Using sensory information for the prediction of future events is essential for survival. Midbrain dopamine neurons are activated by environmental cues that predict rewards, but the cellular mechanisms that underlie this phenomenon remain elusive. We used in vivo voltammetry and in vitro patch-clamp electrophysiology to show that both dopamine release to reward predictive cues and enhanced synaptic strength onto dopamine neurons develop over the course of cue-reward learning. Increased synaptic strength was not observed after stable behavioral responding. Thus, enhanced synaptic strength onto dopamine neurons may act to facilitate the transformation of neutral environmental stimuli to salient reward-predictive cues. Dopamine (DA) neurons, originating in the ventral tegmental area (VTA) and substantia nigra and projecting to forebrain areas, are essential for the expression of goal-directed behaviors for both natural rewards and drugs of abuse (1-3). DA neurons are initially phasically activated by primary rewards such as food but shift their activation to reward-predictive stimuli after extended conditioning (4). Although DA signaling appears to be plastic, and can be modified by manipulating the contingency between conditioned stimuli and rewards (5), the cellular mechanisms that underlie this cue-reward learning remain unclear.Long-term potentiation (LTP) and long-term depression (LTD) are hypothesized cellular mechanisms for learning and memory storage (6). Glutamatergic synapses onto DA neurons can express LTP (7,8), LTD (9-11), and short-term plasticity (7). Furthermore, passive (12-14) or voluntary (15) exposure to cocaine can lead to long-lasting changes in synaptic function in DA neurons. Although excitatory synapses are highly plastic, it is unknown whether associative learning leads to synaptic alterations onto DA neurons.Both the firing of VTA neurons and the release of DA are time-locked to receipt of unpredicted rewards as well as to conditioned stimuli that predict reward delivery (16,17). However, the time course in which DA release develops to reward-predictive stimuli is poorly characterized. Thus, we used fast-scan cyclic voltammetry (FSCV) (figs. S1 and S2 and table S1) (18) to monitor rapid DA fluctuations in the nucleus accumbens (NAc) of rats during the acquisition of a cue-reward association in a Pavlovian conditioning task. Rats (n = 8) underwent single or

Spontaneous "off-line" reactivation of neuronal activity patterns may contribute to the consolidation of memory traces. The ventral striatum exhibits reactivation and has been implicated in the processing of motivational information. It is unknown, however, whether reactivating neuronal ensembles specifically recapitulate information relating to rewards that were encountered during wakefulness. We demonstrate a prolonged reactivation in rat ventral striatum during quiet wakefulness and slow-wave but not rapid eye movement sleep. Reactivation of reward-related information processed in this structure was particularly prominent, and this was primarily attributable to spike trains temporally linked to reward sites. It was accounted for by small, strongly correlated subgroups in recorded cell assemblies and can thus be characterized as a sparse phenomenon. Our results indicate that reactivated memory traces may not only comprise feature-and context-specific information but also contain a value component.

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