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Different neural correlates of reward expectation and reward expectation error in the putamen and caudate nucleus during stimulus-action-reward association learning.

To select appropriate behaviors leading to rewards, the brain needs to learn associations among sensory stimuli, selected behaviors, and rewards. Recent imaging and neural-recording studies have revealed that the dorsal striatum plays an important role in learning such stimulus-action-reward associations. However, the putamen and caudate nucleus are embedded in distinct cortico-striatal loop circuits, predominantly connected to motor-related cerebral cortical areas and frontal association areas, respectively. This difference in their cortical connections suggests that the putamen and caudate nucleus are engaged in different functional aspects of stimulus-action-reward association learning. To determine whether this is the case, we conducted an event-related and computational model-based functional MRI (fMRI) study with a stochastic decision-making task in which a stimulus-action-reward association must be learned. A simple reinforcement learning model not only reproduced the subject's action selections reasonably well but also allowed us to quantitatively estimate each subject's temporal profiles of stimulus-action-reward association and reward-prediction error during learning trials. These two internal representations were used in the fMRI correlation analysis. The results revealed that neural correlates of the stimulus-action-reward association reside in the putamen, whereas a correlation with reward-prediction error was found largely in the caudate nucleus and ventral striatum. These nonuniform spatiotemporal distributions of neural correlates within the dorsal striatum were maintained consistently at various levels of task difficulty, suggesting a functional difference in the dorsal striatum between the putamen and caudate nucleus during stimulus-action-reward association learning.

Adult↗

Reward-period activity in primate dorsolateral prefrontal and orbitofrontal neurons is affected by reward schedules.

Reward-period activity observed in the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) is thought to represent the detection of reward delivery. To investigate whether this activity plays the same role in these areas, we examined this activity under different reward schedules and whether the reward schedule has similar effects on this activity in each of these areas. A monkey performed an oculomotor delayed-response (ODR) task under two reward schedules. In the ODR-1 schedule, the monkey received a large amount of reward only after four successful trials, whereas in the ODR-2 schedule, it received a small amount of reward after every successful trial. Although reward-period activity was observed in both areas, more neurons exhibited this activity in the OFC. Reward-period activity was modulated by the proximity to reward delivery in both areas and this feature was observed more frequently in the OFC. The onset time of this activity also gradually advanced depending on the proximity to reward delivery. Moreover, many OFC neurons with this activity responded to free reward delivery. These results indicate that reward-period activity in the OFC represents the detection of reward delivery and that the gradual change in the magnitude and the onset time of this activity represents the expectation of reward delivery. Similar features of reward-period activity were observed in DLPFC neurons, although a significant number of DLPFC neurons did not respond to free reward delivery and no advance was observed in the onset time of this activity. These results suggest that reward-period activity in the DLPFC participates in whether or not correct performance was achieved. Thus, although similar reward-period activity was observed in both areas, the activity in the OFC represents the detection of reward delivery and is affected by the monkey's motivational state, whereas that in the DLPFC seems to participate in monitoring whether or not the necessary performance is achieved.

Action Potentials↗

Single units in the pigeon brain integrate reward amount and time-to-reward in an impulsive choice task.

BACKGROUND: Animals prefer small over large rewards when the delays preceding large rewards exceed an individual tolerance limit. Such impulsive choice behavior occurs even in situations in which alternative strategies would yield more optimal outcomes. Behavioral research has shown that an animal's choice is guided by the alternative rewards' subjective values, which are a function of reward amount and time-to-reward. Despite increasing knowledge about the pharmacology and anatomy underlying impulsivity, it is still unknown how the brain combines reward amount and time-to-reward information to represent subjective reward value. RESULTS: We trained pigeons to choose between small, immediate rewards and large rewards delivered after gradually increasing delays. Single-cell recordings in the avian Nidopallium caudolaterale, the presumed functional analog of the mammalian prefrontal cortex, revealed that neural delay activation decreased with increasing delay length but also covaried with the expected reward amount. This integrated neural response was modulated by reward amount and delay, as predicted by a hyperbolical equation, of subjective reward value derived from behavioral studies. Furthermore, the neural activation pattern reflected the current reward preference and the time point of the shift from large to small rewards. CONCLUSIONS: The reported activity was modulated by the temporal devaluation of the anticipated reward in addition to reward amount. Our findings contribute to the understanding of neuropathologies such as drug addiction, pathological gambling, frontal lobe syndrome, and attention-deficit disorders, which are characterized by inappropriate temporal discounting and increased impulsiveness.

Animals↗

Instrumental responding for rewards is associated with enhanced neuronal response in subcortical reward systems.

The response of human reward systems to different reinforcers, including food, drugs and money, has been investigated in a number of recent functional neuroimaging studies. They have varied, however, in terms of whether or not a behavioural response was required to obtain rewards. The aim of the present study was to determine whether neuronal responses to financial reward are significantly modulated by the requirement to make a behavioural response. Twelve subjects were scanned using functional magnetic resonance imaging (fMRI) while performing a simple target detection task. Certain targets acted as cues predicting financial reinforcement; some additionally required that a movement be executed, while others did not. There were also targets that required a movement but were not predictive of reward. We observed, as expected, responses within motor and reward systems associated with main effects of movement and reward, respectively. Critically, the reward responses were significantly modulated by the requirement to make an intervening behavioural response. Blood oxygenation level-dependent (BOLD) responses in the amygdala and striatum were significantly enhanced when a movement was required, while reward-related response in the orbitofrontal cortex was independent of movement. These results suggest important dissociations within human reward systems, reflecting different properties of rewards. The striatum and amygdala may mediate the function of rewards in eliciting goal-directed behaviour, while the orbitofrontal cortex mediates incentive value.

Adult↗

Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity.

Nicotine is a major component of tobacco smoke contributing to the initiation and persistence of the harmful tobacco habit in human smokers. The reinforcing effects of nicotine likely arise through its ability to stimulate brain circuitry mediating the detection and experiencing of natural rewards. Nevertheless, remarkably little is known concerning the acute or long-lasting actions of nicotine on brain reward systems in vivo. Here, we investigated the effects of intravenously self-administered nicotine (0.03 mg/kg/infusion, free base) on the sensitivity of brain reward systems, reflected in alterations of intracranial self-stimulation (ICSS) thresholds in rats. Rats self-administered nicotine during 1 or 12 h daily sessions, with reward thresholds assessed 1 h before and 15 min after each self-administration session. Control rats remained nicotine naïve throughout. Nicotine self-administration increased the sensitivity of brain reward systems, detected by post-nicotine lowering of reward thresholds in 1 and 12 h rats. This nicotine-enhanced sensitivity of reward systems was reversed by the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg). Surprisingly, nicotine-induced excitation of reward systems persisted for at least 36 days after nicotine self-administration had ceased. Overall, these data demonstrate that rats can voluntarily consume quantities of nicotine sufficient to increase the sensitivity of brain reward systems, an action likely crucial in establishing and maintaining the nicotine habit. Moreover, self-administered nicotine resets the sensitivity of reward systems to a new increased level, thereby imprinting an indelible 'memory' of its effects in reward systems, an action that so far appears unique to nicotine among drugs of abuse.

Analysis of Variance↗

Reward value invariant place responses and reward site associated activity in hippocampal neurons of behaving rats.

To investigate the involvement of the hippocampal-accumbens system in goal-oriented displacement behaviors, hippocampal neuronal activity was recorded in rats learning and recalling new distributions of different volumes of liquid reward among the arms of a plus maze. Each arm had a reward box containing a water trough and identical visual cues that could be illuminated independently. As the water-restricted rat successively visited the respective boxes, it received 7, 5, and 3 drops of water, and then 1 drop, provided at 1-s intervals. (Reward distributions were reassigned daily and mid-session.) In the training phase, reward boxes were lit individually. In the recall phase, the lamps on all arms were lit and then turned off as the rat visited the boxes in order of descending value. Neuronal firing rates were analyzed for changes related to reward value or to shifts between learning and recall phases. The principal finding is that place responses remained unchanged after these manipulations and that these neurons showed no evidence of explicit coding of reward value. In addition, two other types of responses appeared while the rat was stationary at the reward boxes awaiting multiple rewards. These were observed primarily in neurons within the dentate gyrus, but also in CA1. Position-selective reward site responses were regular at 20-60 impulses per second, while position-independent discharges bursted irregularly at about 5 impulses per second. Such responses could explain controversial reports of reward dependence in hippocampal neurons. The higher incidence of the latter responses in the temporal ("ventral") hippocampus is consistent with the distinctive anatomical and functional properties of this subregion.

Action Potentials↗

Psychopharmacology of conditioned reward: evidence for a rewarding signal at D1-like dopamine receptors.

A neutral stimulus can acquire conditioned rewarding properties through association with an intrinsically rewarding stimulus. The acquisition of responding for conditioned rewards requires that environmental stimuli and reward processes interact in a highly specific manner; analyses of this phenomenon may provide valuable insight into the processes that underlie reward-related learning. The effects of dopaminergic agents with different mechanisms of action in this paradigm have revealed several interesting dissociations suggesting that a rewarding signal at dopamine D1-like receptors may mediate both the acquisition of rewarding properties by neutral stimuli and their ability to control behavior. Dopamine-induced changes in responding for conditioned reward are susceptible to modulation by other neurotransmitter systems. In many cases, the molecular and cellular bases of these interactions support the notion that signaling through D1-like receptors is critical for a conditioned reward to direct responding. The model outlined in this paper reflects a comprehensive integration of the existing literature in the field, and has several implications that are readily testable by future research. Moreover, given the known biochemical coupling of D1-like receptors, this model may help in characterizing the sequence of intracellular events, from signal transduction to possible transcriptional and/or translational regulation, that give rise to the acquisition of rewarding properties by neutral stimuli.

Animals↗

Electrical stimulation of the medial prefrontal cortex supports both 'pure reward' and 'reward-escape' behavior in rats.

In female Sprague-Dawley rats, 8 of 12 medial prefrontal cortex (MPFC) sites that yielded criterion self-stimulation behavior supported only self-stimulation, i.e. were 'pure reward' in type. The remaining 4 sites supported behavior to escape from experimenter-administered stimulation of the same parameters as well, i.e. were 'reward-escape' in type. 'Pure reward' and 'reward-escape' sites in the MPFC were distinguished by both the magnitude and temporal form of the escape response functions generated, and by the prevalence of 'pounce-back', a vigorous and repetitive barpressing during the 3-s MPFC stimulation-escape interval produced by an effective barpress. The finding that both 'pure reward' and 'reward-escape' patterns of behavior can be elicited by stimulation of the MPFC provides a basis for further assessment of similarities and differences in medial prefrontal cortical and lateral hypothalamic (LH) 'reward' systems. It is suggested that 'reward-escape' in the MPFC may be mediated by the activity of 'reward' neurons which respond to stimulus offset, rather than by a secondary aversive process as is proposed to underlie 'reward-escape' in the LH.

Animals↗

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is 'no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the 'taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'.

Animals↗

Anticipation of reward in a nonaversive differential conditioning paradigm and the brain reward system: an event-related fMRI study.

Findings from animal as well as human neuroimaging studies suggest that reward delivery is associated with the activation of subcortical limbic and prefrontal brain regions, including the thalamus, the striatum, the anterior cingulate and the prefrontal cortex. The aim of the present study was to explore if these reward-sensitive regions are also activated during the anticipation of reinforcers that vary with regard to their motivational value. A differential conditioning paradigm was performed, with the presentation of a rewarded reaction time task serving as the unconditioned stimulus (US). Depending on their reaction time, subjects were given (or not given) a monetary reward, or were presented with a verbal feedback consisting of being fast or slow. In a third control condition no task needed to be executed. Each of the three conditions was introduced by a different visual cue (CS). Brain activation of 27 subjects was recorded using event-related functional magnetic resonance imaging. The results showed significant activation of the substantia nigra, thalamic, striatal, and orbitofrontal brain regions as well as of the insula and the anterior cingulate during the presentation of a CS signalling a rewarded task. The anticipation of a monetary reward produced stronger activation in these regions than the anticipation of positive verbal feedback. The results are interpreted as reflecting the motivation-dependent reactivity of the brain reward system with highly motivating stimuli (monetary reward) leading to a stronger activation than those less motivating ones (verbal reward).

Adult↗

Preference for unpredictable food rewards occurs with high proportion of reinforced trials or alcohol if rewards are not delayed.

Organisms typically prefer situations where reward and nonreward are predictable rather than unpredictable. Although many theories can account for this result (e.g., information theory and delay-reduction theory), a recently developed mathematical model (DMOD) also predicts that subjects prefer the unpredictable reward situation under conditions that substantially decrease aversiveness of unpredictable nonreward (Daly & Daly, 1982). Because a high proportion of reinforced trials (lenient schedule) and alcohol injections decrease aversive conditioning, these variables were tested with rats in five E-maze experiments. A choice to one side of the maze resulted in a stimulus uncorrelated with reward outcome (unpredictable situation). A choice to the other side resulted in stimuli correlated with reward and nonreward (predictable situation). The stimuli were not visible until after the choice was made. A lenient reinforcement schedule resulted in preference for the unpredictable reward situation if rewards were not delayed. Alcohol resulted in preference for the unpredictable reward situation if a medium five-pellet reward was given. A lenient reinforcement schedule combined with an alcohol injection resulted in faster acquisition of the preference for the unpredictable reward situation than did a lenient schedule combined with a saline control injection. These results pose a major challenge to most theories, yet were predicted by DMOD.

Animals↗

Dissociation of the role of nucleus accumbens dopamine in responding to reward-predictive cues and waiting for reward.

The choice among behavioral options is influenced by the anticipated cost of working for the reward relative to the anticipated reward magnitude. Dopamine release in the nucleus accumbens (NAc) has been suggested to play an important role in cost/benefit computation. From a behavioral perspective, work involves two elements: the caloric expenditure of energy and the time required to complete the task. In many studies of the contribution of NAc dopamine to cost/benefit decisions, measures of work have conflated these separate elements. Here we describe a novel cued progressive delay task, an analog of the progressive ratio task that minimizes energy expenditure. In this task, rats obtain sucrose reward by entering a reward receptacle in response to a cue and remaining in the receptacle for a required wait that is increased after each successful trial. In an experiment in which the magnitude of reward was varied across sessions, the animals' fail point (maximum wait achieved) was correlated with the amount of reward delivered. Microinjection of D1 or D2 dopamine receptor antagonists into the NAc did not affect the length of time animals were willing to wait for reward (fail point), but did reduce the proportion of cues to which the animal responded. These results suggest that waiting for reward without increased caloric energy expenditure does not require NAc dopamine.

Animals↗

Potentiation of brain stimulation reward by weight loss: evidence for functional heterogeneity in brain reward circuitry.

Physiological need states can influence goal-directed behavior by modulating the neural circuitry underlying the rewarding effects of stimuli and behaviors. Direct electrical stimulation of this circuitry produces a powerful rewarding effect, which is called brain stimulation reward. Chronic food restriction resulting in body weight loss potentiates brain stimulation reward, but in only in a subset of cases. This could reflect individual differences between rats or subtle difference in electrode location that lead to differential excitation of functionally different components of the neural circuitry underlying brain stimulation reward. To distinguish between these views, the influence of chronic food restriction on brain stimulation reward was assessed in rats bearing multiple stimulation electrodes. In 5 of 13 cases, the rewarding effects produced by stimulating different sites in the same rat were altered differentially by weight loss. This finding is interpreted in terms of the subdivision of brain reward circuitry along functional and anatomical lines.

Analysis of Variance↗

Lesions of the medial shell of the nucleus accumbens impair rats in finding larger rewards, but spare reward-seeking behavior.

The goal of this study was to help better understand the importance of the nucleus accumbens (Nacc) in the processing of position and reward value information for goal-directed orientation behaviors. Sixteen male Long-Evans rats, under partial water deprivation, were trained in a plus-maze to find water rewards in the respective arms which were lit in pseudo-random sequence (training trials). Each day one reward arm was selected to deliver six drops of water (at 1 s intervals) the others provided only one drop per visit. After 32 visits, probe trials were intermittently presented among training trials. Here, all four arms were lit and offered the previously assigned reward. The rats rapidly learned to go to the highly rewarded arm. Six trained rats were given bilateral electrolytic lesions in the Nacc shell, two others had unilateral lesions and eight had sham operations (with approved protocols). Field potentials evoked by fornix stimulation were recorded in lesion electrodes to guide placements. Only the lesioned rats showed significant impairments (P<0.05) in selecting the greater reward on probe trials. However on training trials, lesioned (and sham-operated) rats made only rare errors. While the motivation to drink and the capacity for cue-guided goal-directed orientation behavior was spared, lesioned rats were impaired in learning the location of the larger reward. The accumbens lesions apparently impaired integration of position and reward value information, consistent with anatomical and electrophysiological data showing the convergence of hippocampal, amygdalar, ventral tegmental area (VTA) and prefrontal cortical inputs there.

Amygdala↗

Self-stimulating rats combine subjective reward magnitude and subjective reward rate multiplicatively.

For rats that bar pressed for intracranial electrical stimulation in a 2-lever matching paradigm with concurrent variable interval schedules of reward, the authors found that the time allocation ratio is based on a multiplicative combination of the ratio of subjective reward magnitudes and the ratio of the rates of reward. Multiplicative combining was observed in a range covering approximately 2 orders of magnitude in the ratio of the rates of reward from about 1:10 to 10:1) and an order of magnitude change in the size of rewards. After determining the relation between the pulse frequency of stimulation and subjective reward magnitude, the authors were able to predict from knowledge of the subjective magnitudes of the rewards and the obtained relative rates of reward the subject's time allocation ratio over a range in which it varied by more than 3 orders of magnitude.

Action Potentials↗

Reward versus performance in self-stimulation: electrode-specific effects of alpha-methyl-p-tyrosine on reward in the rat.

The hypothesis that alpha-methyl-p-tyrosine (AMPT), an inhibitor of catecholamine synthesis, reduces brain stimulation reward was tested, using a measure of reward previously shown to be relatively unaffected by variables that alter performance but not reward. The rewarding effectiveness of stimulation was determined by the location of the sharp rise in the function relating running speed in an alley to the number of pulses received as a reward. For some electrodes, AMPT depressed self-stimulation performance (speed of running) without producing any sizable effect on the measure of reward (location of rise). For other electrodes, the rewarding effectiveness of the stimulation was greatly reduced by AMPT and restored by L-dopa. These opposing results could be repeatedly demonstrated on different electrodes in the same rat. The electrode-specific differential sensitivity to AMPT suggests neurochemically disparate substrates for reward.

Animals↗