Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories

Hiroshi Nomura, Hiroto Mizuta, Hiroaki Norimoto, Fumitaka Masuda, Yuki Miura, A. Kubo, Hiroto Kojima, Aoi Ashizuka, Noriko Matsukawa, Z. Baraki, Natsuko Hitora-Imamura, Daisuke Nakayama, T. Ishikawa, Mami Okada, Ken Orita, R. Saito, N. Yamauchi, Yamato Sano, Hiroyuki Kusuhara, Masabumi MinamiHidehiko Takahashi, Yuji Ikegaya

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)230-239
Number of pages10
JournalBiological Psychiatry
Volume86
Issue number3
DOIs
Publication statusPublished - 2019 Aug 1

Keywords

  • Histamine H receptor
  • Memory recovery
  • Object recognition memory
  • Perirhinal cortex
  • Retrieval
  • Stochastic resonance

ASJC Scopus subject areas

  • Biological Psychiatry

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  • Cite this

    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., ... Ikegaya, Y. (2019). Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories. Biological Psychiatry, 86(3), 230-239. https://doi.org/10.1016/j.biopsych.2018.11.009