The role of dopamine in the dorsomedial striatum in general and outcome-selective Pavlovian-instrumental transfer

Pavlovian stimuli predictive of appetitive outcomes can influence the selection and initiation of instrumental behaviour. For instance, Pavlovian stimuli can act to enhance those actions with which they share an outcome, but not others with which they do not share an outcome, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (PIT). Furthermore, Pavlovian stimuli can invigorate an action by inducing a general appetitive arousal that elevates instrumental responding, a phenomenon termed general PIT. The dorsomedial striatum has been implicated in outcome-selective, but not general PIT. However, the role of dopamine (DA) signals in this subregion in mediating PIT is unknown. Here we examined in rats the effects of a 6-hydroxydopamine-induced DA depletion of the anterior (aDMS) or posterior (pDMS) subregion of the dorsomedial striatum on outcome-selective and general PIT as well as on instrumental performance on a FR-5 schedule (five lever presses earned one pellet). Results demonstrate that aDMS and pDMS DA depletions compromised the rate of responding on a FR-5 schedule, suggesting that DA signals in the dorsomedial striatum are necessary to maintain high rates of instrumental responding. By contrast, aDMS and pDMS DA depletions did not affect general PIT, suggesting that DA signals in the dorsomedial striatum do not mediate general activating effects of reward-predictive stimuli to invigorate instrumental responding. Furthermore, aDMS DA depletions did not impair outcome-selective PIT, while pDMS DA depletions had no or only minor effects. Thus, DA signals in the DMS may not be involved in mediating the specific cueing effects of reward-predictive stimuli.     

The role of the dorsomedial striatum in instrumental conditioning

Considerable evidence suggests that, in instrumental conditioning, rats learn the relationship between actions and their specific consequences or outcomes. The present study examined the role of the dorsomedial striatum (DMS) in this type of learning after excitotoxic lesions and reversible, muscimol-induced inactivation. In three experiments, rats were first trained to press two levers for distinct outcomes, and then tested after training using a variety of behavioural assays that have been established to detect action-outcome learning. In Experiment 1, pre-training lesions of the posterior DMS abolished the sensitivity of rats' instrumental performance to both outcome devaluation and contingency degradation when tested in extinction, whereas lesions of the anterior DMS had no effect. In Experiment 2, both pre-training and post-training lesions of the posterior DMS were equally effective in reducing the sensitivity of performance both to devaluation and degradation treatments. In Experiment 3, the infusion of muscimol into the posterior DMS selectively abolished sensitivity of performance to devaluation and contingency degradation without impairing the ability of rats to discriminate either the instrumental actions performed or the identity of the earned outcomes. Taken together, these results suggest that the posterior region of the DMS is a crucial neural substrate for the acquisition and expression of action-outcome associations in instrumental conditioning.     

Amygdala central nucleus interacts with dorsolateral striatum to regulate the acquisition of habits

The role of the amygdala central nucleus (CeN) in habit learning was assessed in two experiments. First, we examined the effects of bilateral lesions of the anterior CeN on an overtraining-induced lever press habit evaluated using an outcome devaluation protocol. Overtraining generated habitual performance and rendered sham lesioned rats insensitive to outcome devaluation, an effect that was also found in rats given control lesions of the posterior CeN. In contrast, rats with lesions of the anterior CeN did not show normal habit acquisition and their performance remained goal-directed and sensitive to outcome devaluation. Nevertheless, lesions of either the posterior or the anterior CeN abolished the general excitatory influence of a Pavlovian conditioned stimulus on instrumental performance. Second, we assessed the functional interaction between the CeN and dorsolateral striatum (DLS), a region previously implicated in the acquisition of habits, using asymmetrical lesions to disconnect these structures. Rats were given a unilateral lesion of anterior CeN and a unilateral lesion of the DLS, made either ipsilateral (control) or contralateral (disconnection) to the CeN lesion, and given overtraining followed by outcome devaluation. Although the ipsilateral lesioned rats were insensitive to devaluation, the contralateral CeN-DLS lesion impaired habit acquisition, rendering performance sensitive to the devaluation treatment. These results are the first to implicate the CeN and its connection with a circuit involving DLS in habit learning. They imply that, in instrumental conditioning, regions of amygdala parse the instrumental outcome into the reward and reinforcement signals mediating goal-directed and habitual actions, respectively.     

Modulation of cue‐triggered reward seeking by cholinergic signaling in the dorsomedial striatum

The dorsomedial striatum (DMS) has been strongly implicated in flexible, outcome‐based decision making, including the outcome‐specific Pavlovian‐to‐instrumental transfer effect (PIT), which measures the tendency for a reward‐predictive cue to preferentially motivate actions that have been associated with the predicted reward over actions associated with different rewards. Although the neurochemical underpinnings of this effect are not well understood, there is growing evidence that striatal acetylcholine signaling may play an important role. This study investigated this hypothesis by assessing the effects of intra‐DMS infusions of the nicotinic antagonist mecamylamine or the muscarinic antagonist scopolamine on expression of specific PIT in rats. These treatments produced dissociable behavioral effects. Mecamylamine infusions enhanced rats’ tendency to use specific cue‐elicited outcome expectations to select whichever action was trained with the predicted outcome, relative to their performance when tested after vehicle infusions. In contrast, scopolamine infusions appeared to render instrumental performance insensitive to this motivational influence of reward‐paired cues. These drug treatments had no detectable effect on conditioned food cup approach behavior, indicating that they selectively perturbed cue‐guided action selection without producing more wide‐ranging alterations in behavioral control. Our findings reveal an important role for DMS acetylcholine signaling in modulating the impact of cue‐evoked reward expectations on instrumental action selection.     

Orbitofrontal inactivation impairs reversal of Pavlovian learning by interfering with ‘disinhibition’ of responding for previously unrewarded cues

Orbitofrontal cortex (OFC) is critical for reversal learning. Reversal deficits are typically demonstrated in complex settings that combine Pavlovian and instrumental learning. Yet recent work has implicated the OFC specifically in behaviors guided by cues and the features of the specific outcomes they predict. To test whether the OFC is important for reversing such Pavlovian associations in the absence of confounding instrumental requirements, we trained rats on a simple Pavlovian task in which two auditory cues were presented, one paired with a food pellet reward and the other presented without reward. After learning, we reversed the cue–outcome associations. For half the rats, OFC was inactivated prior to each reversal session. Inactivation of OFC impaired the ability of the rats to reverse conditioned responding. This deficit reflected the inability of inactivated rats to develop normal responding for the previously unrewarded cue; inactivation of OFC had no impact on the ability of the rats to inhibit responding to the previously rewarded cue. These data show that OFC is critical to reversal of Pavlovian responding, and that the role of OFC in this behavior cannot be explained as a simple deficit in response inhibition. Furthermore, the contrast between the normal inhibition of responding, reported here, and impaired inhibition of responding during Pavlovian over‐expectation, reported previously, suggests the novel hypothesis that OFC may be particularly critical for learning (or behavior) when it requires the subject to generate predictions about outcomes by bringing together or integrating disparate pieces of associative information.     

Control over a stressor involves the posterior dorsal striatum and the act/outcome circuit

Controllable/escapable tailshocks (ESs) do not produce the behavioral and neurochemical outcomes produced by equal yoked uncontrollable/inescapable tailshocks (ISs). The prelimbic cortex is known to play a key role in mediating the protective effects of control. The concepts of act/outcome learning and control seem similar, and act/outcome learning is mediated by a circuit involving the prelimbic cortex and posterior dorsomedial striatum (DMS). Thus, we tested the involvement of the DMS in the protective effect of ES, in rats. First, we examined Fos immunoreactivity in both the DMS and dorsolateral striatum (DLS) after ES and yoked IS. We then investigated the effect of blocking DMS or DLS N‐methyl‐d ‐aspartate receptors with the specific antagonist D‐(‐)‐2‐amino‐5‐phosphopentanoic acid (D‐AP5) on the release of dorsal raphe nucleus serotonin (5‐HT) during ES, as well as on the level of anxiety produced by the ES experience 24 h later. ES, but not yoked IS, produced a large increase of Fos activity in the DMS. Consistent with the Fos data, D‐AP5 in the DMS, but not in the DLS, prevented the inhibition of dorsal raphe nucleus 5‐HT release normally produced by ES. Furthermore, D‐AP5 administered into the DMS before ES, but not into the DLS, increased anxiety 24 h later, leading to levels similar to those produced by IS. These results suggest that, as with appetitive act/outcome contingency learning, the protective effects of behavioral control over a stressor require the DMS.     

Avoidance‐based human Pavlovian‐to‐instrumental transfer

The Pavlovian‐to‐instrumental transfer (PIT) paradigm probes the influence of Pavlovian cues over instrumentally learned behavior. The paradigm has been used extensively to probe basic cognitive and motivational processes in studies of animal learning. More recently, PIT and its underlying neural basis have been extended to investigations in humans. These initial neuroimaging studies of PIT have focused on the influence of appetitively conditioned stimuli on instrumental responses maintained by positive reinforcement, and highlight the involvement of the striatum. In the current study, we sought to understand the neural correlates of PIT in an aversive Pavlovian learning situation when instrumental responding was maintained through negative reinforcement. Participants exhibited specific PIT, wherein selective increases in instrumental responding to conditioned stimuli occurred when the stimulus signaled a specific aversive outcome whose omission negatively reinforced the instrumental response. Additionally, a general PIT effect was observed such that when a stimulus was associated with a different aversive outcome than was used to negatively reinforce instrumental behavior, the presence of that stimulus caused a non‐selective increase in overall instrumental responding. Both specific and general PIT behavioral effects correlated with increased activation in corticostriatal circuitry, particularly in the striatum, a region involved in cognitive and motivational processes. These results suggest that avoidance‐based PIT utilizes a similar neural mechanism to that seen with PIT in an appetitive context, which has implications for understanding mechanisms of drug‐seeking behavior during addiction and relapse.     

Impaired sensitivity to Pavlovian stimulus-outcome learning after excitotoxic lesion of the ventrolateral neostriatum

Subregions of the neostriatum have been dissociated according to their role in specific aspects of instrumental and Pavlovian learning. While the dorsomedial striatum is critical for the acquisition of goal-directed behaviours, the dorsolateral striatum has been shown to be necessary for the formation of habits. The ventrolateral subregion of the neostriatum (VLS), which supports a distinct cortical-subcortical circuitry, has not, however, been investigated within these paradigms. Thus, to determine whether the VLS is involved in the formation of action-outcome associations, Experiment 1 used a sensory specific devaluation procedure to assess the role of the VLS in the acquisition of goal-directed instrumental behaviours. Experiment 2 examined the ability of VLS lesion rats to form Pavlovian-outcome associations and to adjust responses according to the current incentive value of the reward by using a Pavlovian approach task, while Experiment 3 assessed the development and expression of habitual responding. Results indicated an intact ability of both sham and VLS lesion rats to form instrumental action-outcome associations and to use such representations to direct behaviour according to the incentive value of the outcome. VLS lesion rats equally demonstrated intact development of habitual lever press responses, which were shown to be impervious to lithium chloride devaluation treatment. VLS lesion rats did, however, demonstrate aberrant goal-directed responding to a Pavlovian auditory stimulus after outcome specific devaluation treatment. Thus, these results indicate that the VLS is necessary for utilising a representation of a Pavlovian stimulus-outcome association to direct behaviour according to the current incentive value of a reward.     

General and outcome-specific forms of Pavlovian-instrumental transfer: the effect of shifts in motivational state and inactivation of the ventral tegmental area

This study compared the contribution of the general activating and specific cueing properties of Pavlovian stimuli to Pavlovian-instrumental transfer (PIT) and the role of the ventral tegmental area (VTA) in mediating these effects. In Experiment 1, hungry rats initially received Pavlovian training, in which three distinct auditory stimuli predicted the delivery of three different food outcomes. Next, the rats were trained to perform two instrumental actions, each earning a unique outcome selected from the three used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Presentation of a stimulus that had been paired with the same outcome as an action increased its performance relative to the other action, demonstrating that PIT effects can be outcome selective. In contrast, presentation of the stimulus that predicted the outcome that was not earned during instrumental training facilitated the performance of both actions indiscriminately. This effect, but not the outcome-selective effect, was abolished by a shift from a hungry to a relatively sated state. Experiment 2 examined the effects of inactivation of the VTA on these two forms of PIT. VTA inactivation was found to attenuate PIT but, unlike satiety, did not appear to differentially affect the general or the outcome-selective forms of PIT. The VTA appears therefore to play an important but general role in the initiation of instrumental actions, enabling cues to influence performance whether they enhance responding by changes in arousal or by retrieving particular actions based on their consequences.     

The response strategy and the place strategy in a plus‐maze have different sensitivities to devaluation of expected outcome

Previous studies have suggested that spatial navigation can be achieved with at least two distinct learning processes, involving either cognitive map‐like representations of the local environment, referred to as the “place strategy”, or simple stimulus‐response (S‐R) associations, the “response strategy”. A similar distinction between cognitive/behavioral processes has been made in the context of non‐spatial, instrumental conditioning, with the definition of two processes concerning the sensitivity of a given behavior to the expected value of its outcome as well as to the response‐outcome contingency (“goal‐directed action” and “S‐R habit”). Here we investigated whether these two versions of dichotomist definitions of learned behavior, one spatial and the other non‐spatial, correspond to each other in a formal way. Specifically, we assessed the goal‐directed nature of two navigational strategies, using a combination of an outcome devaluation procedure and a spatial probe trial frequently used to dissociate the two navigational strategies. In Experiment 1, rats trained in a dual‐solution T‐maze task were subjected to an extinction probe trial from the opposite start arm, with or without prefeeding‐induced devaluation of the expected outcome. We found that a non‐significant preference for the place strategy in the non‐devalued condition was completely reversed after devaluation, such that significantly more animals displayed the use of the response strategy. The result suggests that the place strategy is sensitive to the expected value of the outcome, while the response strategy is not. In Experiment 2, rats with hippocampal lesions showed significant reliance on the response strategy, regardless of whether the expected outcome was devalued or not. The result thus offers further evidence that the response strategy conforms to the definition of an outcome‐insensitive, habitual form of instrumental behavior. These results together attest a formal correspondence between two types of dual‐process accounts of animal learning and behavior.     

Differential representation of Pavlovian–instrumental transfer by prefrontal cortex subregions and striatum

Environmental cues that once predicted reward can restore extinguished behavior directed toward that reward. This process may be modeled by the Pavlovian–instrumental transfer (PIT) paradigm where a previously learned Pavlovian conditioned stimulus (CS) elicits a representation of the reward associated with that CS, prompts motivation toward the absent reward, and triggers an instrumental action. We recorded in the medial and orbital prefrontal cortex (mPFC and OFC) and dorsal striatum (DS) of freely moving rats during PIT and found that a Pavlovian CS, as compared with neutral or no stimuli, amplified the phasic neuronal responses to instrumental nosepokes ('transfer' event). In mPFC and OFC, but not the DS, representation of the transfer event correlated with the strength of PIT behavior. Neurons in all three regions showed CS-selective amplification of Pavlovian approaches toward the reward delivery site. Whereas striatal neurons represented transfer and approach behavior through mostly segregated neuronal subsets, overlapping subsets represented these events in the mPFC and OFC. These findings suggest that parallel phasic activation of mPFC and OFC neuronal subsets participates in the transfer from Pavlovian incentives to instrumental actions.     

Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning

Habits are controlled by antecedent stimuli rather than by goal expectancy. Interval schedules of feedback have been shown to generate habits, as revealed by the insensitivity of behaviour acquired under this schedule to outcome devaluation treatments. Two experiments were conducted to assess the role of the dorsolateral striatum in habit learning. In Experiment 1, sham operated controls and rats with dorsolateral striatum lesions were trained to press a lever for sucrose under interval schedules. After training, the sucrose was devalued by inducing taste aversion to it using lithium chloride, whereas saline injections were given to the controls. Only rats given the devaluation treatment reduced their consumption of sucrose and this reduction was similar in both the sham and the lesioned groups. All rats were then returned to the instrumental chamber for an extinction test, in which the lever was extended but no sucrose was delivered. In contrast to sham operated controls, rats with dorsolateral striatum lesions refrained from pressing the lever if the outcome was devalued. To assess the specificity of the role of dorsolateral striatum in this effect a second experiment was conducted in which a group with lesions of dorsomedial striatum was added. In relation now to both the sham and the dorsomedial lesioned groups, only rats with lesions of dorsolateral striatum significantly reduced responding after outcome devaluation. In conclusion, this study provides direct evidence that the dorsolateral striatum is necessary for habit formation. Furthermore, it suggests that, when the habit system is disrupted, control over instrumental performance reverts to the system controlling the performance of goal-directed instrumental actions.     

Region‐specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6‐AP ubiquitin protein ligase Ube3a (Ube3a^m?/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum‐dependent task. We used whole‐cell patch‐clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a^m?/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild‐type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a^m?/p+ mice were more habitual, impervious to changes in outcome value and action–outcome contingency. In the DMS, but not the DLS, Ube3a^m?/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.     

Lesions of dorsal striatum eliminate lose‐switch responding but not mixed‐response strategies in rats

We used focal brain lesions in rats to examine how dorsomedial (DMS) and dorsolateral (DLS) regions of the striatum differently contribute to response adaptation driven by the delivery or omission of rewards. Rats performed a binary choice task under two modes: one in which responses were rewarded on half of the trials regardless of choice; and another ‘competitive’ one in which only unpredictable choices were rewarded. In both modes, control animals were more likely to use a predictable lose‐switch strategy than animals with lesions of either DMS or DLS. Animals with lesions of DMS presumably relied more on DLS for behavioural control, and generated repetitive responses in the first mode. These animals then shifted to a random response strategy in the competitive mode, thereby performing better than controls or animals with DLS lesions. Analysis using computational models of reinforcement learning indicated that animals with striatal lesions, particularly of the DLS, had blunted reward sensitivity and less stochasticity in the choice mechanism. These results provide further evidence that the rodent DLS is involved in rapid response adaptation that is more sophisticated than that embodied by the classic notion of habit formation driven by gradual stimulus–response learning.     

Blockade of NMDA receptors in the dorsomedial striatum prevents action-outcome learning in instrumental conditioning

Although there is consensus that instrumental conditioning depends on the encoding of action-outcome associations, it is not known where this learning process is localized in the brain. Recent research suggests that the posterior dorsomedial striatum (pDMS) may be the critical locus of these associations. We tested this hypothesis by examining the contribution of N-methyl-D-aspartate receptors (NMDARs) in the pDMS to action-outcome learning. Rats with bilateral cannulae in the pDMS were first trained to perform two actions (left and right lever presses), for sucrose solution. After the pre-training phase, they were given an infusion of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (APV, 1 mg/mL) or artificial cerebral spinal fluid (ACSF) before a 30-min session in which pressing one lever delivered food pellets and pressing the other delivered fruit punch. Learning during this session was tested the next day by sating the animals on either the pellets or fruit punch before assessing their performance on the two levers in extinction. The ACSF group selectively reduced responding on the lever that, in training, had earned the now devalued outcome, whereas the APV group did not. Experiment 2 replicated the effect of APV during the critical training session but found no effect of APV given after acquisition and before test. Furthermore, Experiment 3 showed that the effect of APV on instrumental learning was restricted to the pDMS; infusion into the dorsolateral striatum did not prevent learning. These experiments provide the first direct evidence that, in instrumental conditioning, NMDARs in the dorsomedial striatum are involved in encoding action-outcome associations.     

Dissociable corticostriatal circuits underlie goal‐directed vs. cue‐elicited habitual food seeking after satiation: evidence from a multimodal MRI study

The present multimodal MRI study advances our understanding of the corticostriatal circuits underlying goal‐directed vs. cue‐driven, habitual food seeking. To this end, we employed a computerized Pavlovian‐instrumental transfer paradigm. During the test phase, participants were free to perform learned instrumental responses (left and right key presses) for popcorn and Smarties outcomes. Importantly, prior to this test half of the participants had been sated on popcorn and the other half on Smarties – resulting in a reduced desirability of those outcomes. Furthermore, during a proportion of the test trials, food‐associated Pavlovian cues were presented in the background. In line with previous studies, we found that participants were able to perform in a goal‐directed manner in the absence of Pavlovian cues, meaning that specific satiation selectively reduced responding for that food. However, presentation of Pavlovian cues biased choice toward the associated food reward regardless of satiation. Functional MRI analyses revealed that, in the absence of Pavlovian cues, posterior ventromedial prefrontal cortex tracked outcome value. In contrast, during cued trials, the BOLD signal in the posterior putamen differentiated between responses compatible and incompatible with the cue‐associated outcome. Furthermore, we identified a region in ventral amygdala showing relatively strong functional connectivity with posterior putamen during the cued trials. Structural MRI analyses provided converging evidence for the involvement of corticostriatal circuits: diffusion tensor imaging data revealed that connectivity of caudate‐seeded white‐matter tracts to the ventromedial prefrontal cortex predicted responding for still‐valuable outcomes; and gray matter integrity in the premotor cortex predicted individual Pavlovian cueing effects.     

Altered monoamine levels in the dorsal striatum of the rat are associated with alterations in behavioural selection and motivation following peripheral nerve injury and acute stress

Chronic neuropathic pain and psychological stress interact to compromise goal‐directed control over behaviour following mild psychological stress. The dorsomedial (DMS) and dorsolateral (DLS) striatum in the rat are crucial for the expression of goal‐directed and habitual behaviours, respectively. This study investigated whether changes in monoamine levels in the DMS and DLS following nerve injury and psychological stress reflect these behavioural differences. Neuropathic pain was induced by a chronic constriction injury (CCI) of the sciatic nerve in Sprague–Dawley rats. Acute stress was induced using a 15‐min restraint. Behavioural flexibility was assessed using the outcome devaluation paradigm. Noradrenaline, serotonin, dopamine and associated metabolites were measured bilaterally from the DLS and DMS. In uninjured rats, restraint increased dopaminergic markers in the left and serotonergic markers in the right of both the DMS and DLS, indicating a possible left hemisphere‐mediated dominance. CCI led to a slightly different lateralised effect, with a larger effect in the DMS than in the DLS. Individual differences in behavioural flexibility following CCI negatively correlated with dopaminergic markers in the right DLS, but positively correlated with these markers in the left DMS. A combination of CCI and restraint reduced behavioural flexibility, which was associated with the loss of the left/DMS dominance. These data suggest that behavioural flexibility following psychological stress or pain is associated with a left hemisphere dominance within the dorsal striatum. The loss of behavioural flexibility following the combined stressors is then associated with a transition from left to right, and DMS to DLS dominance.     

Dorsomedial and dorsolateral striatum exhibit distinct phasic neuronal activity during alcohol self‐administration in rats

The development of alcoholism may involve a shift from goal‐directed to habitual drinking. These action control systems are distinct in the dorsal striatum, with the dorsomedial striatum (DMS) important for goal‐directed behavior and the dorsolateral striatum (DLS) required for habit formation. Goal‐directed behavior can be modeled in rats with a fixed ratio (FR) reinforcement schedule, while a variable interval (VI) schedule promotes habitual behavior (e.g. insensitivity to contingency degradation). Using extracellular recordings from chronically implanted electrodes, we investigated how DMS and DLS neurons encoded lever‐press responses and conditioned cues during operant alcohol self‐administration in these two models. In rats self‐administering 10% alcohol on an FR schedule, the DMS neuronal population showed increased firing at the onset of start‐of‐session stimuli. During self‐administration, the most prominent phasic firing patterns in the DMS occurred at the time of reinforcement and reinforcement‐associated cues, while the most prominent phasic activity in the DLS surrounded the lever response. Neural recordings from an additional cohort of rats trained on a VI schedule revealed a similar pattern of results; however, phasic changes in firing were smaller and differences between the medial and lateral dorsal striatum were less marked. In summary, the DMS and DLS exhibited overlapping but specialized phasic firing patterns: DMS excitations were typically time‐locked to reinforcement, while DLS excitations were generally associated with lever responses. Furthermore, the regional specificities and magnitudes of phasic firing differed between reinforcement schedules, which may reflect differences in behavioral flexibility, reward expectancy and the action sequences required to procure reinforcement.     

Dorsolateral neostriatum contribution to incentive salience: opioid or dopamine stimulation makes one reward cue more motivationally attractive than another

Pavlovian cues for rewards can become attractive incentives: approached and ‘wanted’ as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re‐encounter by simultaneous activation of brain limbic circuitry. Here it was reported that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign‐tracking vs. goal‐tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in the DLS of sign‐tracker individuals selectively enhanced their sign‐tracking attraction toward the reward‐predictive lever cue. By contrast, DAMGO or amphetamine in the DLS of goal‐trackers selectively enhanced prepotent attraction toward the reward‐proximal cue of sucrose dish. Amphetamine also enhanced goal‐tracking in some sign‐tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits, was suggested by: (i) sign‐trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection; and (ii) DAMGO in the DLS also made sign‐trackers work harder on a new instrumental nose‐poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, the current results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet.     

Astrocytic equilibrative nucleoside transporter type 1 upregulations in the dorsomedial and dorsolateral striatum distinctly coordinate goal‐directed and habitual ethanol‐seeking behaviours in mice

Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours.