Abstract
Even after memories fade over long time, the lost memories may persist latently in the brain. Reinforcement of positive modulators for retrieval of long-term memory may recover the ostensibly forgotten items. However, how the retrieval of long-term memory is modulated is less understood than short-term memory. Thus, a method that promotes the retrieval of forgotten long-term memories has not been well established. Central histamine is implicated in learning and memory. Histamine H3 receptors inhibit the presynaptic release of histamine and other neurotransmitters and negatively regulate histamine synthesis. Because histamine H3 receptors are constitutively active, their inverse agonists upregulate histamine release. Therefore, histamine H3 receptor inverse agonists may enhance learning and memory. In this study, we examined whether histamine H3 receptor inverse agonists enhance retrieval of long-term memory and recover the forgotten long-term memory in mice and humans.
We employed the novel object recognition task, wherein the test session mice were presented with a novel and a familiar object that was presented during the training session. A single treatment of histamine H3 receptor inverse agonists (thioperamide and betahistine) followed by memory retrieval tests restored forgotten object recognition memories in mice. The treatment induced the recall of forgotten memories even 1 week and 1 month after training. Activation of histamine receptor signaling in the perirhinal cortex (PRh) was critical for thioperamide-induced memory recovery because intraperitoneal thioperamide treatment increased PRh histamine release, and intra-PRh injection of ranitidine (H2 receptor antagonist) blocked the thioperamide-induced memory recovery. In neuronal and neuronal circuit levels, histamine depolarized PRh neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neurons. Chemogenetically increased spontaneous activity in the PRh was sufficient for the memory recovery. Moreover, in a human clinical trial, betahistine treatment enhanced retrieval of object recognition memory. The enhancement of memory retrieval was more evident for items that are more difficult to remember and subjects with poorer performance. Betahistine treatment did not alter working memory or attention.
In conclusion, our findings indicate that activation of histamine receptor signaling in the PRh boosts reactivation of weak memory engrams and restores the apparently forgotten memories.
