Namboodiri, V. M. K. | bioRxiv Science

bioRxiv2026

Memory erasure by dopamine-gated retrospective learning

Erasing outdated memories is crucial for adaptive behavior. Yet once a cue-outcome association is learned, repeated cue exposure without outcome suppresses conditioned behavior without erasing the underlying memory. This allows rapid behavioral recovery when outcomes are reintroduced. Here, we confirm this limitation for standard "prospective extinction" protocols that present cues without the associated outcome, but show that true memory erasure is achieved by inverting the paradigm: presenting outcomes without associated cues, i.e., "retrospective extinction". We demonstrate that orbitofrontal cortex activity at outcome is necessary for the rapid behavioral recovery following prospective extinction, and that mesolimbic dopamine activity at outcome is necessary for retrospective extinction. These findings reconceptualize extinction mechanisms and suggest complementary strategies to mitigate relapse and erase maladaptive memories.

neuroscience↗

bioRxiv2023

Mesostriatal dopamine is sensitive to specific cue-reward contingencies

Learning causal relationships relies on understanding how often one event precedes another. To gain an understanding of how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Two cues were paired with distinct food rewards, one of which was also delivered in the absence of either cue. Conditioned approach was attenuated for the cue-reward contingency that was degraded. Dopamine neuron activity in the midbrain and dopamine release in the ventral striatum showed a profile of changes in cue- and reward-evoked responding that was not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture evoked dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.

neuroscience↗