Hippocampus Leads Ventral Striatum in Replay of Place-Reward Information

Associating spatial locations with rewards is fundamental to survival in natural environments and requires the integrity of the hippocampus and ventral striatum. In joint multineuron recordings from these areas, hippocampal–striatal ensembles reactivated together during sleep. This process was especially strong in pairs in which the hippocampal cell processed spatial information and ventral striatal firing correlated to reward. Replay was dominated by cell pairs in which the hippocampal “place” cell fired preferentially before the striatal reward-related neuron. Our results suggest a plausible mechanism for consolidating place-reward associations and are consistent with a central tenet of consolidation theory, showing that the hippocampus leads reactivation in a projection area.     

Subjective socioeconomic status predicts human ventral striatal responses to social status information

The enormous influence of hierarchical rank on social interactions [1] suggests that neural mechanisms exist to process status-related information [2] and ascribe value to it. The ventral striatum is prominently implicated in processing value and salience, independent of hedonic properties [3, 4], and a functional magnetic resonance imaging (fMRI) study of social status perception in humans demonstrated that viewing higher-ranked compared to lower-ranked individuals evokes a ventral striatal response [5], indicative of a greater assignment of value/salience to higher status. Consistent with this interpretation, nonhuman primates value information associated with higher-ranked conspecifics more than lower-ranked, as illustrated using a choice paradigm in which monkeys preferentially take the opportunity to view high-status monkeys [6]. Interestingly, this status-related value assignment in nonhuman primates is influenced by one's own hierarchical rank: high-status monkeys preferentially attend to conspecifics of high status, whereas low-status monkeys will also attend to other low-status monkeys [7]. Complementary to these findings, using fMRI and a social status judgment task in humans, we suggest a neurobiological mechanism by which one's own relative hierarchical rank influences the value attributed to particular social status information by demonstrating that one's subjective socioeconomic status differentially influences ventral striatal activity during processing of status-related information.     

Recognition Memory for Colored and Black-and-White Scenes in Normal and Color Deficient Observers (Dichromats)

Color deficient (dichromat) and normal observers’ recognition memory for colored and black-and-white natural scenes was evaluated through several parameters: the rate of recognition, discrimination (A’), response bias (B”D), response confidence, and the proportion of conscious recollections (Remember responses) among hits. At the encoding phase, 36 images of natural scenes were each presented for 1 sec. Half of the images were shown in color and half in black-and-white. At the recognition phase, these 36 pictures were intermixed with 36 new images. The participants’ task was to indicate whether an image had been presented or not at the encoding phase, to rate their level of confidence in his her/his response, and in the case of a positive response, to classify the response as a Remember, a Know or a Guess response. Results indicated that accuracy, response discrimination, response bias and confidence ratings were higher for colored than for black-and-white images; this advantage for colored images was similar in both groups of participants. Rates of Remember responses were not higher for colored images than for black-and-white ones, whatever the group. However, interestingly, Remember responses were significantly more often based on color information for colored than for black-and-white images in normal observers only, not in dichromats.     

Reward Anticipation in Ventral Striatum and Individual Sensitivity to Reward: A Pilot Study of a Child-Friendly fMRI Task

Reward processing has been implicated in developmental disorders. However, the classic task to probe reward anticipation, the monetary incentive delay task, has an abstract coding of reward and no storyline and may therefore be less appropriate for use with developmental populations. We modified the task to create a version appropriate for use with children. We investigated whether this child-friendly version could elicit ventral striatal activation during reward anticipation in typically developing children and young adolescents (aged 9.5–14.5). In addition, we tested whether our performance-based measure of reward sensitivity was associated with anticipatory activity in ventral striatum. Reward anticipation was related to activity in bilateral ventral striatum. Moreover, we found an association between individual reward sensitivity and activity in ventral striatum. We conclude that this task assesses ventral striatal activity in a child-friendly paradigm. The combination with a performance-based measure of reward sensitivity potentially makes the task a powerful tool for developmental imaging studies of reward processing.     

Imbalanced Decision Hierarchy in Addicts Emerging from Drug-Hijacked Dopamine Spiraling Circuit

Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts'' “self-described mistake”. We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems.     

Topographic distribution of dopamine uptake,choline uptake,choline acetyltransferase,and GABA uptake in the striata of weaver mutant mice

The topographic distribution of dopamine (DA) uptake, choline uptake, choline acetyltransferase (ChAT) activity and GABA uptake within the striata of weaver mutant mice and control mice was determined. Uptake of [³H]dopamine, [³H]choline and [¹⁴C]GABA, as well as ChAT activity were determined in samples prepared from the dorsolateral, dorsomedial, ventrolateral and ventromedial portions of the striatum. In 45–60 day old control mice, dopamine uptake was homogeneously distributed throughout the striatum. On the other hand, striata from weaver mice exhibited an uneven distribution with the ventral aspects having greater uptake activity than the dorsal regions. Thus, although the ventral portion of the striatum is less severely affected than the dorsal portion, all areas of the striatum exhibited significantly reduced uptake rates. In 9 and 12 month old mice, choline uptake was higher in lateral than medial zones of the striatum of both genotypes and no differences were observed between genotypes. GABA uptake was higher in the ventral striatum than in the dorsal striatum but again no differences were found between weaver and control mice. The results of this study indicate that the entire weaver striatum is severely deficient in its ability to recapture dopamine and thus is functionally compromised. The results also indicate that the striatal cholinergic and GABAergic interneurons are not directly or indirectly affected by the weaver gene.Special ïssue dedicated to Dr. Morris H. Aprison     

Regional Differences in Striatal Dopamine Uptake and Release Associated with Recovery from MPTP-Induced Parkinsonism

Abstract : This study directly assessed striatal dopamine (DA) uptake rates and peak release in response to KCl in normal, symptomatic, and recovered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats using in vivo electrochemistry. DA uptake rates measured after direct application of known concentrations of DA to the striatum were slowed significantly in both dorsal and ventral striatum in symptomatic cats compared with rates recorded in normal animals. DA uptake rates remained significantly slowed in recovered cats and were not significantly different from the rates recorded in symptomatic animals. In symptomatic cats, both DA uptake rates and the signal recorded in response to KCl stimulation were significantly decreased from normal in all dorsal and ventral striatal regions sampled. Reduction/oxidation (redox) ratios recorded in response to KCl stimulation suggested DA to be the predominant electroactive species. In spontaneously recovered MPTP-treated cats, recordings in the ventral striatum subsequent to KCl stimulation again suggested DA to be the predominant electroactive species released, and peak levels were significantly higher than those recorded in symptomatic animals. In the dorsal striatum of recovered cats, redox ratios recorded subsequent to KCl stimulation suggested serotonin rather than DA to be the predominant electroactive species released. Peak levels of release in the dorsal striatum were not significantly greater than those recorded in symptomatic animals. These results suggest that in spontaneously recovered MPTP-treated cats, there is partial recovery of ventral striatal DAergic terminals, persistent loss of dorsal striatal DAergic terminals, and a down-regulation of DA transporter number/function throughout the striatum. These processes may contribute to volume transmission of DA in the striatum and promote functional recovery.     

Human striatal responses to monetary reward depend on saliency

While the striatum has been implicated in reward processing, an alternative view contends that the striatum processes salient events in general. Using fMRI, we investigated human striatal responses to monetary reward while modulating the saliency surrounding its receipt. Money was maximally salient when its receipt depended on a correct response (active) and minimally salient when its receipt was completely independent of the task (passive). The saliency manipulation was confirmed by skin conductance responses and subjective ratings of the stimuli. Significant caudate and nucleus accumbens activations occurred following the active compared to passive money. Such activations were attributed to saliency rather than the motor requirement associated with the active money because striatal activations were not observed when the money was replaced by inconsequential, nonrewarding stimuli. The present study provides evidence that the striatum's role in reward processing is dependent on the saliency associated with reward, rather than value or hedonic feelings.     

Cholinergic interneuron characteristics and nicotinic properties in the striatum

The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.     

Monetary Reward Modulates Task-Irrelevant Perceptual Learning for Invisible Stimuli

Task Irrelevant Perceptual Learning (TIPL) shows that the brain’s discriminative capacity can improve also for invisible and unattended visual stimuli. It has been hypothesized that this form of “unconscious” neural plasticity is mediated by an endogenous reward mechanism triggered by the correct task performance. Although this result has challenged the mandatory role of attention in perceptual learning, no direct evidence exists of the hypothesized link between target recognition, reward and TIPL. Here, we manipulated the reward value associated with a target to demonstrate the involvement of reinforcement mechanisms in sensory plasticity for invisible inputs. Participants were trained in a central task associated with either high or low monetary incentives, provided only at the end of the experiment, while subliminal stimuli were presented peripherally. Our results showed that high incentive-value targets induced a greater degree of perceptual improvement for the subliminal stimuli, supporting the role of reinforcement mechanisms in TIPL.     

Motor Preparatory Activity in Posterior Parietal Cortex is Modulated by Subjective Absolute Value

For optimal response selection, the consequences associated with behavioral success or failure must be appraised. To determine how monetary consequences influence the neural representations of motor preparation, human brain activity was scanned with fMRI while subjects performed a complex spatial visuomotor task. At the beginning of each trial, reward context cues indicated the potential gain and loss imposed for correct or incorrect trial completion. FMRI-activity in canonical reward structures reflected the expected value related to the context. In contrast, motor preparatory activity in posterior parietal and premotor cortex peaked in high “absolute value” (high gain or loss) conditions: being highest for large gains in subjects who believed they performed well while being highest for large losses in those who believed they performed poorly. These results suggest that the neural activity preceding goal-directed actions incorporates the absolute value of that action, predicated upon subjective, rather than objective, estimates of one''s performance.     

“An Eye for an Eye”? Neural Correlates of Retribution and Forgiveness

Humans have evolved strong preferences for equity and fairness. Neuroimaging studies suggest that punishing unfairness is associated with the activation of a neural network comprising the anterior cingulate cortex, anterior insula, the ventral striatum, and the dorsolateral prefrontal cortex (DLPFC). Here, we report the neuronal correlates of retribution and “forgiveness” in a scenario, in which individuals first acted as a recipient in an Ultimatum Game, and subsequently assumed the position of a proposer in a Dictator Game played against the same opponents as in the Ultimatum Game. Most subjects responded in a tit-for-tat fashion, which was accompanied by activation of the ventral striatum, corroborating previous findings that punishing unfair behaviour has a rewarding connotation. Subjects distinguished between the human opponent and computer condition by activation of the ventromedial PFC in the human condition, indicative of mentalising. A substantial number of subjects did not retaliate. Neurally, this “forgiveness” behaviour was associated with the activation of the right (and to a lesser degree left) DLPFC, a region that serves as a cognitive control region and thus may be involved in inhibiting emotional responses against unfairness.     

Heterogeneous coding of temporally discounted values in the dorsal and ventral striatum during intertemporal choice

In choosing between different rewards expected after unequal delays, humans and animals often prefer the smaller but more immediate reward, indicating that the subjective value or utility of reward is depreciated according to its delay. Here, we show that neurons in the primate caudate nucleus and ventral striatum modulate their activity according to temporally discounted values of rewards with a similar time course. However, neurons in the caudate nucleus encoded the difference in the temporally discounted values of the two alternative targets more reliably than neurons in the ventral striatum. In contrast, neurons in the ventral striatum largely encoded the sum of the temporally discounted values, and therefore, the overall goodness of available options. These results suggest a more pivotal role for the dorsal striatum in action selection during intertemporal choice.     

The Ranking Probability Approach and Its Usage in Design and Analysis of Large-Scale Studies

In experiments with many statistical tests there is need to balance type I and type II error rates while taking multiplicity into account. In the traditional approach, the nominal -level such as 0.05 is adjusted by the number of tests, , i.e., as 0.05/. Assuming that some proportion of tests represent “true signals”, that is, originate from a scenario where the null hypothesis is false, power depends on the number of true signals and the respective distribution of effect sizes. One way to define power is for it to be the probability of making at least one correct rejection at the assumed -level. We advocate an alternative way of establishing how “well-powered” a study is. In our approach, useful for studies with multiple tests, the ranking probability is controlled, defined as the probability of making at least correct rejections while rejecting hypotheses with smallest P-values. The two approaches are statistically related. Probability that the smallest P-value is a true signal (i.e., ) is equal to the power at the level , to an excellent approximation. Ranking probabilities are also related to the false discovery rate and to the Bayesian posterior probability of the null hypothesis. We study properties of our approach when the effect size distribution is replaced for convenience by a single “typical” value taken to be the mean of the underlying distribution. We conclude that its performance is often satisfactory under this simplification; however, substantial imprecision is to be expected when is very large and is small. Precision is largely restored when three values with the respective abundances are used instead of a single typical effect size value.     

Predictive neural coding of reward preference involves dissociable responses in human ventral midbrain and ventral striatum

Food preferences are acquired through experience and can exert strong influence on choice behavior. In order to choose which food to consume, it is necessary to maintain a predictive representation of the subjective value of the associated food stimulus. Here, we explore the neural mechanisms by which such predictive representations are learned through classical conditioning. Human subjects were scanned using fMRI while learning associations between arbitrary visual stimuli and subsequent delivery of one of five different food flavors. Using a temporal difference algorithm to model learning, we found predictive responses in the ventral midbrain and a part of ventral striatum (ventral putamen) that were related directly to subjects' actual behavioral preferences. These brain structures demonstrated divergent response profiles, with the ventral midbrain showing a linear response profile with preference, and the ventral striatum a bivalent response. These results provide insight into the neural mechanisms underlying human preference behavior.     

Somatosensory evoked potentials and pain discrimination in man

The relationship between 10 components of somatosensory evoked potentials (EPs) and pain discrimination in man was studied using Signal Detection Theory (SDT) psychophysics. Two painful electrical stimuli were delivered to the right index finger in random order over all trials. EPs were recorded from the scalp at the contralateral primary somatic projection area while subjects performed SDT discrimination. The stimulus-response combination was classified into 4 categories according to SDT response: hits, misses, false alarms (FAs) and correct rejections (CRs). The amplitudes and peak latencies of EPs in 4 categories were compared with each other. EPs associated with hits and FAs had significantly greater amplitude at P 190, N 220 and P 270 than those associated with misses and CRs, while there was no change in the amplitude of other components. The amplitude of these 3 components systematically increased with an increase in the magnitude of subjective response. Peak latencies of all components were not related to the response categories. These results indicate that the amplitude of the 3 last components may be concerned with the pain evaluating system in the brain.     

Prodromal Huntington Disease as a Model for Functional Compensation of Early Neurodegeneration

Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.     

Parallel Representation of Value-Based and Finite State-Based Strategies in the Ventral and Dorsal Striatum

Previous theoretical studies of animal and human behavioral learning have focused on the dichotomy of the value-based strategy using action value functions to predict rewards and the model-based strategy using internal models to predict environmental states. However, animals and humans often take simple procedural behaviors, such as the “win-stay, lose-switch” strategy without explicit prediction of rewards or states. Here we consider another strategy, the finite state-based strategy, in which a subject selects an action depending on its discrete internal state and updates the state depending on the action chosen and the reward outcome. By analyzing choice behavior of rats in a free-choice task, we found that the finite state-based strategy fitted their behavioral choices more accurately than value-based and model-based strategies did. When fitted models were run autonomously with the same task, only the finite state-based strategy could reproduce the key feature of choice sequences. Analyses of neural activity recorded from the dorsolateral striatum (DLS), the dorsomedial striatum (DMS), and the ventral striatum (VS) identified significant fractions of neurons in all three subareas for which activities were correlated with individual states of the finite state-based strategy. The signal of internal states at the time of choice was found in DMS, and for clusters of states was found in VS. In addition, action values and state values of the value-based strategy were encoded in DMS and VS, respectively. These results suggest that both the value-based strategy and the finite state-based strategy are implemented in the striatum.     

The homeobox gene Gsh2 is required for retinoid production in the embryonic mouse telencephalon

We have examined the role of the homeobox gene Gsh2 in retinoid production and signaling within the ventral telencephalon of mouse embryos. Gsh2 mutants exhibit altered ventral telencephalic development, including a smaller striatum with fewer DARPP-32 neurons than wild types. We show that the expression of the retinoic acid (RA) synthesis enzyme, retinaldehyde dehydrogenase 3 (Raldh3, also known as Aldh1a3), is reduced in the lateral ganglionic eminence (LGE) of Gsh2 mutants. Moreover, using a retinoid reporter cell assay, we found that retinoid production in the Gsh2 mutants is markedly reduced. The striatal defects in Gsh2 mutants are thought to result from ectopic expression of Pax6 in the LGE. Previously, we had shown that removal of Pax6 from the Gsh2 mutant background improves the molecular identity of the LGE in these double mutants; however, Raldh3 expression is not improved. The Pax6;Gsh2 double mutants possess a larger striatum than the Gsh2 mutants, but the disproportionate reduction in DARPP-32 neurons is not improved. These findings suggest that reduced retinoid production in the Gsh2 mutant contributes to the striatal differentiation defects. As RA promotes the expression of DARPP-32 in differentiating LGE cells in vitro, we examined whether exogenous RA can improve striatal neuron differentiation in the Gsh2 mutants. Indeed, RA supplementation of Gsh2 mutants, during the period of striatal neurogenesis, results in a significant increase in DARPP-32 expression. Thus, in addition to the previously described role for Gsh2 to maintain correct molecular identity in the LGE, our results demonstrate a novel requirement of this gene for retinoid production within the ventral telencephalon.     

Intrastriatal Grafting of Cos Cells Stably Expressing Human Aromatic l-Amino Acid Decarboxylase: Neurochemical Effects

Abstract: To study the possibility that increasing striatal activity of aromatic l -amino acid decarboxylase (AADC; EC 4.1.1.28) can increase dopamine production in dopamine denervated striatum in response to l -3,4-dihydroxyphenylalanine ( l -DOPA) administration, we grafted Cos cells stably expressing the human AADC gene (Cos- haadc cells) into 6-hydroxydopamine denervated rat striatum. Before grafting, the catalytic activity of the enzyme was assessed in vitro via the generation of ¹⁴CO₂ from l -[¹⁴C]DOPA. The K _m value for l -DOPA in intact and disrupted cells was 0.60 and 0.56 m M , respectively. The cofactor, pyridoxal 5-phosphate, enhanced enzymatic activity with maximal effect at 0.1 m M . The pH optimum for enzyme activity was 6.8. Grafting Cos- haadc cells into denervated rat striatum enhanced striatal dopamine levels measured after systemic administration of l -DOPA. When measured 2 h after l -DOPA administration, the mean dopamine level in the striata of Cos- haadc -grafted animals was 2 µg/g of tissue, representing 31% of normal striatal dopamine concentration. The mean dopamine concentration in the striata grafted with untransfected Cos cells (Cos-ut cells) was 1 µg/g. At 6–8 h after l -DOPA administration, striatal dopamine content in the Cos- haadc -grafted animals was 0.67 µg/g of tissue weight, representing 9% of intact striatum dopamine content. By contrast, the average dopamine content in the Cos-ut-grafted animals was undetectable. These findings demonstrate that enhancing striatal AADC activity can improve dopamine bioformation in response to systemically administered l -DOPA.