Abstract:
BACKGROUND:A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. METHODS:Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans. RESULTS:The treatment of H3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance. CONCLUSIONS:These results highlight a novel interaction between the central histamine signaling and memory engrams.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Nomura H,Mizuta H,Norimoto H,Masuda F,Miura Y,Kubo A,Kojima H,Ashizuka A,Matsukawa N,Baraki Z,Hitora-Imamura N,Nakayama D,Ishikawa T,Okada M,Orita K,Saito R,Yamauchi N,Sano Y,Kusuhara H,Minami M,Takahashi H,Ikegdoi
10.1016/j.biopsych.2018.11.009subject
Has Abstractpub_date
2019-08-01 00:00:00pages
230-239issue
3eissn
0006-3223issn
1873-2402pii
S0006-3223(18)32021-3journal_volume
86pub_type
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