Histamine H₃ receptor density is negatively correlated with neural activity related to working memory in humans

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  • Ito, Takehito
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Kimura, Yasuyuki
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Seki, Chie
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Ichise, Masanori
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Yokokawa, Keita
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Kawamura, Kazunori
    Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Takahashi, Hidehiko
    Department of Psychiatry, Graduate School of Medicine, Kyoto University
  • Higuchi, Makoto
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Zhang, Ming-Rong
    Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology
  • Suhara, Tetsuya
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba
  • Yamada, Makiko
    Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba

Abstract

Background: The histamine H₃ receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H₃ receptor are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H₃ receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H₃ receptors in the prefrontal cortex.

Findings: Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H₃ receptor density was measured with the selective PET radioligand [¹¹C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H₃ receptors in this region.

Conclusions: Higher neural activity of working memory was associated with lower H₃ receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H₃ receptor in working memory and indicates the potential of H₃ receptor as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.

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