Parallel formation of opposing memories tunes online and pre-emptive control of learned behavior in eyeblink conditioning

Animals change their behavior and adapt to the environments through associating patterns of sensory experiences, making memories to acquire and/or cease actions. However, it remains to be clarified how distinct memories are formed and interact in response to altered sensory inputs. Here we studied this issue using contrasting paradigms for eyeblink conditioning in mice, and demonstrated a fundamental mechanism of memory counteraction to fine-tune the adaptive change of animal behavior. Excessive neutral sensory stimulation intermingled with the paired presentation of two sensory stimuli did not disturb the acquisition of conditioned responses, but gradually suppressed the occurrence of learned behavior during individual daily sessions. Modeling of acquisition and extinction processes, coupled with experimental validation of a model prediction, unveiled independent and parallel formation of long-term opposing memories for execution of eyeblink and its suppression irrespective of the temporal order: the memory to suppress the conditioned response can, surprisingly, be formed even before its acquisition. Consequently, the negative memory formed either online or pre-emptively calibrates the acquired behavior, optimizing motor performance reflecting both positive and negative sensory histories.