Histamine N-methyltransferase inhibition as a novel therapeutic strategy for idiopathic hypersomnia
Birkan Girgin, Fumito Naganuma, Kyosuke Hirano, Motoki Fujiya, Toshimasa Mimura, Ren Ebina, Ruoyu Zhu, Ayaka Nishibe, Tadaho Nakamura, Ramalingam Vetrivelan, Chika Miyoshi, Takatoshi Mochizuki, Hiromasa Funato, Masahiko Watanabe, Masashi Yanagisawa, Takeo Yoshikawa
European Journal of Pharmacology, 1011, 178475, 178475, Elsevier BV, Jan. 2026, [Peer-reviewed]
Scientific journal

[Deep brain imaging by using GRIN lens].
Kyosuke Hirano, Hiroshi Nomura
Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 160, 1, 53, 57, 2025, [Domestic magazines]
Japanese, Scientific journal, Elucidating the neural mechanisms governing changes in individual animal behavior is a key goal in neuroscience. Such research has important implications for behavioral pharmacology and could lead to the development of treatments for psychiatric and neurological disorders. Given that the brain likely represents vast amounts of information through the combined activity of multiple neurons, studying these mechanisms requires the simultaneous recording of many neurons. Recent years have seen significant advancements in techniques for multi-cellular activity recording. Calcium imaging utilizing fluorescent sensors has emerged as a powerful method, enabling the concurrent acquisition of spatial arrangements and temporal activity changes in neuronal populations. This article focuses on deep brain imaging using GRIN lenses, particularly deep brain calcium imaging in freely behaving animals with miniaturized head-mounted microscopes. We compare the strengths and limitations of this approach to other calcium imaging methods, electrophysiological techniques, and fiber photometry. Finally, we discuss future developments in this field, including two-photon microscopy for imaging beyond cell bodies, membrane potential imaging using voltage sensors, and single-cell resolution manipulation of neural activity by integrating spatial light modulators and electrically tunable lenses.

Regulation of wakefulness by neurotensin neurons in the lateral hypothalamus
Fumito Naganuma, Mudasir Khanday, Sathyajit Sai Bandaru, Whidul Hasan, Kyosuke Hirano, Takeo Yoshikawa, Ramalingam Vetrivelan
Experimental Neurology, 383, 115035, 115035, Elsevier BV, Jan. 2025
Scientific journal

Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy
Fumito Naganuma, Birkan Girgin, Anne Bernadette S Agu, Kyosuke Hirano, Tadaho Nakamura, Kazuhiko Yanai, Ramalingam Vetrivelan, Takatoshi Mochizuki, Masashi Yanagisawa, Takeo Yoshikawa
SLEEP, 48, 1, Oxford University Press (OUP), 23 Oct. 2024
Scientific journal, Abstract

Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Furthermore, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behavior, including the sleep–wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioral tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behavior. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy.

The impact of pitolisant, an H3 receptor antagonist/inverse agonist, on perirhinal cortex activity in individual neuron and neuronal population levels
Kyosuke Hirano, Yoshikazu Morishita, Masabumi Minami, Hiroshi Nomura
Scientific Reports, 12, 1, Springer Science and Business Media LLC, 12 May 2022
Scientific journal, Abstract

Histamine is a neurotransmitter that modulates neuronal activity and regulates various brain functions. Histamine H₃ receptor (H₃R) antagonists/inverse agonists enhance its release in most brain regions, including the cerebral cortex, which improves learning and memory and exerts an antiepileptic effect. However, the mechanism underlying the effect of H₃R antagonists/inverse agonists on cortical neuronal activity in vivo remains unclear. Here, we show the mechanism by which pitolisant, an H₃R antagonist/inverse agonist, influenced perirhinal cortex (PRh) activity in individual neuron and neuronal population levels. We monitored neuronal activity in the PRh of freely moving mice using in vivo Ca²⁺ imaging through a miniaturized one-photon microscope. Pitolisant increased the activity of some PRh neurons while decreasing the activity of others without affecting the mean neuronal activity across neurons. Moreover, it increases neuron pairs with synchronous activity in excitatory-responsive neuronal populations. Furthermore, machine learning analysis revealed that pitolisant altered the neuronal population activity. The changes in the population activity were dependent on the neurons that were excited and inhibited by pitolisant treatment. These findings indicate that pitolisant influences the activity of a subset of PRh neurons by increasing the synchronous activity and modifying the population activity.

Therapeutic effects of a histamine-metabolizing enzyme inhibitor in hypersomnia
長沼史登, BIRKAN Girgin, 平野匡佑, 中村正帆, 中村正帆, 三好千香, 望月貴年, 船戸弘正, 柳沢正史, 吉川雄朗, 日本薬学会年会要旨集(Web), 145th, 2025

【時間の神経科学-時を生み出すこころと脳の仕組み】時間の心理学と神経科学 失われた記憶想起の回復　　　　　　　　　　　　　　　
平野 匡佑, 野村 洋, Clinical Neuroscience, 41, 8, 1063, 1066, Aug. 2023
(株)中外医学社, Japanese

PharmacologyⅠ　　　　　　　　　　　　　　　
Hokkaido University
Apr. 2025 - Present

Pharmacology practicum　　　　　　　　　　　　　　　
Hokkaido University
Jul. 2024 - Present

Pharmacology　　　　　　　　　　　　　　　
Hokkaido University
Jul. 2024 - Present

Jun. 2025 - Present
北米神経科学学会　　　　　　　　　　　　　　　

Jul. 2022 - Present
日本神経科学学会　　　　　　　　　　　　　　　

Nov. 2021 - Present
日本薬理学会