Heterogeneity in striatal dopamine circuits: Form and function in dynamic reward seeking.

The striatal dopamine system has long been studied in the context of reward learning, motivation, and movement. Given the prominent role dopamine plays in a variety of adaptive behavioral states, as well as diseases like addiction, it is essential to understand the full complexity of dopamine neurons and the striatal systems they target. A growing number of studies are uncovering details of the heterogeneity in dopamine neuron subpopulations. Here, we review that work to synthesize current understanding of dopamine system heterogeneity across three levels, anatomical organization, functions in behavior, and modes of action, wherein we focus on signaling profiles and local mechanisms for modulation of dopamine release. Together, these studies reveal new and emerging dimensions of the striatal dopamine system, informing its contribution to dynamic motivational and decision-making processes.

Cue-evoked cocaine "craving": role of dopamine in the accumbens core.

Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state ("wanting" or "craving") that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self-administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process.

Sensory Cues Potentiate VTA Dopamine Mediated Reinforcement.

Sensory cues are critical for shaping decisions and invigorating actions during reward seeking. Dopamine neurons in the ventral tegmental area (VTA) are central in this process, supporting associative learning in Pavlovian and instrumental settings. Studies of intracranial self-stimulation (ICSS) behavior, which show that animals will work hard to receive stimulation of dopamine neurons, support the notion that dopamine transmits a reward or value signal to support learning. Recent studies have begun to question this, however, emphasizing dopamine's value-free functions, leaving its contribution to behavioral reinforcement somewhat muddled. Here, we investigated the role of sensory stimuli in dopamine-mediated reinforcement, using an optogenetic ICSS paradigm in tyrosine hydroxylase (TH)-Cre rats. We find that while VTA dopamine neuron activation in the absence of explicit external cues is sufficient to maintain robust self-stimulation, the presence of cues dramatically potentiates ICSS behavior. Our results support a framework where dopamine can have some base value as a reinforcer, but the impact of this signal is modulated heavily by the sensory learning context.

Basolateral amygdala population coding of a cued reward seeking state depends on orbitofrontal cortex.

Basolateral amygdala (BLA) neuronal responses to conditioned stimuli are closely linked to the expression of conditioned behavior. An area of increasing interest is how the dynamics of BLA neurons relate to evolving behavior. Here, we recorded the activity of individual BLA neurons across the acquisition and extinction of conditioned reward seeking and employed population-level analyses to assess ongoing neural dynamics. We found that, with training, sustained cue-evoked activity emerged that discriminated between the CS+ and CS- and correlated with conditioned responding. This sustained population activity continued until reward receipt and rapidly extinguished along with conditioned behavior during extinction. To assess the contribution of orbitofrontal cortex (OFC), a major reciprocal partner to BLA, to this component of BLA neural activity, we inactivated OFC while recording in BLA and found blunted sustained cue-evoked activity in BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in BLA also reduced reward seeking. Our data suggest that sustained cue-driven activity in BLA, which in part depends on OFC input, underlies conditioned reward-seeking states.

Valence ambiguity dynamically shapes striatal dopamine heterogeneity.

Adaptive decision making relies on dynamic updating of learned associations where environmental cues come to predict positive and negatively valenced stimuli, such as food or threat. Flexible cue-guided behaviors depend on a network of brain systems, including dopamine signaling in the striatum, which is critical for learning and maintenance of conditioned behaviors. Critically, it remains unclear how dopamine signaling encodes multi-valent, dynamic learning contexts, where positive and negative associations must be rapidly disambiguated. To understand this, we employed a Pavlovian discrimination paradigm, where cues predicting positive and negative outcomes were intermingled during conditioning sessions, and their meaning was serially reversed across training. We found that rats readily distinguished these cues, and updated their behavior rapidly upon valence reversal. Using fiber photometry, we recorded dopamine signaling in three major striatal subregions -,the dorsolateral striatum (DLS), the nucleus accumbens core, and the nucleus accumbens medial shell - and found heterogeneous responses to positive and negative conditioned cues and their predicted outcomes. Valence ambiguity introduced by cue reversal reshaped striatal dopamine on different timelines: nucleus accumbens core and shell signals updated more readily than those in the DLS. Together, these results suggest that striatal dopamine flexibly encodes multi-valent learning contexts, and these signals are dynamically modulated by changing contingencies to resolve ambiguity about the meaning of environmental cues.

Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning.

Environmental cues, through Pavlovian learning, become conditioned stimuli that invigorate and guide animals toward acquisition of rewards. Dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SNC) are crucial for this process. Dopamine neurons are embedded in a reciprocally connected network with their striatal targets, the functional organization of which remains poorly understood. Here, we investigated how learning during optogenetic Pavlovian cue conditioning of VTA or SNC dopamine neurons directs cue-evoked behavior and shapes subregion-specific striatal dopamine dynamics. We used a fluorescent dopamine biosensor to monitor dopamine in the nucleus accumbens (NAc) core and shell, dorsomedial striatum (DMS), and dorsolateral striatum (DLS). We demonstrate spatially heterogeneous, learning-dependent dopamine changes across striatal regions. While VTA stimulation evoked robust dopamine release in NAc core, shell, and DMS, cues predictive of this activation preferentially recruited dopamine release in NAc core, starting early in training, and DMS, late in training. Corresponding negative prediction error signals, reflecting a violation in the expectation of dopamine neuron activation, only emerged in the NAc core and DMS, and not the shell. Despite development of vigorous movement late in training, conditioned dopamine signals did not similarly emerge in the DLS, even during Pavlovian conditioning with SNC dopamine neuron activation, which elicited robust DLS dopamine release. Together, our studies show broad dissociation in the fundamental prediction and reward-related information generated by different dopamine neuron populations and signaled by dopamine across the striatum. Further, they offer new insight into how larger-scale plasticity across the striatal network emerges during Pavlovian learning to coordinate behavior.

Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning.

Environmental cues, through Pavlovian learning, become conditioned stimuli that invigorate and guide animals toward rewards. Dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) are crucial for this process, via engagement of a reciprocally connected network with their striatal targets. Critically, it remains unknown how dopamine neuron activity itself engages dopamine signals throughout the striatum, across learning. Here, we investigated how optogenetic Pavlovian cue conditioning of VTA or SNc dopamine neurons directs cue-evoked behavior and shapes subregion-specific striatal dopamine dynamics. We used a fluorescent biosensor to monitor dopamine in the nucleus accumbens (NAc) core and shell, dorsomedial striatum (DMS), and dorsolateral striatum (DLS). We demonstrate spatially heterogeneous, learning-dependent dopamine changes across striatal regions. Although VTA stimulation-evoked robust dopamine release in NAc core, shell, and DMS, predictive cues preferentially recruited dopamine release in NAc core, starting early in training, and DMS, late in training. Negative prediction error signals, reflecting a violation in the expectation of dopamine neuron activation, only emerged in the NAc core and DMS. Despite the development of vigorous movement late in training, conditioned dopamine signals did not emerge in the DLS, even during Pavlovian conditioning with SNc dopamine neuron activation, which elicited robust DLS dopamine release. Together, our studies show a broad dissociation in the fundamental prediction and reward-related information generated by VTA and SNc dopamine neuron populations and signaled by dopamine across the striatum. Further, they offer new insight into how larger-scale adaptations across the striatal network emerge during learning to coordinate behavior.

Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition.

Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.

Aversive stimuli differentially modulate real-time dopamine transmission dynamics within the nucleus accumbens core and shell.

Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems.

Sensory cues potentiate VTA dopamine mediated reinforcement.

Sensory cues are critical for shaping decisions and invigorating actions during reward seeking. Dopamine neurons in the ventral tegmental area (VTA) are critical in this process, supporting associative learning in Pavlovian and instrumental settings. Studies of intracranial self stimulation (ICSS) behavior, which show that animals will work hard to receive stimulation of dopamine neurons, support the notion that dopamine transmits a reward or value signal to support learning. Recent studies have begun to question this, however, emphasizing dopamine's value-free functions, leaving its contribution to behavioral reinforcement somewhat muddled. Here, we investigated the role of sensory stimuli in dopamine-mediated reinforcement, using an optogenetic ICSS paradigm in tyrosine hydroxylase (TH)-cre rats. We find that while VTA dopamine neuron activation in the absence of any external cueing stimulus is sufficient to maintain robust self stimulation, the presence of cues dramatically potentiates ICSS behavior. Our results support a framework where dopamine can have some base value as a reinforcer, but the impact of this signal is modulated heavily by the sensory learning context.

Hierarchical cue control of cocaine seeking in the face of cost.

RATIONALE: Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce drug seeking. OBJECTIVE: To establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. METHODS: Male and female rats were trained to self-administer cocaine on an intermittent access schedule, where brief drug-availability states were signaled by a shift in the ambient lighting of the environment, and cocaine infusions were signaled by a separate proximal discrete cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We then completed relapse tests where the drug-delivery cue was noncontingently presented alone, or in the context of dynamic drug-availability state transitions. RESULTS: Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs during conflict. In relapse tests, the ability of a proximal discrete drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. CONCLUSIONS: Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual's willingness to endure high costs associated with drug seeking. Furthermore, our studies indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.

Contexts facilitate dynamic value encoding in the mesolimbic dopamine system.

Adaptive behavior in a dynamic environment often requires rapid revaluation of stimuli that deviates from well-learned associations. The divergence between stable value-encoding and appropriate behavioral output remains a critical test to theories of dopamine's function in learning, motivation, and motor control. Yet how dopamine neurons are involved in the revaluation of cues when the world changes to alter our behavior remains unclear. Here we make use of pharmacology, in vivo electrophysiology, fiber photometry, and optogenetics to resolve the contributions of the mesolimbic dopamine system to the dynamic reorganization of reward-seeking. Male and female rats were trained to discriminate when a conditioned stimulus would be followed by sucrose reward by exploiting the prior, non-overlapping presentation of a separate discrete cue - an occasion setter. Only when the occasion setter's presentation preceded the conditioned stimulus did the conditioned stimulus predict sucrose delivery. As a result, in this task we were able to dissociate the average value of the conditioned stimulus from its immediate expected value on a trial-to-trial basis. Both the activity of ventral tegmental area dopamine neurons and dopamine signaling in the nucleus accumbens were essential for rats to successfully update behavioral responding in response to the occasion setter. Moreover, dopamine release in the nucleus accumbens following the conditioned stimulus only occurred when the occasion setter indicated it would predict reward. Downstream of dopamine release, we found that single neurons in the nucleus accumbens dynamically tracked the value of the conditioned stimulus. Together these results reveal a novel mechanism within the mesolimbic dopamine system for the rapid revaluation of motivation.

The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses.

The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value ('incentive salience') to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of pavlovian-conditioned approach behavior--one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goal-tracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus-reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties.

Dopamine Circuit Mechanisms of Addiction-Like Behaviors.

Addiction is a complex disease that impacts millions of people around the world. Clinically, addiction is formalized as substance use disorder (SUD), with three primary symptom categories: exaggerated substance use, social or lifestyle impairment, and risky substance use. Considerable efforts have been made to model features of these criteria in non-human animal research subjects, for insight into the underlying neurobiological mechanisms. Here we review evidence from rodent models of SUD-inspired criteria, focusing on the role of the striatal dopamine system. We identify distinct mesostriatal and nigrostriatal dopamine circuit functions in behavioral outcomes that are relevant to addictions and SUDs. This work suggests that striatal dopamine is essential for not only positive symptom features of SUDs, such as elevated intake and craving, but also for impairments in decision making that underlie compulsive behavior, reduced sociality, and risk taking. Understanding the functional heterogeneity of the dopamine system and related networks can offer insight into this complex symptomatology and may lead to more targeted treatments.

Ring of Power: A Band of Peptidergic Midbrain Neurons that Binds Motivation.

A recent Cell paper identifies a novel population of neurons within the ventral tegmental area producing the endogenous opioid nociceptin that regulates dopamine neuron firing and acts uniquely to gate motivation in reward seeking. These results highlight neuropeptidergic signaling as a critical component of functional heterogeneity in the midbrain.

Effects of acute and repeated administration of caffeine on temporal discounting in rats.

Delay to presentation is one variable that can weaken the reinforcing efficacy of an outcome in a choice situation and drugs have been shown to modify such choices. A growing body of literature has examined effects of stimulant drugs on temporal (delay) discounting, but effects of caffeine, the most widely used stimulant in the world, have not previously been assessed. In the present experiment, effects of caffeine (administered acutely and repeatedly) on temporal discounting were analyzed. Male Sprague-Dawley rats (n=7) chose between a single food pellet delivered immediately after a lever press and three food pellets delivered after a delay. The delay to the three pellets increased within each session, from 0 to 16 s. High doses of caffeine increased large-reinforcer choice relative to control conditions. With repeated caffeine exposure, percent choice for the large reinforcer decreased relative to acute administration, but was still greater than pre-drug baseline. Following withdrawal of drug administration, choice returned to levels seen during pre-drug baseline. Reintroduction of caffeine increased the percent choice for a larger, delayed reinforcer to near acute levels. The results from the present study are consistent with previous research in which stimulant drugs have decreased temporal (delay) discounting.

Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties.

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals toward the acquisition of rewards (for example, food) that are necessary for survival. We tested the fundamental role of midbrain dopamine neurons in conferring predictive and motivational properties to cues, independent of external rewards. We found that brief phasic optogenetic excitation of dopamine neurons, when presented in temporal association with discrete sensory cues, was sufficient to instantiate those cues as conditioned stimuli that subsequently both evoked dopamine neuron activity on their own and elicited cue-locked conditioned behavior. Notably, we identified highly parcellated functions for dopamine neuron subpopulations projecting to different regions of striatum, revealing dissociable dopamine systems for the generation of incentive value and conditioned movement invigoration. Our results indicate that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to create, gate, and shape cue-controlled behaviors.

Contemporary approaches to neural circuit manipulation and mapping: focus on reward and addiction.

Tying complex psychological processes to precisely defined neural circuits is a major goal of systems and behavioural neuroscience. This is critical for understanding adaptive behaviour, and also how neural systems are altered in states of psychopathology, such as addiction. Efforts to relate psychological processes relevant to addiction to activity within defined neural circuits have been complicated by neural heterogeneity. Recent advances in technology allow for manipulation and mapping of genetically and anatomically defined neurons, which when used in concert with sophisticated behavioural models, have the potential to provide great insight into neural circuit bases of behaviour. Here we discuss contemporary approaches for understanding reward and addiction, with a focus on midbrain dopamine and cortico-striato-pallidal circuits.

Sign-tracking to an appetitive cue predicts incubation of conditioned fear in rats.

Although post-traumatic stress disorder (PTSD) and addiction are very different disorders, both are characterized by hyperreactivity to trauma- or drug-related cues, respectively. We investigated whether an appetitive conditioning task, Pavlovian conditioned approach, which predicts vulnerability to reinstatement of cocaine-seeking, also predicts fear incubation, which may be a marker for vulnerability to PTSD. We classified rats based on whether they learned to approach and interact with a food predictive cue (sign-trackers), or, whether upon cue presentation they went to the location of impending food delivery (goal-trackers). Rats were then exposed to extensive Pavlovian tone-shock pairings, which causes the fear response to increase or "incubate" over time. We found that the fear incubation effect was only present in sign-trackers. The behavior of goal-trackers was more consistent with a normal fear response-it was most robust immediately after training and decayed slowly over time. Sign-trackers also had lower levels of brain-derived neurotrophic factor (BDNF) protein in the prefrontal cortex than goal-trackers. These results indicate that, while many factors likely contribute to the disproportionate co-occurrence of PTSD and substance abuse, one such factor may be a core psychological trait that biases some individuals to attribute excessive motivational significance to predictive cues, regardless of the emotional valence of those cues. High levels of BDNF in the prefrontal cortex may be protective against developing excessive emotional and motivational responses to salient cues.