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  • Histamine in the central nervous system is

    2021-09-22

    Histamine in the central nervous system is produced mainly in the tuberomammillary nucleus and is implicated in learning and memory as well as sleep and wakefulness, feeding and drinking, and neuroendocrine regulation . For instance, treatment with antihistamines not only produces drowsiness but also impairs learning and memory , , . Histamine H receptors are located primarily in the axon terminals and somata of neurons, and they inhibit the presynaptic release of opiate receptors and other neurotransmitters and negatively regulate histamine synthesis . Because histamine H receptors are constitutively active, their inverse agonists upregulate histamine release . Therefore, histamine H receptor inverse agonists may enhance learning and memory. Indeed, several pioneering studies have found that histamine H receptor inverse agonists enhance memory performance , , , , , , . However, whether H receptor inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined, as indicated by the following reasoning. First, because many of the previous studies administered H receptor inverse agonists before or shortly after training, their results demonstrate the drug effect on memory acquisition and/or consolidation, but not retrieval , . Second, in some studies examining the drug effect on memory retrieval, basal memory performance was high without administration of H receptor inverse agonists because they employed aversive learning tasks , . Thus, they could not examine the drug effect on forgotten memories. Third, the other studies successfully examined the drug effect on retrieval of forgotten memories, but they targeted short-term memories (1–2 hours) and not long-term memories (24 hours or longer) , , . Fourth, all the previous studies targeting memory retrieval have tested memory performance within only 1 day of training , , , , . From a clinical view, it is important to know whether H receptor inverse agonists are effective long after training and forgetting. More important, it is unclear whether H receptor inverse agonists affect human long-term memory. Previous studies have shown that H receptor inverse agonists have no effect on the performance in memory-related tasks , , . Taken together, it is unclear whether and how H receptor inverse agonists promote retrieval of forgotten long-term memory. In the current study, we examined whether the histamine H receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice and humans. The treatment induced the recall of forgotten memories even 1 week and 1 month after training through disinhibition of histamine release in the perirhinal cortex (PRh) in mice. Histamine depolarized PRh neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neurons. Moreover, in a human clinical trial, betahistine treatment enhanced the retrieval of object recognition memory. Methods and Materials
    Results
    Discussion Memories persist latently in the brain even after they fade out due to the passage of time, treatment of amnestic drugs, or neurodegeneration. Although a few animal studies have shown that several experimental manipulations recover the forgotten memories 1, 2, they need long-term and/or highly invasive manipulation. In this study, we found that a treatment of histamine H3 receptor inverse agonists promotes retrieval of apparently forgotten memories. A single treatment followed by retrieval test was sufficient for the improvement of memory retrieval. The treatment with betahistine mesilate has a high level of safety and was effective in humans as well as mice. The upregulated histamine release and the following activation of histamine H2 receptor contribute to the increase in PRh spontaneous activity, which promotes memory retrieval. We showed that thioperamide enhances histamine release in the PRh (Figure 2). In situ hybridization data (Allen Mouse Brain Atlas) reveals histamine H2 receptor expression in the PRh (30). Histamine perfusion depolarized a membrane potential (Figure 3) and decreases calcium-activated potassium conductance in an H2 receptor-dependent manner (31), both of which contribute to histamine’s excitatory effect. Histamine H2 receptor antagonist blocked histamine-induced increase in spontaneous neuronal activity (Figure 4) and thioperamide-induced memory retrieval (Figure 2). Taken together, these findings suggest that thioperamide increases PRh spontaneous activity through upregulated histamine release and activation of histamine H2 receptor and promotes retrieval of the apparently forgotten memories. The increase in PRh spontaneous activity is sufficient to promote memory retrieval because CNO injection in mice that received AAV-hSyn-hM3Dq in the PRh improved memory retrieval (Figure 5).