Jeremy J. Day

Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens

The ability to predict favorable outcomes using environmental cues is an essential part of learned behavior. Dopamine neurons in the midbrain encode such stimulus-reward relationships in a manner consistent with contemporary learning models, but it is unclear how encoding this translates into actual dopamine release in target regions. Here, we sampled dopamine levels in the rat nucleus accumbens on a rapid (100 ms) timescale using electrochemical technology during a classical conditioning procedure. Early in conditioning, transient dopamine-release events signaled a primary reward, but not predictive cues. After repeated cue-reward pairings, dopamine signals shifted in time to predictive cue onset and were no longer observed at reward delivery. In the absence of stimulus-reward conditioning, there was no shift in the dopamine signal. Consistent with proposed roles in reward prediction and incentive salience, these results indicate that rapid dopamine release provides a reward signal that is dynamically modified by associative learning.

DNA methylation and memory formation

Memory formation and storage require long-lasting changes in memory-related neuronal circuits. Recent evidence indicates that DNA methylation may serve as a contributing mechanism in memory formation and storage. These emerging findings suggest a role for an epigenetic mechanism in learning and long-term memory maintenance and raise apparent conundrums and questions. For example, it is unclear how DNA methylation might be reversed during the formation of a memory, how changes in DNA methylation alter neuronal function to promote memory formation, and how DNA methylation patterns differ between neuronal structures to enable both consolidation and storage of memories. Here we evaluate the existing evidence supporting a role for DNA methylation in memory, discuss how DNA methylation may affect genetic and neuronal function to contribute to behavior, propose several future directions for the emerging subfield of neuroepigenetics, and begin to address some of the broader implications of this work.

Preferential Enhancement of Dopamine Transmission within the Nucleus Accumbens Shell by Cocaine Is Attributable to a Direct Increase in Phasic Dopamine Release Events

Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations after global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events after cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell, and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell after cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration, and subregion differences were abolished when cocaine was administered in the absence of autoregulation. Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors.

The Nucleus Accumbens and Pavlovian Reward Learning

The ability to form associations between predictive environmental events and rewarding outcomes is a fundamental aspect of learned behavior. This apparently simple ability likely requires complex neural processing evolved to identify, seek, and use natural rewards and redirect these activities based on updated sensory information. Emerging evidence from both animal and human research suggests that this type of processing is mediated in part by the nucleus accumbens (NAc) and a closely associated network of brain structures. The NAc is required for a number of reward-related behaviors and processes specific information about reward availability, value, and context. In addition, this structure is critical for the acquisition and expression of most Pavlovian stimulus-reward relationships, and cues that predict rewards produce robust changes in neural activity in the NAc. Although processing within the NAc may enable or promote Pavlovian reward learning in natural situations, it has also been implicated in aspects of human drug addiction, including the ability of drug-paired cues to control behavior. This article provides a critical review of the existing animal and human literature concerning the role of the NAc in Pavlovian learning with nondrug rewards and considers some clinical ture concerning the role of the NAc in Pavlovian learning with nondrug implications of these findings. NEUROSCIENTIST 13(2):148—159, 2007.

Phasic Nucleus Accumbens Dopamine Release Encodes Effort- and Delay-Related Costs

BACKGROUND Optimal decision-making requires that organisms correctly evaluate both the costs and benefits of potential choices. Dopamine transmission within the nucleus accumbens (NAc) has been heavily implicated in reward-learning and decision-making, but it is unclear how dopamine release might contribute to decisions that involve costs. METHODS Cost-based decision-making was examined in rats trained to associate visual cues with either immediate or delayed rewards (delay manipulation) or low-effort or high-effort rewards (effort manipulation). After training, dopamine concentration within the NAc was monitored on a rapid time scale with fast-scan cyclic voltammetry. RESULTS Animals exhibited a preference for immediate or low-effort rewards over delayed or high-effort rewards of equal magnitude. Reward-predictive cues but not response execution or reward delivery evoked increases in NAc dopamine concentration. When only one response option was available, cue-evoked dopamine release reflected the value of the future reward, with larger increases in dopamine signaling higher-value rewards. In contrast, when both options were presented simultaneously, dopamine signaled the better of two options, regardless of the future choice. CONCLUSIONS Phasic dopamine signals in the NAc reflect two different types of reward cost and encode potential rather than chosen value under choice situations.

DNA methylation regulates associative reward learning.

Reward-related memories are essential for adaptive behavior and evolutionary fitness, but they are also a core component of maladaptive brain diseases such as addiction. Reward learning requires dopamine neurons located in the ventral tegmental area (VTA), which encode relationships between predictive cues and future rewards. Recent evidence suggests that epigenetic mechanisms, including DNA methylation, are essential regulators of neuronal plasticity and experience-driven behavioral change. However, the role of epigenetic mechanisms in reward learning is poorly understood. Here we show that the formation of reward-related associative memories in rats upregulates key plasticity genes in the VTA, which are correlated with memory strength and associated with gene-specific changes in DNA methylation. Moreover, DNA methylation in the VTA is required for the formation of stimulus-reward associations. These results provide the first evidence that that activity-dependent methylation and demethylation of DNA is an essential substrate for the behavioral and neuronal plasticity driven by reward-related experiences.

Regional specificity in the real‐time development of phasic dopamine transmission patterns during acquisition of a cue–cocaine association in rats

Drug seeking is significantly regulated by drug‐associated cues and associative learning between environmental cues and cocaine reward is mediated by dopamine transmission within the nucleus accumbens (NAc). However, dopamine transmission during early acquisition of a cue–cocaine association has never been assessed because of the technical difficulties associated with resolving cue‐evoked and cocaine‐evoked dopamine release within the same conditioning trial. Here, we used fast‐scan cyclic voltammetry to measure sub‐second fluctuations in dopamine concentration within the NAc core and shell during the initial acquisition of a cue–cocaine Pavlovian association. Within the NAc core, cue‐evoked dopamine release developed during conditioning. However, within the NAc shell, the predictive cue appeared to cause an unconditioned decrease in dopamine concentration. The pharmacological effects of cocaine also differed between sub‐regions, as cocaine increased phasic dopamine release events within the NAc shell but not the core. Thus, real‐time measurements not only revealed the initial development of a conditioned neurochemical response but also demonstrated differential phasic dopamine transmission patterns across NAc sub‐regions during the acquisition of a cue–cocaine association.

Phasic nucleus accumbens dopamine encodes risk-based decision-making behavior

BACKGROUND To optimize behavior, organisms evaluate the risks and benefits of available choices. The mesolimbic dopamine (DA) system encodes information about response costs and reward delays that bias choices. However, it remains unclear whether subjective value associated with risk-taking behavior is encoded by DA release. METHODS Rats (n = 11) were trained on a risk-based decision-making task in which visual cues predicted the opportunity to respond for smaller certain (safer) or larger uncertain (riskier) rewards. Following training, DA release within the nucleus accumbens (NAc) was monitored on a rapid time scale using fast-scan cyclic voltammetry during the risk-based decision-making task. RESULTS Individual differences in risk-taking behavior were observed as animals displayed a preference for either safe or risky rewards. When only one response option was available, reward predictive cues evoked increases in DA concentration in the NAc core that scaled with each animals preferred reward contingency. However, when both options were presented simultaneously, cue-evoked DA release signaled the animals preferred reward contingency, regardless of the future choice. Furthermore, DA signaling in the NAc core also tracked unexpected presentations or omissions of rewards following prediction error theory. CONCLUSIONS These results suggest that the dopaminergic projections to the NAc core encode the subjective value of future rewards that may function to influence future decisions to take risks.

Nucleus accumbens neurons encode Pavlovian approach behaviors: Evidence from an autoshaping paradigm

Environmental stimuli predictive of appetitive events can elicit Pavlovian approach responses that enhance an organisms ability to track and secure natural rewards, but may also contribute to the compulsive nature of drug addiction. Here, we examined the activity of individual nucleus accumbens (NAc) neurons during an autoshaping paradigm. One conditioned stimulus (CS+, a retractable lever presented for 10 s) was immediately followed by the delivery of a 45‐mg sucrose pellet to a food receptacle, while another stimulus (CS–, a separate retractable lever presented for 10 s) was never followed by sucrose. Approach responses directed at the CS+ and CS– were recorded as lever presses and had no experimental consequence. Rats (n = 9) selectively approached the CS+ on more than 80% of trials and were surgically prepared for electrophysiological recording. Of 76 NAc neurons, 57 cells (75%) exhibited increases and/or decreases in firing rate (i.e. termed ‘phasically active’) during the CS+ presentation and corresponding approach response. Forty‐seven percent of phasically active cells (27 out of 57) were characterized by time‐locked but transient increases in cell firing, while 53% (30 out of 57) showed a significant reduction in firing for the duration of the CS+. In contrast, the same excitatory subpopulation exhibited smaller increases in activity relative to CS– onset, while the inhibitory subpopulation showed no change in firing during the CS– period. The magnitude and prevalence of cue‐related neural responses reported here indicates that the NAc encodes biologically significant, repetitive approach responses that may model the compulsive nature of drug addiction in humans.

Cocaine Cues Drive Opposing Context-Dependent Shifts in Reward Processing and Emotional State

BACKGROUND Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release but disagree as to whether repeated drug experience blunts or enhances this system. Although drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending on the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration. METHODS Fast-scan cyclic voltammetry was used to examine real-time dopamine release while simultaneously monitoring behavioral indexes of aversion as rats experienced a sweet taste cue that predicted delayed cocaine availability and during self-administration. Furthermore, the impact of cues signaling delayed drug availability on intracranial self-stimulation, a broad measure of reward function, was assessed. RESULTS We observed decreased mesolimbic dopamine concentrations, decreased reward sensitivity, and negative affect in response to the cocaine-predictive taste cue that signaled delayed cocaine availability. Importantly, dopamine concentration rapidly switched to elevated levels to cues signaling imminent cocaine delivery in the subsequent self-administration session. CONCLUSIONS These findings show rapid, bivalent contextual control over brain reward processing, affect, and motivated behavior and have implications for mechanisms mediating substance abuse.