Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories

Biol Psychiatry. 2019 Aug 1;86(3):230-239. doi: 10.1016/j.biopsych.2018.11.009. Epub 2019 Jan 8.


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.

Keywords: Histamine H(3) receptor; Memory recovery; Object recognition memory; Perirhinal cortex; Retrieval; Stochastic resonance.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Betahistine
  • Cognition / drug effects
  • Double-Blind Method
  • Female
  • Histamine Agonists / pharmacology*
  • Humans
  • Male
  • Memory Disorders / drug therapy*
  • Mental Recall / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Object Attachment
  • Perirhinal Cortex / drug effects*
  • Piperidines
  • Stochastic Processes
  • Young Adult


  • Histamine Agonists
  • Piperidines
  • thioperamide
  • Betahistine