Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior – and thus many opportunities for error-driven learning – is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions.

The dominant models of learning and memory, such as Hebbian plasticity, propose that experiences are transformed into memories through input-specific synaptic plasticity at the time of learning. However, synaptic plasticity is neither strictly input-specific nor restricted to the time of its induction. The impact of such forms of non-Hebbian plasticity on memory has been difficult to test, and hence poorly understood. Here, we demonstrate that synaptic manipulations can deviate from the Hebbian model of learning, yet produce a lasting memory. First, we established a weak associative conditioning protocol in mice, where optogenetic stimulation of sensory thalamic input to the amygdala was paired with a footshock, but no detectable memory was formed. However, when the same input was potentiated minutes before or after, or even 24 hr later, the associative experience was converted into a lasting memory. Importantly, potentiating an independent input to the amygdala minutes but not 24 hr after the pairing produced a lasting memory. Thus, our findings suggest that the process of transformation of a transient experience into a memory is neither restricted to the time of the experience nor to the synapses triggered by it; instead, it can be influenced by past and future events.