our results show that in line with previous behavioral observations, episodic memory accuracy increases with the magnitude of signed (i.e., better/worse-than-expected) RPEs (SRPEs). Neurally, we observe that SRPEs are encoded in the ventral striatum (VS). Crucially, we demonstrate through mediation analysis that activation in the VS mediates the experimental manipulation of SRPEs on episodic memory accuracy. In particular, SRPE-based responses in the VS (during learning) predict the strength of subsequent episodic memory (during recollection). Furthermore, functional connectivity between task-relevant processing areas (i.e., face-selective areas) and hippocampus and ventral striatum increased as a function of RPE value (during learning), suggesting a central role of these areas in episodic memory formation. Our results consolidate reinforcement learning theory and striatal RPEs as key factors subtending the formation of episodic memory.SIGNIFICANCE STATEMENT Recent behavioral research has shown that reward prediction errors (RPEs), a key concept of reinforcement learning theory, are crucial to the formation of episodic memories. In this study, we reveal the neural underpinnings of this process. Using fMRI, we show that signed RPEs (SRPEs) are encoded in the ventral striatum (VS), and crucially, that SRPE VS activity is responsible for the subsequent recollection accuracy of one-shot learned episodic memory associations.     

Dopamine gating of glutamatergic sensorimotor and incentive motivational input signals to the striatum

Dopamine (DA) neurons of the substantia nigra (SN) and ventral tegmental area (VTA) respond to a wide category of salient stimuli. Activation of SN and VTA DA neurons, and consequent release of nigrostriatal and mesolimbic DA, modulates the processing of concurrent glutamate inputs to dorsal and ventral striatal target regions. According to the view described here, this occurs under conditions of unexpected environmental change regardless of whether that change is rewarding or aversive. Nigrostriatal and mesolimbic DA activity gates the input of sensory, motor, and incentive motivational (e.g. reward) signals to the striatum. In light of recent single-unit and brain imaging data, it is suggested that the striatal reward signals originate in the orbitofrontal cortex and basolateral amygdala (BLA), regions that project strongly to the striatum. A DA signal of salient unexpected event occurrence, from this framework, gates the throughput of the orbitofrontal glutamate reward input to the striatum just as it gates the throughput of corticostriatal sensory and motor signals needed for normal response execution. Processing of these incoming signals is enhanced when synaptic DA levels are high, because DA enhances the synaptic efficacy of strong concurrent glutamate inputs while reducing the efficacy of weak glutamate inputs. The impairments in motor performance and incentive motivational processes that follow from nigrostriatal and mesolimbic DA loss can be understood in terms of a single mechanism: abnormal processing of sensorimotor and incentive motivation-related glutamate input signals to the striatum.     

Striatal and midbrain connectivity with the hippocampus selectively boosts memory for contextual novelty

The role of contextual expectation in processing familiar and novel stimuli was investigated in a series of experiments combining eye tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detection at retrieval was used. The detection of unexpected familiar and novel stimuli, which were characterized by lower probability, engaged activity in midbrain and striatal structures. Specifically, detecting unexpected novel stimuli, relative to expected novel stimuli, produced greater activity in the substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity in the striatum/globus pallidus (GP). An effective connectivity analysis showed greater functional coupling between these two seed areas (GP and SN/VTA) and the hippocampus, for unexpected than for expected stimuli. Within this network of midbrain/striatal–hippocampal interactions two pathways are apparent; the direct SN–hippocampal pathway sensitive to unexpected novelty and the perirhinal–GP–hippocampal pathway sensitive to unexpected familiarity. In addition, increased eye fixations and pupil dilations also accompanied the detection of unexpected relative to expected familiar and novel stimuli, reflecting autonomic activity triggered by the functioning of these two pathways. Finally, subsequent memory for unexpected, relative to expected, familiar, and novel stimuli was characterized by enhanced recollection, but not familiarity, accuracy. Taken together, these findings suggest that a hippocampal–midbrain network, characterized by two distinct pathways, mediates encoding facilitation and most critically, that this facilitation is driven by contextual novelty, rather than by the absolute novelty of a stimulus. This contextually sensitive neural mechanism appears to elicit increased exploratory behavior, leading subsequently to greater recollection of the unexpected stimulus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Influence of ventral tegmental area input on cortico‐subcortical networks underlying action control and decision making

It is argued that the mesolimbic system has a more general function in processing all salient events, including and extending beyond rewards. Saliency was defined as an event that is unexpected due to its frequency of occurrence and elicits an attentional‐behavioral switch. Using functional magnetic resonance imaging (fMRI), signals were measured in response to the modulation of salience of rewarding and nonrewarding events during a reward‐based decision making task, the so called desire‐reason dilemma paradigm (DRD). Replicating previous findings, both frequent and infrequent, and therefore salient, reward stimuli elicited reliable activation of the ventral tegmental area (VTA) and ventral striatum (vStr). When immediate reward desiring contradicted the superordinate task‐goal, we found an increased activation of the VTA and vStr when the salient reward stimuli were presented compared to the nonsalient reward stimuli, indicating a boosting of activation in these brain regions. Furthermore, we found a significantly increased functional connectivity between the VTA and vStr, confirming the boosting of vStr activation via VTA input. Moreover, saliency per se without a reward association led to an increased activation of brain regions in the mesolimbic reward system as well as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC). Finally, findings uncovered multiple increased functional interactions between cortical saliency‐processing brain areas and the VTA and vStr underlying detection and processing of salient events and adaptive decision making.     

Attentional modulation of reward processing in the human brain

Although neural signals of reward anticipation have been studied extensively, the functional relationship between reward and attention has remained unclear: Neural signals implicated in reward processing could either reflect attentional biases towards motivationally salient stimuli, or proceed independently of attentional processes. Here, we sought to disentangle reward and attention‐related neural processes by independently modulating reward value and attentional task demands in a functional magnetic resonance imaging study in healthy human participants. During presentation of a visual reward cue that indicated whether monetary reward could be obtained in a subsequent reaction time task, participants either attended to the reward cue or performed an unrelated attention‐demanding task at two different levels of difficulty. In ventral striatum and ventral tegmental area, neural responses were modulated by reward anticipation irrespective of attentional demands, thus indicating attention‐independent processing of reward cues. By contrast, additive effects of reward and attention were observed in visual cortex. Critically, reward‐related activations in right anterior insula strongly depended on attention to the reward cue. Dynamic causal modelling revealed that the attentional modulation of reward processing in insular cortex was mediated by enhanced effective connectivity from ventral striatum to anterior insula. Our results provide evidence for distinct functional roles of the brain regions involved in the processing of reward‐indicating information: While subcortical structures signal the motivational salience of reward cues even when attention is fully engaged elsewhere, reward‐related responses in anterior insula depend on available attentional resources, likely reflecting the conscious evaluation of sensory information with respect to motivational value. Hum Brain Mapp 35:3036–3051, 2014. © 2013 Wiley Periodicals, Inc.     

Differentiation of the midbrain dopaminergic pathways during mouse development

Dopaminergic (DA) neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. Disruptions in this system have been implicated in Parkinson's disease, drug addiction, schizophrenia, and attention deficit hyperactivity disorder. However, progress in our understanding has been hindered by a lack of knowledge of how these pathways develop. In this study, different retrograde tracers, placed into the dorsolateral caudate/putamen and the nucleus accumbens, were used to analyze the development of the dopaminergic pathways. In embryonic day 15 mouse embryos, both SN and VTA neurons, as well as their fibers, were doubly labeled by striatal injections into the dorsolateral and ventromedial striatum. However, by birth, the SN DA neurons were labeled exclusively by DiA placed in the dorsolateral striatum, and the VTA DA neurons were labeled only by DiI injected into the ventromedial striatum. These data suggest that initial projections from midbrain DA neurons target nonspecifically to both the dorsolateral striatum and the nucleus accumbens. Later during development, the separate mesostriatal and mesolimbic pathways differentiate through the selective elimination of mistargeted collaterals.     

Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia

Schizophrenia is characterized by substantial dysfunctions of reward processing, leading to detrimental consequences for decision-making. The neurotransmitter dopamine is responsible for the transmission of reward signals and also known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), sixteen medicated patients with schizophrenia and sixteen healthy controls performed the ‘desire-reason dilemma’ (DRD) paradigm. This paradigm allowed us to directly investigate reward-related brain activations depending on the interaction of bottom–up and top–down mechanisms, when a previously conditioned reward stimulus had to be rejected to achieve a superordinate long-term goal. Both patients and controls showed significant activations in the mesolimbic reward system. In patients with schizophrenia, however, we found a significant hyperactivation of the left ventral striatum (vStr) when they were allowed to accept the conditioned reward stimuli, and a reduced top–down regulation of activation in the ventral striatum (vStr) and ventral tegmental area (VTA) while having to reject the immediate reward to pursue the superordinate task-goal. Moreover, while healthy subjects exhibited a negative functional coupling of the vStr with both the anteroventral prefrontal cortex (avPFC) and the ventromedial prefrontal cortex (VMPFC) in the dilemma situation, this functional coupling was significantly impaired in the patient group. These findings provide evidence for an increased ventral striatal activation to reward stimuli and an impaired top–down control of reward signals by prefrontal brain regions in schizophrenia.     

Infusions of 3alpha,5alpha-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3alpha,5alpha-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

17beta-Estradiol (E2) and progesterone (P4) influence the onset and duration of sexual behavior and are also associated with changes in behaviors that may contribute to mating, such as exploration, anxiety, and social behaviors (socio-sexual behaviors). In the midbrain ventral tegmental area (VTA), the P4 metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), modulates lordosis of E2-primed rodents; 3alpha,5alpha-THP can also influence anxiety and social behaviors. To examine if 3alpha,5alpha-THP in the VTA mediates socio-sexual behaviors, we infused 3alpha,5alpha-THP to the VTA of diestrous and proestrous rats. As expected, proestrous, compared to diestrous, rats showed more exploratory (open field), anxiolytic (elevated plus maze), pro-social (partner preference, social interaction), and sexual (paced mating) behavior and had increased E2, P4, dihydroprogesterone (DHP), and 3alpha,5alpha-THP in serum, midbrain, hippocampus, diencephalon, and cortex. Infusions of 3alpha,5alpha-THP to the VTA, but not control sites, such as the substantia nigra (SN) or central grey (CG), of diestrous rats produced behavioral and endocrine effects akin to that of proestrous rats and increased DHP and 3alpha,5alpha-THP levels in midbrain, hippocampus, and diencephalon. Levels of DHP and 3alpha,5alpha-THP, but neither E2 nor P4 concentrations, in midbrain, hippocampus, diencephalon, and/or cortex were positively correlated with socio-sexual behaviors. Thus, 3alpha,5alpha-THP infusions to the VTA, but not SN or CG, can enhance socio-sexual behaviors and increase levels in midbrain, hippocampus, and diencephalon.     

A close relationship between verbal memory and SN/VTA integrity in young and older adults

Age-related dysfunction in dopaminergic neuromodulation is assumed to contribute to age-associated memory impairment. However, to date there are no in vivo data on how structural parameters of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic projections, relate to memory performance in healthy young and older adults. We investigated this relationship in a cross-sectional study including data from the hippocampus and frontal white matter (FWM) and also assessing working memory span and attention. In groups of young and older adults matched for the variance of their age distribution, gender and body mass index, we observed a robust positive correlation between Magnetization Transfer Ratio (MTR) - a measure of structural integrity - of the SN/VTA and FWM with verbal learning and memory performance among older adults, while there was a negative correlation in the young. Two additional imaging parameters, anisotropy of diffusion and diffusion coefficient, suggested that in older adults FWM changes reflected vascular pathology while SN/VTA changes pointed towards neuronal loss and loss of water content. The negative correlation in the young possibly reflected maturational changes. Multiple regression analyses indicated that in both young and older adults, SN/VTA MTR explained more variance of verbal learning and memory than FWM MTR or hippocampal MTR, and contributed less to explaining variance of working memory span. Together these findings indicate that structural integrity in the SN/VTA has a relatively selective impact on verbal learning and memory and undergoes specific changes from young adulthood to older age that qualitatively differ from changes in the FWM and hippocampus.     

Elevated cognitive control over reward processing in recovered female patients with anorexia nervosa

Background

Individuals with anorexia nervosa are thought to exert excessive self-control to inhibit primary drives.

Methods

This study used functional MRI (fMRI) to interrogate interactions between the neural correlates of cognitive control and motivational processes in the brain reward system during the anticipation of monetary reward and reward-related feedback. In order to avoid confounding effects of undernutrition, we studied female participants recovered from anorexia nervosa and closely matched healthy female controls. The fMRI analysis (including node-to-node functional connectivity) followed a region of interest approach based on models of the brain reward system and cognitive control regions implicated in anorexia nervosa: the ventral striatum, medial orbitofrontal cortex (mOFC) and dorsolateral prefrontal cortex (DLPFC).

Results

We included 30 recovered patients and 30 controls in our study. There were no behavioural differences and no differences in hemodynamic responses of the ventral striatum and the mOFC in the 2 phases of the task. However, relative to controls, recovered patients showed elevated DLPFC activity during the anticipation phase, failed to deactivate this region during the feedback phase and displayed greater functional coupling between the DLPFC and mOFC. Recovered patients also had stronger associations than controls between anticipation-related DLPFC responses and instrumental responding.

Limitations

The results we obtained using monetary stimuli might not generalize to other forms of reward.

Conclusion

Unaltered neural responses in ventral limbic reward networks but increased recruitment of and connectivity with lateral–frontal brain circuitry in recovered patients suggests an elevated degree of self-regulatory processes in response to rewarding stimuli. An imbalance between brain systems subserving bottom–up and top–down processes may be a trait marker of the disorder.     

Neural correlates of long-term intense romantic love

The present study examined the neural correlates of long-term intense romantic love using functional magnetic resonance imaging (fMRI). Ten women and 7 men married an average of 21.4 years underwent fMRI while viewing facial images of their partner. Control images included a highly familiar acquaintance; a close, long-term friend; and a low-familiar person. Effects specific to the intensely loved, long-term partner were found in: (i) areas of the dopamine-rich reward and basal ganglia system, such as the ventral tegmental area (VTA) and dorsal striatum, consistent with results from early-stage romantic love studies; and (ii) several regions implicated in maternal attachment, such as the globus pallidus (GP), substantia nigra, Raphe nucleus, thalamus, insular cortex, anterior cingulate and posterior cingulate. Correlations of neural activity in regions of interest with widely used questionnaires showed: (i) VTA and caudate responses correlated with romantic love scores and inclusion of other in the self; (ii) GP responses correlated with friendship-based love scores; (iii) hypothalamus and posterior hippocampus responses correlated with sexual frequency; and (iv) caudate, septum/fornix, posterior cingulate and posterior hippocampus responses correlated with obsession. Overall, results suggest that for some individuals the reward-value associated with a long-term partner may be sustained, similar to new love, but also involves brain systems implicated in attachment and pair-bonding.     

GABA(A) receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems

In the midbrain ventral tegmental area (VTA), both dopaminergic and nondopaminergic neural substrates mediate various behavioural reward phenomena. VTA GABAergic neurons are anatomically positioned to influence the activity of both the mesolimbic dopamine system and nondopamine efferents from the VTA. In order to examine the possible functional role of VTA GABA(A) receptors in neural reward processes, we performed discrete, bilateral microinjections of the GABA(A) receptor agonist, muscimol, or the GABA(A) receptor antagonist, bicuculline, into the VTA. Using a fully counterbalanced, unbiased conditioned place-preference paradigm, we demonstrate that activation of VTA GABA(A) receptors, with the GABA(A) receptor agonist muscimol (5--50 ng/microL), or inhibition of VTA GABA(A) receptors, with the GABA(A) receptor antagonist bicuculline (5--50 ng/microL), both produce robust rewarding effects. Furthermore, these rewarding effects can be pharmacologically dissociated: blockade of dopamine receptors with a dopamine receptor antagonist, alpha-flupenthixol (0.8 mg/kg; i.p.), or concurrent activation of VTA GABA(B) receptors with a GABA(B) receptor agonist, baclofen (70 ng/microL), blocked the rewarding properties of the GABA(A) receptor agonist, but had no effect on the rewarding properties of the GABA(A) receptor antagonist. These results suggest that, within the VTA, a single GABA(A) receptor substrate controls bidirectional reward signalling between dopaminergic and nondopaminergic brain reward systems.     

Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression

The dopaminergic system influences motor behavior, signals reward and novelty, and is an essential component of the basal ganglia in all vertebrates including the lamprey, one of the phylogenetically oldest vertebrates. The intrinsic organization and function of the lamprey basal ganglia is highly conserved. For instance, the direct and indirect pathways are modulated through dopamine D1 and D2 receptors in lamprey and in mammals. The nucleus of the tuberculum posterior, a homologue of the substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) is present in lamprey, but only scarce data exist about its connectivity. Likewise, the D2 receptor is expressed in the striatum, but little is known about its localization in other brain areas. We used in situ hybridization and tracer injections, both in combination with tyrosine hydroxylase immunohistochemistry, to characterize the SNc/VTA efferent and afferent connectivity, and to relate its projection pattern with D2 receptor expression in particular. We show that most features of the dopaminergic system are highly conserved. As in mammals, the direct pallial (cortex in mammals) input and the basal ganglia connectivity with the SNc/VTA are present as part of the evaluation system, as well as input from the tectum as the evolutionary basis for salience/novelty detection. Moreover, the SNc/VTA receives sensory information from the olfactory bulbs, optic tectum, octavolateral area, and dorsal column nucleus, and it innervates, apart from the nigrostriatal pathway, several motor‐related areas. This suggests that the dopaminergic system also contributes to the control of different motor centers at the brainstem level. J. Comp. Neurol. 522:3775–3794, 2014. © 2014 Wiley Periodicals, Inc.     

The novelty exploration bonus and its attentional modulation

We hypothesized that novel stimuli represent salient learning signals that can motivate ‘exploration’ in search for potential rewards. In computational theories of reinforcement learning, this is referred to as the novelty ‘exploration bonus’ for rewards. If true, stimulus novelty should enhance the reward anticipation signals in brain areas that are part of dopaminergic circuitry and thereby reduce responses to reward outcomes. We investigated this hypothesis in two fMRI experiments. Images of complex natural scenes predicted monetary reward or a neutral outcome by virtue of depicting either indoor or outdoor scenes. Half of the reward-predicting and neutral images had been familiarized the day before, the other half were novel. In experiment 1, subjects indicated whether images were novel or familiar, whereas in experiment 2, they explicitly decided whether or not images predicted reward by depicting indoor or outdoor scenes. Novelty led to the hypothesized enhancement of mesolimbic reward prediction responses and concomitant reduction of mesolimbic responses to reward outcomes. However, this effect was strongly task-dependent and occurred only in experiment 2, when the reward-predicting property of each image was attended. Recognition memory for the novel and familiar stimuli (after 24 h) was enhanced by reward anticipation in both tasks. These findings are compatible with the proposition that novelty can act as a bonus for rewards under conditions when rewards are explicitly attended, thus biasing the organism towards reward anticipation and providing a motivational signal for exploration.     

c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery

Evidence suggests that dopaminergic neurons of the ventral mesencephalic tegmentum (VMT) could be important for paradoxical sleep (PS). Here, we examined whether dopamine (DA) and adjacent gamma-aminobutyric acid (GABA)-synthesizing neurons are active in association with PS recovery as compared to PS deprivation or control conditions in different groups of rats by using c-Fos expression as a reflection of neural activity, combined with dual immunostaining for tyrosine hydroxylase (TH) or glutamic acid decarboxylase (GAD). Numbers of TH+/c-Fos+ neurons in the substantia nigra (SN) were not significantly different across groups, whereas those in the ventral tegmental area (VTA) were significantly different and greatest in PS recovery. Numbers of GAD+/c-Fos+ neurons in both VTA and SN were greatest in PS recovery. Thus, DA neuronal activity does not appear to be suppressed by local GABAergic neuronal activity during PS but might be altered in pattern by this inhibitory as well as other excitatory, particularly cholinergic, inputs such as to allow DA VTA neurons to become maximally active during PS and thereby contribute to the unique physiological and cognitive aspects of that state.