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.

Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in post-mitotic neurons as a means of consolidating, and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an “epigenetic code” in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation, and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.

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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 following 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 following 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 following cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration and sub-region 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 reinforcing properties of cocaine are significantly mediated by enhanced dopamine transmission (Kelley, 2004;Wise, 2004;Everitt and Robbins, 2005) and cocaine exerts its greatest increase in extracellular dopamine concentration ([DA]) within the shell sub-region of the nucleus accumbens (NAc) (Di Chiara and Bassareo, 2007). Cocaine increases [DA] by slowing uptake via blockade of dopamine transporters (DAT) (Giros et al., 1996) and by increasing the amount of dopamine exocytosed through mobilization of vesicles normally unavailable for release (Venton et al., 2006). However, neither mechanism can account for preferential enhancement of dopamine transmission within the NAc shell, because both are mediated through terminal DATs and DAT expression is significantly lower in the NAc shell compared to the core (Nirenberg et al., 1997). KeywordsIt has been suggested that this paradox may be explained by an increased number of dopamine release events within the shell following cocaine administration (Di Chiara and Bassareo, 2007). However, this hypothesis cannot be confirmed using microdialysis because it m...

Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation1. Epigenetic mechanisms regulate both types of consolidation2–7, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain8–12 and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence forH2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.

Reward-related memories are essential for adaptive behavior and evolutionary fitness, but 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 reveal 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.

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 utilize 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 and a closely associated network of brain structures. The nucleus accumbens is required for a number of rewardrelated behaviors, and processes specific information about reward availability, value, and context. Additionally, 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 nucleus accumbens. While processing within the nucleus accumbens 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 will provide a critical review of the existing animal and human literature concerning the role of the NAc in Pavlovian learning with non-drug rewards and consider some clinical implications of these findings. KeywordsLearning; Reward; Nucleus Accumbens; Drug Addiction; Conditioning Species survival and propagation requires that individual organisms learn about their surroundings and continually adjust behavior accordingly. One elementary yet biologically critical form of learning involves the connection of positive outcomes with predictive cues. This ability enables organisms to track, locate, and secure food and necessary materials in demanding environments, revealing obvious survival value. Moreover, such Pavlovian learning is often the background for both normal and maladaptive human behaviors. Thus, understanding reward-related Pavlovian learning could shed light on a variety of human activities, including drug taking, food seeking, social attachment, and sexual behavior.Recent endeavors have sought to identify and deconstruct the neurobiological correlates of Pavlovian learning, and there is now little doubt that a distributed network of brain nuclei mediates the ability to form associations between rewarding events and their predictors. The nucleus accumbens (NAc) is central to this network, and ongoing research focuses on how this area processes natural and drug rewards as well as related behaviors. This review will Correspondence to: Regina M. Carelli. NIH Public Access Author ManuscriptNeuroscientist. Author manuscript; available in PMC 2011 July 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript discuss the behavioral importance of Pavlovian learning (with particular attention to natural rewards), examine the involvement of the nucleus accumbens in this process, and consider how these factors may contribute to drug abuse and ...

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 may 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 timescale using 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.