Reactivation of memory engram neurons underlies
Reactivation of memory engram neurons underlies memory retrieval. Neurons activated during memory formation are reactivated during the memory test 24, 25, 32. The reactivation is observed in the cerebral cortex as well as in the hippocampus and amygdala 33, 34. The ratio of the reactivation correlates with performance at the memory test 24, 25, 35. In addition, artificial reactivation of neurons activated during training triggers memory retrieval (23). In this study, we found that histamine perfusion increased reactivation of PRh neurons that were activated during training (dVenus+ neurons). The PRh neurons that were not activated during training were not sensitive to histamine perfusion. Boosting the reactivation could underlie thioperamide-induced memory retrieval. Although our physiological analysis in cytoskeleton slices provided experimental evidence showing that histamine enhances the reactivation of memory-related neurons, we note that there is a gap between the behavioral and physiological experiments. In future, long-lasting labeling of memory-related neurons would be better to perform physiological experiments 3 to 10 days after training, in which mice are not able to discriminate between novel and familiar objects. Stochastic resonance (36) is a possible mechanism by which enhanced spontaneous activity promotes the retrieval of forgotten memories. Stochastic resonance is a phenomenon where adding nonzero noise to a subthreshold signal boosts detecting the signal in nonlinear physical and biological systems, including neuronal circuits (37). The possible mechanism by which enhanced spontaneous activity promotes the retrieval of forgotten memories through stochastic resonance is as follows. First, long after training, a recall cue is no longer strong enough to activate engram neurons, and this subthreshold activity of engram neurons is not enough for memory retrieval (24). Second, however, the activity of engram neurons exceeds a threshold level with support of enhanced background activity, leading to successful recall. Third, the activity of nonengram neurons does not exceed the threshold level because they do not receive an input of the recall cue. Indeed, we found that histamine perfusion increases overall spontaneous activity and concurrently enhances reactivation of behaviorally activated neurons and that both activation of histamine signaling and the increase in spontaneous activity promoted the retrieval of forgotten memories. In theory of stochastic resonance, adding nonzero noise to a subthreshold signal allows the signal to reach threshold, while adding noise to a suprathreshold signal leads to a low signal-to-noise ratio, which is conceptually consistent with our findings in the human object recognition task. Betahistine treatment enhanced retrieval of items that are more difficult to remember and in subjects with poorer performance. In contrast, betahistine treatment deteriorated retrieval of easier items and in subjects with better performance. The retrieval-enhancing effect is likely to depend on how subjects originally remember the items. It is important to note that histamine and histamine H3 receptor inverse agonists by themselves have no specificity to reactivate specific memories. In the test session of our novel object recognition task, mice were presented with novel and familiar objects in an open field. The specificity to reactivate the specific object memories is based on the exposure of the familiar object in the open field. Histamine boosts the overall neuronal activity in the PRh and probably supports the recall cues to reactivate the memory-related neurons. It has not been determined how object memories are stored and retrieved in neuronal ensembles in the PRh because most studies for memory engram neurons have targeted the hippocampus and amygdala using fear conditioning. A long-standing view is that reduction of firing rate in the PRh encodes object familiarity on the basis of the findings that the firing rates are higher when a stimulus is novel (19). On the other hand, several newer studies showed that neuronal activity does not decrease over stimulus repetition in rats and monkeys 38, 39, 40. In addition, they reported that a subset of PRh neurons respond to specific objects (40). These object-selective neurons might be responsible for the storage and retrieval of object memories, although it cannot be concluded without manipulation of these neurons.