TAKANAMI Keiko

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• Name (Japanese)

  Takanami

• Name (Kana)

  Keiko

Research Areas

• Life sciences, Laboratory animal science
• Life sciences, Neuroanatomy and physiology
• Life sciences, Neuroscience - general
• Life sciences, Animals: biochemistry, physiology, behavioral science

Research Experience

• Apr. 2022, 9999, Nara Women's University, Department of Environmental Health, Associate Professor, Japan
• Mar. 2018, Mar. 2022, National Institute of Genetics, Mouse Genomics Resource Laboratory, Assistant Professor
• Jul. 2018, Mar. 2019, University of California, Davis,, Biological Sciences, Neurobiology, Physiology and Behavior, 客員研究員
• Apr. 2015, Feb. 2018, Okayama University, 自然科学研究科・理学部附属臨海実験所, 日本学術振興会特別研究員(RPD)
• Apr. 2010, Mar. 2015, Kyoto Prefectural University of Medicine, 医学部 解剖学・生体構造科学部門, 博士研究員

Education

• Apr. 2006, Mar. 2010, Kyoto Prefectural University of Medicine, Graduate School of Medicine, Anatomy and Neurobiology

Ⅱ．研究活動実績

Published Papers

• Refereed, Oct. 2023, 139, 70, 15, 20
• Refereed, Journal of Comparative Neurology, Wiley, Characterization of the expression of gastrin‐releasing peptide and its receptor in the trigeminal and spinal somatosensory systems of Japanese macaque monkeys: Insight into humans, Keiko Takanami; Takumi Oti; Yasuhisa Kobayashi; Koki Hasegawa; Takashi Ito; Naoaki Tsutsui; Yasumasa Ueda; Earl Carstens; Tatsuya Sakamoto; Hirotaka Sakamoto, Nov. 2022, 530, 16, 2804, 2819, Scientific journal, 10.1002/cne.25376

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• Refereed, Science (New York, N.Y.), A spinal microglia population involved in remitting and relapsing neuropathic pain., Keita Kohno; Ryoji Shirasaka; Kohei Yoshihara; Satsuki Mikuriya; Kaori Tanaka; Keiko Takanami; Kazuhide Inoue; Hirotaka Sakamoto; Yasuyuki Ohkawa; Takahiro Masuda; Makoto Tsuda, Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c+ microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c+ microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c+ microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies., Apr. 2022, 376, 6588, 86, 90, Scientific journal, True, 10.1126/science.abf6805

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• Refereed, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons, Keiko Takanami; Daisuke Uta; Ken Ichi Matsuda; Mitsuhiro Kawata; Earl Carstens; Tatsuya Sakamoto; Hirotaka Sakamoto, There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR., Aug. 2021, 118, 31, e2103536118, e2103536118, Scientific journal, True, 10.1073/pnas.2103536118

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• Refereed, Scientific Reports, Springer Science and Business Media LLC, The gastrin-releasing peptide/bombesin system revisited by a reverse-evolutionary study considering Xenopus, Asuka Hirooka; Mayuko Hamada; Daiki Fujiyama; Keiko Takanami; Yasuhisa Kobayashi; Takumi Oti; Yukitoshi Katayama; Tatsuya Sakamoto; Hirotaka Sakamoto, Bombesin is a putative antibacterial peptide isolated from the skin of the frog, Bombina bombina. Two related (bombesin-like) peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been found in mammals. The history of GRP/bombesin discovery has caused little attention to be paid to the evolutionary relationship of GRP/bombesin and their receptors in vertebrates. We have classified the peptides and their receptors from the phylogenetic viewpoint using a newly established genetic database and bioinformatics. Here we show, by using a clawed frog (Xenopus tropicalis), that GRP is not a mammalian counterpart of bombesin and also that, whereas the GRP system is widely conserved among vertebrates, the NMB/bombesin system has diversified in certain lineages, in particular in frog species. To understand the derivation of GRP system in the ancestor of mammals, we have focused on the GRP system in Xenopus. Gene expression analyses combined with immunohistochemistry and Western blotting experiments demonstrated that GRP peptides and their receptors are distributed in the brain and stomach of Xenopus. We conclude that GRP peptides and their receptors have evolved from ancestral (GRP-like peptide) homologues to play multiple roles in both the gut and the brain as one of the ‘gut-brain peptide’ systems., Jun. 2021, 11, 1, 13315, 13315, Scientific journal, True, 10.1038/s41598-021-92528-x

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• Refereed, Journal of Comparative Neurology, Wiley, Variation of pro‐vasopressin processing in parvocellular and magnocellular neurons in the paraventricular nucleus of the hypothalamus: Evidence from the vasopressin‐related glycopeptide copeptin, Natsuko Kawakami; Akito Otubo; Sho Maejima; Ashraf H. Talukder; Keita Satoh; Takumi Oti; Keiko Takanami; Yasumasa Ueda; Keiichi Itoi; John F. Morris; Tatsuya Sakamoto; Hirotaka Sakamoto, May 2021, Scientific journal, 10.1002/cne.25026

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• Refereed, Current Biology, Elsevier BV, Oxytocin Influences Male Sexual Activity via Non-synaptic Axonal Release in the Spinal Cord, Takumi Oti; Keita Satoh; Daisuke Uta; Junta Nagafuchi; Sayaka Tateishi; Ryota Ueda; Keiko Takanami; Larry J. Young; Antony Galione; John F. Morris; Tatsuya Sakamoto; Hirotaka Sakamoto, Jan. 2021, 31, 1, 103, 114.e5, Scientific journal, 10.1016/j.cub.2020.09.089

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• Refereed, Neuroscience, Elsevier BV, Detection and Characterization of Estrogen Receptor Beta Expression in the Brain with Newly Developed Transgenic Mice, Shoko Sagoshi; Sho Maejima; Masahiro Morishita; Satoshi Takenawa; Akito Otubo; Keiko Takanami; Tatsuya Sakamoto; Hirotaka Sakamoto; Shinji Tsukahara; Sonoko Ogawa, Two types of nuclear estrogen receptors, ERα and ERβ, have been shown to be differentially involved in the regulation of various types of behaviors. Due to a lack of tools for identifying ERβ expression, detailed anatomical distribution and neurochemical characteristics of ERβ expressing cells and cellular co-expression with ERα remain unclear. We have generated transgenic mice ERβ-RFPtg, in which RFP was inserted downstream of ERβ BAC promotor. We verified RFP signals as ERβ by confirming: (1) high ERβ mRNA levels in RFP-expressing cells collected by fluorescence-activated cell sorting; and (2) co-localization of ERβ mRNA and RFP proteins in the paraventricular nucleus (PVN). Strong ERβ-RFP signals were found in the PVN, medial preoptic area (MPOA), bed nucleus of the stria terminalis, medial amygdala (MeA), and dorsal raphe nucleus (DRN). In the MPOA and MeA, three types of cell populations were identified; those expressing both ERα and ERβ, and those expressing exclusively either ERα or ERβ. The majority of PVN and DRN cells expressed only ERβ-RFP. Further, ERβ-RFP positive cells co-expressed oxytocin in the PVN, and tryptophan hydroxylase 2 and progesterone receptors in the DRN. In the MeA, some ERβ-RFP positive cells co-expressed oxytocin receptors. These findings collectively suggest that ERβ-RFPtg mice can be a powerful tool for future studies on ERβ function in the estrogenic regulation of social behaviors., Jul. 2020, 438, 182, 197, Scientific journal, True, 10.1016/j.neuroscience.2020.04.047

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• Refereed, Frontiers in Physiology,, The Amphibious Mudskipper: A Unique Model Bridging the Gap of Central Actions of Osmoregulatory Hormones Between Terrestrial and Aquatic Vertebrates., Katayama K; Sakamoto T; Takanami K; Takei Y, Aug. 2018, 9, 1112
• Refereed, Endocrinology, Effects of sex steroids on the spinal gastrin-releasing peptide system controlling male sexual function in rats., Oti T; Takanami K; Ito S; Ueda T; Matsuda KI; Kawata M; Soh J; Ukimura O; Sakamoto T; Sakamoto H, The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord controls male sexual function in rats. In contrast, in female rats, GRP neurons could scarcely be detected around puberty when circulating ovarian steroid hormones such as estradiol and progesterone levels are increasing. However, little information is available on feminizing or demasculinizing effects of ovarian steroids on the central nervous system in female puberty and adulthood. In this study, to visualize the spinal GRP neurons in vivo, we generated a GRP-promoter-Venus transgenic (Tg) rat line and studied the effects of the sex steroid hormones on GRP expression in the rat lumbar cord by examining the Venus fluorescence. In these Tg rats, the sexually dimorphic spinal GRP neurons controlling male sexual function were clearly labeled with Venus fluorescence. As expected, Venus fluorescence in the male lumbar cord was markedly decreased after castration and restored by chronic androgen replacement. Furthermore, androgen-induced Venus expression in the spinal cord of adult Tg males was significantly attenuated by chronic treatment with progesterone but not with estradiol. A luciferase assay using a human GRP-promoter construct showed that androgens enhance the spinal GRP system, and more strikingly, that progesterone acts to inhibit the GRP system via an androgen receptor-mediated mechanism. These results demonstrate that circulating androgens may play an important role in the spinal GRP system controlling male sexual function not only in rats but also in humans and that progesterone could be an important feminizing factor in the spinal GRP system in females during pubertal development., Apr. 2018, 159, 4, 1886, 1896, Scientific journal, True, 10.1210/en.2018-00043

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• Refereed, Spinal Cord, Nature Publishing Group, A sexually dimorphic peptidergic system in the lower spinal cord controlling penile function in non-human primates, T. Ito; T. Oti; K. Takanami; K. Satoh; Y. Ueda; T. Sakamoto; H. Sakamoto, Study design: Experimental animal study. Objectives: Although a population of gastrin-releasing peptide (GRP) neurons in the lumbar spinal cord has an important role in erection and ejaculation in rats, little information exists on this GRP system in primates. To identify the male-specific GRP system in the primate spinal cord, we studied the lumbosacral cord in macaque monkeys as a non-human primate model. Setting: University laboratory in Japan. Methods: To determine the gene sequence of GRP precursors, the rhesus macaque monkey genomic sequence data were searched, followed by phylogenetic analysis. Subsequently, immunocytochemical analysis for GRP was performed in the monkey spinal cord. Results: We have used bioinformatics to identify the ortholog gene for GRP precursor in macaque monkeys. Phylogenetic analysis suggested that primate prepro-GRP is separated from that of other mammalian species and clustered to an independent branch as primates. Immunocytochemistry for GRP further demonstrated that male-dominant sexual dimorphism was found in the spinal GRP system in monkeys as in rodents. Conclusion: We have demonstrated in macaque monkeys that the GRP system in the lower spinal cord shows male-specific dimorphism and May have an important role in penile functions not only in rodents but also in primates., 2018, 56, 1, 57, 62, Scientific journal, 10.1038/sc.2017.105

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• Refereed, JOURNAL OF COMPARATIVE NEUROLOGY, WILEY, Identification of the sexually dimorphic gastrin-releasing peptide system in the lumbosacral spinal cord that controls male reproductive function in the mouse and Asian house musk shrew (Suncus murinus), Kei Tamura; Yasuhisa Kobayashi; Asuka Hirooka; Keiko Takanami; Takumi Oti; Takamichi Jogahara; Sen-ichi Oda; Tatsuya Sakamoto; Hirotaka Sakamoto, Several regions of the brain and spinal cord control male reproductive function. We previously demonstrated that the gastrin-releasing peptide (GRP) system, located in the lumbosacral spinal cord of rats, controls spinal centers to promote penile reflexes during male copulatory behavior. However, little information exists on the male-specific spinal GRP system in animals other than rats. The objective of this study was to examine the functional generality of the spinal GRP system in mammals using the Asian house musk shrew (Suncus murinus; suncus named as the laboratory strain), a specialized placental mammal model. Mice are also used for a representative model of small laboratory animals. We first isolated complementary DNA encoding GRP in suncus. Phylogenetic analysis revealed that suncus preproGRP was clustered to an independent branch. Reverse transcription-PCR showed that GRP and its receptor mRNAs were both expressed in the lumbar spinal cord of suncus and mice. Immunohistochemistry for GRP demonstrated that the sexually dimorphic GRP system and male-specific expression/distribution patterns of GRP in the lumbosacral spinal cord in suncus are similar to those of mice. In suncus, we further found that most GRP-expressing neurons in males also express androgen receptors, suggesting that this male-dominant system in suncus is also androgen-dependent. Taken together, these results indicate that the sexually dimorphic spinal GRP system exists not only in mice but also in suncus, suggesting that this system is a conserved property in mammals. J. Comp. Neurol. 525:1586-1598, 2017. (c) 2016 Wiley Periodicals, Inc., May 2017, 525, 7, 1586, 1598, Scientific journal, 10.1002/cne.24138

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• Refereed, Biological psychiatry, Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition., Yuki Takayanagi; Masahide Yoshida; Akihide Takashima; Keiko Takanami; Shoma Yoshida; Katsuhiko Nishimori; Ichiko Nishijima; Hirotaka Sakamoto; Takanori Yamagata; Tatsushi Onaka, BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. CONCLUSIONS: The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits., 01 Feb. 2017, 81, 3, 243, 251, True, 10.1016/j.biopsych.2015.11.021

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• Refereed, NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, Decrease in neuronal spine density in the postpartum period in the amygdala and bed nucleus of the stria terminalis in rat, Seiki Matsuo; Ken Ichi Matsuda; Keiko Takanami; Taisuke Mori; Masaki Tanaka; Mitsuhiro Kawata; Jo Kitawaki, In pregnancy and the postpartum period, many women have emotional instability and some suffer from depression. The ovarian steroid hormone milieu is markedly changed during these periods, and this hormonal change may be an important cause of peripartum emotional instability. The amygdala is a central region of emotion, and the bed nucleus of the stria terminalis (BNST), which is considered to be the extended amygdala, is also involved in the emotional response. The amygdala and BNST are well characterized as target brain regions for ovarian steroid hormones, and this suggests that the functional response of neurons in these regions to hormonal fluctuation is affected in the peripartum period. In this study, we investigated the neuronal morphology in the central (CeA) and basolateral (BLA) nucleus of the amygdala and BNST on gestational days 15 (G15) (mid-gestation) and 20 (G20) (late gestation) and 4 days after delivery (P4) (early postpartum) in rat. Golgi staining showed that the dendritic spine density, and particularly the number of mature mushroom-type spines, in the CeA, BLA and BNST was significantly decreased at P4, compared with G15 and G20 and with virgin females in the estrous phase in the normal estrous cycle (Est). Interestingly, the presence of pups after delivery influenced the spine density in the BNST. The density was significantly decreased with pup presence compared with pup absence at P4, and compared with G15, G20 and Est. These results provide fundamental insights into the neuronal basis underlying emotional instability during pregnancy and postpartum. (C) 2017 Elsevier B.V. All rights reserved., Feb. 2017, 641, 21, 25, Scientific journal, 10.1016/j.neulet.2017.01.040

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• Refereed, PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES, JAPAN ACAD, Postnatal development of the gastrin-releasing peptide system in the lumbosacral spinal cord controlling male reproductive function in rats, Nao Katayama; Takumi Oti; Keiko Takanami; Tatsuya Sakamoto; Hirotaka Sakamoto, A sexually dimorphic spinal gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord, which projects to the lower spinal centers, controls erection and ejaculation in rats. However, little is known about the postnatal development of this system. In this study, we therefore examined the postnatal development of the male-dominant spinal GRP system and its sexual differentiation in rats using immunohistochemistry. Our results show that male-dominant expression of GRP is prominent from the onset of puberty and that sexually dimorphism persists into adulthood. These results suggest that androgen surge during male puberty plays an important role in the development and maintenance of the male-specific GRP function in the rat spinal cord., Feb. 2016, 92, 2, 69, 75, Scientific journal, 10.2183/pjab.92.69

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• Refereed, BIOLOGY OF SEX DIFFERENCES, BIOMED CENTRAL LTD, Perinatal testosterone exposure is critical for the development of the male-specific sexually dimorphic gastrin-releasing peptide system in the lumbosacral spinal cord that mediates erection and ejaculation, Takumi Oti; Keiko Takanami; Nao Katayama; Tomoca Edey; Keita Satoh; Tatsuya Sakamoto; Hirotaka Sakamoto, Background: In rats, a sexually dimorphic spinal gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord projects to spinal centers that control erection and ejaculation. This system controls the sexual function of adult males in an androgen-dependent manner. In the present study, we assessed the influence of androgen exposure on the spinal GRP system during a critical period of the development of sexual dimorphism. Methods: Immunohistochemistry was used to determine if the development of the spinal GRP system is regulated by the perinatal androgen surge. We first analyzed the responses of neonates administered with anti-androgen flutamide. To remove endogenous androgens, rats were castrated at birth. Further, neonatal females were administered androgens during a critical period to evaluate the development of the male-specific spinal GRP system. Results: Treatment of neonates with flutamide on postnatal days 0 and 1 attenuated the spinal GRP system during adulthood. Castrating male rats at birth resulted in a decrease in the number of GRP neurons and the intensity of neuronal GRP in the spinal cord during adulthood despite testosterone supplementation during puberty. This effect was prevented if the rats were treated with testosterone propionate immediately after castration. Moreover, treating female rats with androgens on the day of birth and the next day, masculinized the spinal GRP system during adulthood, which resembled the masculinized phenotype of adult males and induced a hypermasculine appearance. Conclusions: The perinatal androgen surge plays a key role in masculinization of the spinal GRP system that controls male sexual behavior. Further, the present study provides potentially new approaches to treat sexual disorders of males., Jan. 2016, 7, 4, Scientific journal, 10.1186/s13293-016-0058-x

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• Refereed, ACTA HISTOCHEMICA ET CYTOCHEMICA, JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY, Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse, Shigeyuki Mukudai; Ken Ichi Matsuda; Hideki Bando; Keiko Takanami; Takeshi Nishio; Yoichiro Sugiyama; Yasuo Hisa; Mitsuhiro Kawata, The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor alpha (ER alpha), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ER alpha were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ER alpha. There was no difference in expression of sex steroid hormone receptors between trachea-and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus., 2016, 49, 1, 37, 46, Scientific journal, 10.1267/ahc.15037

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• Refereed, ACTA HISTOCHEMICA ET CYTOCHEMICA, JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY, Comparative Anatomy of Gastrin-releasing Peptide Pathways in the Trigeminal Sensory System of Mouse and the Asian House Musk Shrew Suncus murinus, Keiko Takanami; Kaihei Inoue; Hiroki Mukai; Kei Tamura; Takamichi Jogahara; Sen-ichi Oda; Mitsuhiro Kawata; Tatsuya Sakamoto; Hirotaka Sakamoto, Gastrin-releasing peptide (GRP) has recently been identified as an itch-signaling molecule in the primary afferents and spinal cord of rodents. However, little information exists on the expression and localization of GRP in the trigeminal somatosensory system other than in rats. We examined the generality of the trigeminal GRP system in mammals using two distinct species, suncus as a model of specialized placental mammals known to have a well-developed trigeminal sensory system and mice as a representative small laboratory animal. We first analyzed the gross morphology of the trigeminal somatosensory system in suncus to provide a brainstem atlas on which to map GRP distribution. Immunohistochemical analyses showed that 8% of trigeminal ganglion neurons in suncus and 6% in mice expressed GRP. Expression was restricted to cells with smaller somata. The GRP-containing fibers were densely distributed in the superficial layers of the caudal part of the trigeminal spinal nucleus (Vc) but rare in the rostral parts, both in suncus and mice. Expression of GRP receptor mRNA and protein was also detected in the Vc of suncus. Taken together, these results suggest that the trigeminal GRP system mediating itch sensation is conserved in mammals., 2016, 49, 6, 181, 190, Scientific journal, 10.1267/ahc.16030

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• Refereed, NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, Critical role of androgen receptor in the postnatal period in male sexual behavior in rats, Shunji Yamada; Miku Ohoya; Keiko Takanami; Ken Ichi Matsuda; Mitsuhiro Kawata, Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), Il (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages land II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood. (C) 2015 Elsevier Ireland Ltd. All rights reserved., Nov. 2015, 609, 189, 193, Scientific journal, 10.1016/j.neulet.2015.10.040

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• Refereed, Data in Brief, Elsevier Inc., Three-dimensional visualization of multiple synapses in thick sections using high-voltage electron microscopy in the rat spinal cord, Keita Satoh†; Keiko Takanami†; Kazuyoshi Murata; Mitsuhiro Kawata; Tatsuya Sakamoto; Hirotaka Sakamoto (†:co-first author), This data article contains complementary figure and movies (Supplementary Movies 1-3) related to the research article entitled, "Effective synaptome analysis of itch-mediating neurons in the spinal cord: a novel immunohistochemical methodology using high-voltage electron microscopy" [7]. It is important to show the synaptic connections at the ultrastructural level to understand the neural circuit, which requires the three-dimensional (3-D) analyses in the electron microscopy. Here, we applied a new sample preparation method, a high-contrast en bloc staining according to the protocol of the National Center for Microscopy and Imaging Research (NCMIR), University of California, San Diego, CA, USA to high-voltage electron microscopy (HVEM) tomography in order to examine the 3-D chemical neuroanatomy of the rat spinal cord. Pre-embedding immunoelectron microscopy was used in this study. HVEM has an excellent potential to directly visualize the ultrastructures in semi-thin sections (~5. μm thick), and we have successfully visualized many itch-mediating synaptic connections and neural networks in the spinal cord using "HVEM tomography". Moreover, the methodology used in this study is simple and can be applied in multiple ways. This is an important contribution to ultrastructural investigations of the central nervous system in the present post-genomic age., 01 Sep. 2015, 4, 566, 570, Scientific journal, 10.1016/j.dib.2015.07.005

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• Refereed, NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, Effective synaptome analysis of itch-mediating neurons in the spinal cord: A novel immunohistochemical methodology using high-voltage electron microscopy, Keita Satoh†; Keiko Takanami†; Kazuyoshi Murata; Mitsuhiro Kawata; Tatsuya Sakamoto; Hirotaka Sakamoto (†:co-first author), Transmission electron microscopy (TEM) is used for three-dimensional (3-D) analysis of synaptic connections in neuroscience research. However, 3-D reconstruction of the synapses using serial ultrathin sections is a powerful but tedious approach requiring advanced technical skills. High-voltage electron microscopy (HVEM) allows examination of thicker sections of biological specimens due to the increased penetration of the more accelerated electrons, which is useful to analyze the 3-D structure of biological specimens. However, it is still difficult to visualize the neural networks and synaptic connections in 3-D using HVEM because of insufficient and non uniform heavy metal staining in the membranous structures in semi-thin sections. Here, we present the successful chemical 3-D neuroanatomy of the rat spinal dorsal horn at the ultrastructural level as a first step for effective synaptome analysis by applying a high-contrast en bloc staining method to immune-HVEM tomography. Our new approach made it possible to examine many itch-mediating synaptic connections and neural networks in the spinal cord simultaneously using HVEM tomography. This novel 3-D electron microscopy is very useful for the analysis of synaptic structure and the chemical neuroanatomy at the 3-D ultrastructural level. (C) 2015 Elsevier Ireland Ltd. All rights reserved., Jul. 2015, 599, 86, 91, Scientific journal, 10.1016/j.neulet.2015.05.031

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• Refereed, JOURNAL OF COMPARATIVE NEUROLOGY, WILEY-BLACKWELL, Distribution of Gastrin-Releasing Peptide in the Rat Trigeminal and Spinal Somatosensory Systems, Keiko Takanami; Hirotaka Sakamoto; Ken Ichi Matsuda; Keita Satoh; Takashi Tanida; Shunji Yamada; Kaihei Inoue; Takumi Oti; Tatsuya Sakamoto; Mitsuhiro Kawata, Gastrin-releasing peptide (GRP) has recently been identified as an itch-specific neuropeptide in the spinal sensory system in mice, but there are no reports of the expression and distribution of GRP in the trigeminal sensory system in mammals. We characterized and compared GRP-immunoreactive (ir) neurons in the trigeminal ganglion (TG) with those in the rat spinal dorsal root ganglion (DRG). GRP immunoreactivity was expressed in 12% of TG and 6% of DRG neurons and was restricted to the small- and medium-sized type cells. In both the TG and DRG, many GRP-ir neurons also expressed substance P and calcitonin gene-related peptide, but not isolectin B-4. The different proportions of GRP and transient receptor potential vanilloid 1 double-positive neurons in the TG and DRG imply that itch sensations via the TG and DRG pathways are transmitted through distinct mechanisms. The distribution of the axon terminals of GRP-ir primary afferents and their synaptic connectivity with the rat trigeminal sensory nuclei and spinal dorsal horn were investigated by using light and electron microscopic histochemistry. Although GRP-ir fibers were rarely observed in the trigeminal sensory nucleus principalis, oralis, and interpolaris, they were predominant in the superficial layers of the trigeminal sensory nucleus caudalis (Vc), similar to the spinal dorsal horn. Ultrastructural analysis revealed that GRP-ir terminals contained clear microvesicles and large dense-cored vesicles, and formed asymmetric synaptic contacts with a few dendrites in the Vc and spinal dorsal horn. These results suggest that GRP-dependent orofacial and spinal pruriceptive inputs are processed mainly in the superficial laminae of the Vc and spinal dorsal horn. J. Comp. Neurol. 522:1858-1873, 2014. (c) 2013 Wiley Periodicals, Inc., Jun. 2014, 522, 8, 1858, 1873, Scientific journal, 10.1002/cne.23506

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• Refereed, CURRENT NEUROPHARMACOLOGY, BENTHAM SCIENCE PUBL LTD, The Gastrin-Releasing Peptide Receptor (GRPR) in the Spinal Cord as a Novel Pharmacological Target, Keiko Takanami; Hirotaka Sakamoto, Gastrin-releasing peptide (GRP) is a mammalian neuropeptide that acts through the G protein-coupled receptor, GRP receptor (GRPR). Increasing evidence indicates that GRPR-mediated signaling in the central nervous system plays an important role in many physiological processes in mammals. Additionally, we have recently reported that the GRP system within the lumbosacral spinal cord not only controls erection but also triggers ejaculation in male rats. This system of GRP neurons is sexually dimorphic, being prominent in male rats but vestigial or absent in females. It is suggested that the sexually dimorphic GRP/GRPR system in the lumbosacral spinal cord plays a critical role in the regulation of male sexual function. In parallel, it has been reported that the somatosensory GRP/GRPR system in the spinal cord contributes to the regulation of itch specific transmission independently of the pain transmission. Interestingly, these two distinct functions in the same spinal region are both regulated by the neuropeptide, GRP. In this report, we review findings on recently identified GRP/GRPR systems in the spinal cord. These GRP/GRPR systems in the spinal cord provide new insights into pharmacological treatments for psychogenic erectile dysfunction as well as for chronic pruritus., 2014, 12, 5, 434, 443, Scientific journal
• Refereed, GLIA, WILEY-BLACKWELL, G protein-coupled receptor 30 contributes to improved remyelination after cuprizone-induced demyelination, Yukie Hirahara; Ken Ichi Matsuda; Hisao Yamada; Akira Saitou; Shinsuke Morisaki; Keiko Takanami; Joan M. Boggs; Mitsuhiro Kawata, Estrogen exerts neuroprotective and promyelinating actions. The therapeutic effect has been shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether estrogen is directly involved in remyelination via the myelin producing cells, oligodendrocytes, or which estrogen receptors are involved. In this study, we found that the membrane-associated estrogen receptor, the G protein-coupled receptor 30 (GPR30), also known as GPER, was expressed in oligodendrocytes in rat spinal cord and corpus callosum. Moreover, GPR30 was expressed throughout oligodendrocyte differentiation and promyelinating stages in primary oligodendrocyte cultures derived from rat spinal cords and brains. To evaluate the role of signaling via GPR30 in promyelination, a specific agonist for GPR30, G1, was administered to a rat model of demyelination induced by cuprizone treatment. Histological examination of the corpus callosum with oligodendrocyte differentiation stage-specific markers showed that G1 enhanced oligodendrocyte maturation in corpus callosum of cuprizone-treated animals. It also enhanced oligodendrocyte ensheathment of dorsal root ganglion (DRG) neurons in co-culture and myelination in cuprizone-treated animals. This study is the first evidence that GPR30 signaling promotes remyelination by oligodendrocytes after demyelination. GPR30 ligands may provide a novel therapy for the treatment of multiple sclerosis. (C) 2012 Wiley Periodicals, Inc., Mar. 2013, 61, 3, 420, 431, Scientific journal, 10.1002/glia.22445

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• Refereed, BRAIN RESEARCH, ELSEVIER SCIENCE BV, Testosterone has sublayer-specific effects on dendritic spine maturation mediated by BDNF and PSD-95 in pyramidal neurons in the hippocampus CA1 area, Meihua Li; Miwako Masugi-Tokita; Keiko Takanami; Shunji Yamada; Mitsuhiro Kawata, Testosterone has a number of important physiological roles and acts on peripheral target tissues and the central nervous system. Testosterone exerts many of its effects through the androgen receptor (AR). ARs are widely distributed in nervous tissues and particularly strongly expressed in hippocampal CA1 pyramidal neurons, which play critical roles in spatial memory tasks. Dendritic spines are specialized to receive synaptic inputs, and a change in spine morphology is correlated with the strength and maturity of each synapse. In this study, we used thy1-GFP transgenic male adult mice to analyze the morphology of dendritic spines in the hippocampal CA1 area. Gonadectomy (GDX) induced aberrant morphologies with less mushroom-type and more stubby- and thin-type spines in the proximal part of the stratum radiatum after two weeks. These morphological changes were also observed in the distal part of the stratum radiatum, whereas there was no change in the stratum lacunosum-moleculare after GDX. Testosterone replacement in GDX mice recovered the changes in spine types to those found in controls. To determine the mechanism of the testosterone-dependent morphological changes, we examined expression of brain-derived neurotrophic factor (BDNF) and its downstream target post-synaptic density protein 95 (PSD-95). GDX induced a significant decrease in the protein levels of BDNF and PSD-95 in the CA1 area, which were prevented by testosterone replacement. These findings reveal a novel role of testosterone in prevented the differential response properties of spine maturation in sublayers of dendritic spines in the CA1 area via the actions of BDNF and PSD-95. (C) 2012 Elsevier B.V. All rights reserved., Nov. 2012, 1484, 76, 84, Scientific journal, 10.1016/j.brainres.2012.09.028

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• Refereed, FRONTIERS IN BIOSCIENCE-LANDMARK, FRONTIERS IN BIOSCIENCE INC, Rapid signaling of steroid hormones in the vertebrate nervous system, Hirotaka Sakamoto; Hideya Takahashi; Ken-Ichi Matsuda; Mayumi Nishi; Keiko Takanami; Maho Ogoshi; Tatsuya Sakamoto; Mitsuhiro Kawata, Steroid hormones easily cross the blood-brain barrier because of their physicochemical lipid solubility. The hormones act through nuclear receptor-mediated mechanisms and modulate gene transcription. In contrast to their genomic actions, the non-genomic rapid action of steroid hormones, acting via various types of membrane-associated receptors, reveals pharmacological properties that are distinct from the actions of the intracellular nuclear receptors. As a result, non-genomic rapid actions have gained increased scientific interest. However, insight into the phylogenic and/or comparative actions of steroids in the brain is still poorly understood. In this review, we summarize recent findings concerning the rapid, non-genomic signaling of steroid hormones in the vertebrate central nervous system, and we discuss (using a comparative view from fish to mammals) recently published data regarding the mechanism underlying physiology and behavior., Jan. 2012, 17, 996, 1019, Scientific journal, 10.2741/3970

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• Refereed, BRAIN RESEARCH, ELSEVIER SCIENCE BV, Expression of G protein-coupled receptor 30 in the spinal somatosensory system, Keiko Takanami; Hirotaka Sakamoto; Ken-Ichi Matsuda; Koji Hosokawa; Mayumi Nishi; Eric R. Prossnitz; Mitsuhiro Kawata, Estrogens were originally identified as the primary sex steroid hormones in females and regulators of reproductive function and sexual behavior, but it has long been suggested that estrogens also have local effects on the somatosensory system at the spinal cord level. it is well known that the effects of estrogens are mediated by nuclear estrogen receptors (ERs) through genomic action, but recently a membrane-bound G protein-coupled receptor, GPR30, was identified as a non-genomic estrogen receptor. in this study we investigated the presence and localization of GPR30 in the rat spinal cord and dorsal root ganglion (DRG) in comparison with ER alpha. Using immunohistochemistry and in situ hybridization, we showed the expression of GPR30 in DRG neurons in male and female rats at mRNA and protein levels without specific sexual difference. A dense accumulation of GPR30 immunoreactivity was observed in the outer layer of the spinal dorsal horn, and selective spinal dorsal rhizotomy revealed that GPR30 was transported from the DRG to terminals located in the spinal dorsal horn. GPR30 expression was downregulated in DRG neurons of ovariectomized female rats. The spinal somatosensory system might be modulated by estradiol via putative membrane ER, GPR30-mediated mechanism. (C) 2009 Elsevier B.V. All rights reserved., Jan. 2010, 1310, 17, 28, Scientific journal, 10.1016/j.brainres.2009.11.004

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• Refereed, ENDOCRINOLOGY, ENDOCRINE SOC, Androgen Regulates the Sexually Dimorphic Gastrin-Releasing Peptide System in the Lumbar Spinal Cord that Mediates Male Sexual Function, Hirotaka Sakamoto; Keiko Takanami; Damian G. Zuloaga; Ken-ichi Matsuda; Cynthia L. Jordan; S. Marc Breedlove; Mitsuhiro Kawata, A collection of neurons in the upper lumbar spinal cord of male rats projects to the lower lumbar spinal cord, releasing gastrin-releasing peptide (GRP) onto somatic and autonomic centers known to regulate male sexual reflexes such as erection and ejaculation. Because these reflexes are androgen dependent, we asked whether manipulating levels of androgen in adult rats would affect GRP expression in this spinal center. We found that castration resulted, 28 d later, in a profound decrease in the expression of GRP in the spinal cord, as reflected in immunocytochemistry and competitive ELISA for the protein as well as real-time quantitative PCR for the transcript. These effects were prevented if the castrates were treated with testosterone propionate. Genetically male (XY) rats with the dysfunctional testicular feminization allele for the androgen receptor (AR) displayed GRP mRNA and protein levels in the spinal cord similar to those of females, indicating that androgen normally maintains the system through AR. We saw no effect of castration or the testicular feminization allele on expression of the receptor for GRP in the spinal cord, but castration did reduce expression of AR transcripts within the spinal cord as revealed by real-time quantitative PCR and Western blots. Taken together, these results suggest that androgen signaling plays a pivotal role in the regulation of GRP expression in male lumbar spinal cord. A greater understanding of how androgen modulates the spinal GRP system might lead to new therapeutic approaches to male sexual dysfunction. (Endocrinology 150: 3672-3679, 2009), Aug. 2009, 150, 8, 3672, 3679, Scientific journal, 10.1210/en.2008-1791

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• Refereed, PLOS ONE, PUBLIC LIBRARY SCIENCE, Stress Affects a Gastrin-Releasing Peptide System in the Spinal Cord That Mediates Sexual Function: Implications for Psychogenic Erectile Dysfunction, Hirotaka Sakamoto; Ken-Ichi Matsuda; Damian G. Zuloaga; Nobuko Nishiura; Keiko Takanami; Cynthia L. Jordan; S. Marc Breedlove; Mitsuhiro Kawata, Background: Many men suffering from stress, including post-traumatic stress disorder (PTSD), report sexual dysfunction, which is traditionally treated via psychological counseling. Recently, we identified a gastrin-releasing peptide (GRP) system in the lumbar spinal cord that is a primary mediator for male reproductive functions. Methodology/Principal Findings: To ask whether an acute severe stress could alter the male specific GRP system, we used a single-prolonged stress (SPS), a putative rat model for PTSD in the present study. Exposure of SPS to male rats decreases both the local content and axonal distribution of GRP in the lower lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Remarkably, pharmacological stimulation of GRP receptors restores penile reflexes in SPS-exposed males, and induces spontaneous ejaculation in a dose-dependent manner. Furthermore, although the level of plasma testosterone is normal 7 days after SPS exposure, we found a significant decrease in the expression of androgen receptor protein in this spinal center. Conclusions/Significance: We conclude that the spinal GRP system appears to be a stress-vulnerable center for male reproductive functions, which may provide new insight into a clinical target for the treatment of erectile dysfunction triggered by stress and psychiatric disorders., Jan. 2009, 4, 1, e4276, Scientific journal, 10.1371/journal.pone.0004276

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• Refereed, JOURNAL OF NEUROENDOCRINOLOGY, BLACKWELL PUBLISHING, Steroid receptor signalling in the brain - Lessons learned from molecular imaging, M. Kawata; M. Nishi; K. Matsuda; H. Sakamoto; N. Kaku; M. Masugi-Tokita; K. Fujikawa; Y. Hirahara-Wada; K. Takanami; H. Mori, Studies with green fluorescent protein (GFP) have revealed the subcellular distribution of many steroid hormone receptors to be much more dynamic than previously thought. Fluorescence resonance energy transfer (FRET) and fluorescence recovery after photobleaching (FRAP) are powerful techniques with which to examine protein-protein interaction and the mobility of tagged proteins, respectively. FRET analysis revealed that steroid treatment (with corticosterone or testosterone) induces direct interaction of the glucocorticoid receptor (GR) and importin alpha in the cytoplasm and that, shortly after nuclear entry, the GR detaches from importin alpha. The mineralocorticoid receptor (MR) and androgen receptor (AR) show the same trafficking. Upon oestradiol treatment, ER alpha and ER beta in the same cell are relocalised to form a discrete pattern and are localised in the same discrete cluster (subnuclear foci). FRAP analysis showed that nuclear ER alpha and ER beta are most dynamic and mobile in the absence of the ligand, and that mobility decreases slightly after ligand treatment. Genomic as well as non-genomic actions of steroid hormones influence the cellular function of target tissues spacio-temporally., Jun. 2008, 20, 6, 673, 676, 10.1111/j.1365-2826.2008.01727.x

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• Refereed, Proceedings of the Royal Society B: Biological Sciences, The Royal Society, Footedness for scratching itchy eyes in rodents, Yukitoshi Katayama; Ayane Miura; Tatsuya Sakamoto; Keiko Takanami; Hirotaka Sakamoto, The neural bases of itchy eye transmission remain unclear compared with those involved in body itch. Here, we show in rodents that the gastrin-releasing peptide receptor (GRPR) of the trigeminal sensory system is involved in the transmission of itchy eyes. Interestingly, we further demonstrate a difference in scratching behaviour between the left and right hindfeet in rodents; histamine instillation into the conjunctival sac of both eyes revealed right-foot biased laterality in the scratching movements. Unilateral histamine instillation specifically induced neural activation in the ipsilateral sensory pathway, with no significant difference between the activations following left- and right-eye instillations. Thus, the behavioural laterality is presumably due to right-foot preference in rodents. Genetically modified rats with specific depletion of Grpr- expressing neurons in the trigeminal sensory nucleus caudalis of the medulla oblongata exhibited fewer and shorter histamine-induced scratching movements than controls and eliminated the footedness. These results taken together indicate that the Grpr -expressing neurons are required for the transmission of itch sensation from the eyes, but that foot preference is generated centrally. These findings could open up a new field of research on the mechanisms of the laterality in vertebrates and also offer new potential therapeutic approaches to refractory pruritic eye disorders., 26 Oct. 2022, 289, 1985, 20221126, 20221126, Scientific journal, True, 10.1098/rspb.2022.1126

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• Refereed, Communications Biology, Springer Science and Business Media LLC, Nanobody-based RFP-dependent Cre recombinase for selective anterograde tracing in RFP-expressing transgenic animals, Ayumu Inutsuka; Sho Maejima; Hiroyuki Mizoguchi; Ryosuke Kaneko; Rei Nomura; Keiko Takanami; Hirotaka Sakamoto; Tatsushi Onaka, Abstract Transgenic animals expressing fluorescent proteins are widely used to label specific cells and proteins. By using a split Cre recombinase fused with mCherry-binding nanobodies or designed ankyrin repeat proteins, we created Cre recombinase dependent on red fluorescent protein (RFP) (Cre-DOR). Functional binding units for monomeric RFPs are different from those for polymeric RFPs. We confirmed selective target RFP-dependent gene expression in the mouse cerebral cortex using stereotaxic injection of adeno-associated virus vectors. In estrogen receptor-beta (Esr2)-mRFP1 mice and gastrin-releasing peptide receptor (Grpr)-mRFP1 rats, we confirmed that Cre-DOR can be used for selective tracing of the neural projection from RFP-expressing specific neurons. Cellular localization of RFPs affects recombination efficiency of Cre-DOR, and light and chemical-induced nuclear translocation of an RFP-fused protein can modulate Cre-DOR efficiency. Our results provide a method for manipulating gene expression in specific cells expressing RFPs and expand the repertory of nanobody-based genetic tools., 16 Sep. 2022, 5, 1, 979, 979, Scientific journal, True, 10.1038/s42003-022-03944-2

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• Refereed, eLife, eLife Sciences Publications, Ltd, Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla in mice, Taylor Follansbee; Dan Domocos; Eileen Nguyen; Amanda Nguyen; Aristea Bountouvas; Lauren Velasquez; Mirela Iodi Carstens; Keiko Takanami; Sarah E Ross; Earl Carstens, The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if the RVM also modulates spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while producing mild mechanical sensitization. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the modulation of pruriceptive transmission., 16 Aug. 2022, 11, e69626, Scientific journal, 10.7554/elife.69626

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• Refereed, General and Comparative Endocrinology, Elsevier BV, Chronic corticosterone exposure evokes itch hypersensitivity and sexual dysfunction in male rats: Relationship between the two distinct gastrin-releasing peptide systems in the spinal cord, Keiko Takanami; Makoto Morishita; Tatsuya Sakamoto; Hirotaka Sakamoto, Aug. 2023, 339, 114289, 114289, Scientific journal, 10.1016/j.ygcen.2023.114289

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• Refereed, Frontiers in Molecular Neuroscience, Frontiers Media SA, Function of gastrin-releasing peptide receptors in ocular itch transmission in the mouse trigeminal sensory system, Keiko Takanami; Masaya Kuroiwa; Ren Ishikawa; Yuji Imai; Akane Oishi; Midori Hashino; Yasushi Shimoda; Hirotaka Sakamoto; Tsuyoshi Koide, The prevalence of allergic conjunctivitis in itchy eyes has increased constantly worldwide owing to environmental pollution. Currently, anti-allergic and antihistaminic eye drops are used; however, there are many unknown aspects about the neural circuits that transmit itchy eyes. We focused on the gastrin-releasing peptide (GRP) and GRP receptor (GRPR), which are reportedly involved in itch transmission in the spinal somatosensory system, to determine whether the GRP system is involved in itch neurotransmission of the eyes in the trigeminal sensory system. First, the instillation of itch mediators, such as histamine (His) and non-histaminergic itch mediator chloroquine (CQ), exhibited concentration-dependent high levels of eye scratching behavior, with a significant sex differences observed in the case of His. Histological analysis revealed that His and CQ significantly increased the neural activity of GRPR-expressing neurons in the caudal part of the spinal trigeminal nucleus of the medulla oblongata in GRPR transgenic mice. We administered a GRPR antagonist or bombesin-saporin to ablate GRPR-expressing neurons, followed by His or CQ instillation, and observed a decrease in CQ-induced eye-scratching behavior in the toxin experiments. Intracisternal administration of neuromedin C (NMC), a GRPR agonist, resulted in dose-dependent excessive facial scratching behavior, despite the absence of an itch stimulus on the face. To our knowledge, this is the first study to demonstrate that non-histaminergic itchy eyes were transmitted centrally via GRPR-expressing neurons in the trigeminal sensory system, and that NMC in the medulla oblongata evoked facial itching., Nov. 2023, 16, 1280024, Scientific journal, 10.3389/fnmol.2023.1280024

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MISC

• Refereed, 日本神経科学学会 神経科学トピックス, 女性ホルモンが「かゆみ」の感受性を変えるしくみ, 高浪景子, Sep. 2021
• Not Refereed, 日本実験動物学会 実験動物ニュース, 痒み研究と野生由来マウス系統との出会い, 高浪景子, Oct. 2020, 69, 4, 142, 143
• Refereed, ACTA DERMATO-VENEREOLOGICA, Morphological and molecular evolutional analyses of itch focused on the gastrin-releasing peptide system in mammals, Keiko Takanami; Keita Satoh; Kazuyoshi Murata; Tatsuya Sakamoto; Hirotaka Sakamoto, Sep. 2017, 97, 8, 1049, 1050

Books etc

• 979-8886977578

Presentations

• 高浪景子, 日本繊維製品消費科学会 第63回 快適性・健康を考えるシンポジウム－汗とかゆみのサイエンス－、基調講演, ヒトはなぜかゆみを感じるのか, Keynote oral presentation, Apr. 2022
• 高浪景子; 坂本浩隆, 第127回日本解剖学会総会・全国学術集会 シンポジウム「信号伝達分子として働く神経ペプチドの多彩な作用を理解する」, ガストリン放出ペプチド神経系による体性感覚調節機構, Public symposium, Mar. 2022
• 大石あかね; 高浪景子; 小出剛, 第33回生物学技術研究会, 所内共同研究に基づく透過型電子顕微鏡解析支援の取り組み, Oral presentation, Feb. 2022
• 高浪景子, 奈良女子大学ライフサイエンスセミナー, 女性ホルモンが痒みの感受性を調節するメカニズム, Public discourse, Jan. 2022
• 高浪景子; 小出剛, 国立遺伝学研究所 行動遺伝学研究会 「家畜化機構の解明」, 野生由来系統・実験系統・愛玩系統マウスにおける知覚閾値の系統差, Poster presentation, Dec. 2021
• Lalitha Devi; Keiko Takanami; Akira Tanave; Yuji Imai; Tsuyoshi Koide, Neuroscience 2021- 50th Annual Meeting- Society for Neuroscience, Affect of Esr1 polymorphisms in maternal behavior in mouse, Poster presentation, Nov. 2021
• Lalitha Devi; Keiko Takanami; Akira Tanave; Yuji Imai; Tsuyoshi Koide, 第47回日本神経内分泌学会学術集会, Affect of Esr1 polymorphisms in maternal behavior in mouse, Oral presentation, Oct. 2021
• 高浪景子; 歌大介; 松田賢一; 河田光博; Earl Carstens; 坂本竜哉; 坂本浩隆, 第47回日本神経内分泌学会学術集会, 17β-エストラジオールによる痒み閾値調節, Oral presentation, Oct. 2021
• Keiko Takanami, International Federation of Societies for Histochemistry and Cytochemistry, IFSHC Workshop 2021, Session Japan, Histochemical challenges to the itch neurotransmission and evolution, Nominated symposium, Sep. 2021
• Keiko Takanami, International Federation of Societies for Histochemistry and Cytochemistry, IFSHC Workshop 2021, Session Japan, Histochemical challenges to the itch neurotransmission and evolution, Sep. 2021
• Lalitha Devi; Akira Tanave; Yuji Imai; Keiko Takanami; Tsuyoshi Koide, 第44回日本神経科学大会, Affect of Esr1 polymorphisms in maternal behavior in mouse, Poster presentation, Jul. 2021
• Keiko Takanami; Tsuyoshi Koide, The 44th Annual Meeting of the Japan Neuroscience Society, Species and strain differences in the itch threshold in rodents, Poster presentation, Jul. 2021
• ビーム バハドゥ ビシュワ (Bhim B. Biswa); 高浪景子; 豊田敦; 森宙史; 黒川顕; 小出 剛, 第68回日本実験動物学会総会, マウスの家畜化に伴う腸内微生物叢の変化, Oral presentation, May 2021
• Keiko Takanami; Tsuyoshi Koide, The 68th Annual Meeting of Japanese Association for Laboratory Animal Science, Mouse strain difference in the sensory threshold, Oral presentation, May 2021
• 高浪景子; 小出 剛; 坂本浩隆, 第94回日本内分泌学会学術総会・シンポジウム「神経内分泌研究のアップデート」, 痒みの神経伝達基盤 ―疾患モデル動物を用いた検討―, Nominated symposium, Apr. 2021
• Keiko Takanami, 第126回日本解剖学会総会・全国学術集会・第98回日本生理学会大会合同大会・公募シンポジウム「皮膚感覚の処理機構とその応用」, Approach from morphology of molecular and functional evolution of itch, Public symposium, Mar. 2021
• 高浪景子, 環境医学研究所・順天堂かゆみ研究センター 第6回学術シンポジウム ~難治性かゆみの克服を目指して~, 女性ホルモンによるかゆみ閾値調節, Nominated symposium, 19 Dec. 2020
• TAKANAMI Keiko; MORISHITA Makoto; SAKAMOTO Tatsuya; SAKAMOTO Hirotaka, 10th World Congress of Itch, Chronic stress affects itch sensitivity and male sexual function in rats, Oral presentation, Nov. 2019
• 高浪 景子, 第46回日本神経内分泌学会学術集会・若手助成金成果報告, 遺伝子改変動物を用いた難治性掻痒症におけるペプチドニューロンの機能解析, Others, Oct. 2019
• 高浪 景子; Amanda Nguyen; 小出 剛, 第31回日本行動神経内分泌研究会, 脳が引き起こす痒み, Oral presentation, Sep. 2019
• 高浪 景子, 第60回日本組織細胞化学会総会・学術集会・シンポジウム 女性研究者セッション, 組織学解析による痒み伝達機構の可視化, Nominated symposium, Sep. 2019
• 高浪 景子, 第41回関西実験動物研究会, 痒みの神経回路の解析, Public discourse, Mar. 2019
• TAKANAMI Keiko; SAKAMOTO Hirotaka; KOIDE Tsuyoshi, 第41回日本分子生物学会・ワークショップ, Comparative analysis of itch transmission using mouse and rat, Public symposium, Nov. 2018
• 前嶋 翔; 野村 黎; 高浪景子; 坂本竜哉; 坂本浩隆, 第47回日本神経内分泌学会学術集会, 内側視索前野の性的二型核に発現するガストリン放出ペプチド系は雄ラットの性的活性を制御する, Oral presentation, Oct. 2021
• Sho Maejima; Rei Nomura; Keiko Takanami; Tatsuya Sakamoto; Hirotaka Sakamoto, 第97回日本生理学会大会, The gastrin-releasing peptide system in the medial preoptic area controls male sexual activity in rats, Mar. 2020
• K Takanami; D Fujiyama; A Hirooka; H Sakamoto, THE 48th NAITO CONFERENCE on Integrated Sensory Sciences―Pain, Itch, Smell and Taste, Molecular and functional evolutionary analysis of itch focused on the gastrin-releasing peptide system in vertebrate, Poster presentation, Oct. 2019
• Effects of sociality on; the; social contagious behavior, The 42th Annual Meeting of the Japan Neuroscience Society, K Takanami, O Yakimenko, H Nagayama, T Koide, Poster presentation, Jul. 2019
• 高浪景子; 小出剛, 第66回日本実験動物学会総会, マウスの系統間における痒覚および痛覚閾値の比較解析, Poster presentation, May 2019
• K Takanami; O Yakimenko; H Nagayama; T Koide, The 3rd Sino-Japan Symposium on the Frontier of Behavioral Neuroendocrinology, DOES SOCIALITY AFFECT THE SOCIAL CONTAGIOUS BEHAVIOR?, Poster presentation, Mar. 2019
• 野村 黎; 高浪景子; 坂本竜哉; 坂本浩隆, 第45回日本神経内分泌学会学術集会, ラット内側視索前野において雄の性行動を司る神経回路系の解析, Oral presentation, Oct. 2018
• 大坪 秋人; 綿部崇久; 佐藤慧太; 高浪景子; 坂本竜哉; 坂本浩隆, 第45回日本神経内分泌学会学術集会, マウス脳におけるエストロゲン受容体β免疫組織化学の再検討, Oral presentation, Oct. 2018
• 野村 黎; 高浪景子; 坂本竜哉; 坂本浩隆, 第29回日本行動神経内分泌研究会, ラット内側視索前野における雄の性行動を制御する神経回路系の解明, Oral presentation, Sep. 2018
• 藤山大輝; 廣岡あすか; 高浪景子; 坂本竜哉; 坂本浩隆, 日本動物学会第89回大会, 魚類メダカから探るガストリン放出ペプチド系の機能進化〜痒みに着目して, Oral presentation, Sep. 2018
• Makoto Morishita; Keiko Takanami; Tatsuya Sakamoto; Hirotaka Sakamoto, 9th International Congress of Neuroendocrinology, Effects of chronic corticosterone administration on male sexual function and itch sensation in rats, Poster presentation, Jul. 2018
• K Takanami; K Murata; T Sakamoto; H Sakamoto, 9th International Congress of Neuroendocrinology, Ultrastructural analysis of the peptidergic neurons mediating itch sensation, Poster presentation, Jul. 2018
• 藤山大輝; 廣岡あすか; 高浪景子; 坂本竜哉; 坂本浩隆, 中国四国地区生物系三学会（日本動物学会・日本植物学会・日本生態学会）合同大会, メダカを用いて魚類の体性感覚の存在を探る, Oral presentation, May 2018
• 高浪景子; 伊藤隆志; 越智拓海; 小林靖尚; 佐藤慧太; 上田康雅; 坂本竜哉; 坂本浩隆, 第123回日本解剖学会総会・全国学術集会, 霊長類ニホンザルにおけるGastrin-releasing peptide神経系の機能局在, Poster presentation, Mar. 2018
• 高浪景子; 坂本浩隆, 国立遺伝学研究所研究会「マウスとラットで拓く新しい比較実験動物学」, ラットとマウスにおける痒み感受性の相違, Poster presentation, Dec. 2017
• Keiko Takanami, National Institute of Genetics, Biological Symposium, Gastrin-releasing peptide system as itch neural circuits in rodents, Nov. 2017
• 坂本浩隆; 佐藤慧太; 高浪景子; 大坪秋人; 坂本竜哉; John; F. Morris, 第44回日本神経内分泌学会学術集会, コペプチンからバソプレシン遺伝子の転写-翻訳-プロセシングを解析する試み, Oct. 2017
• K Takanami; K Satoh; K Murata; T Sakamoto; H Sakamoto, The 9th World Congress of Itch, Morphological and molecular evolutional analyses of itch focused on the gastrin-releasing peptide system in mammals, Oct. 2017
• 森下 誠; 高浪景子; 越智拓海; 坂本竜哉; 坂本浩隆, Brainstorming 2017、受賞者講演, 慢性ストレスは男性性機能障害と痒覚過敏を誘発する, Sep. 2017
• 坂本竜哉; 高浪景子, Brainstorming 2017, 岡山大学理学部附属牛窓臨海実験所・文部科学省認定共同利用拠点, Sep. 2017
• 高浪景子, 第58回日本組織細胞化学会総会・学術集会、若手研究者学術奨励賞受賞講演, 組織化学的解析による痒みの伝達機構, Sep. 2017
• 森下 誠; 高浪景子; 越智拓海; 坂本竜哉; 坂本浩隆, 日本動物学会・日本植物学会・日本生態学会 中国四国地区生物系三学会合同大会, 慢性ストレスは男性性機能障害とかゆみ感覚の過敏を引き起こす, May 2017
• 森下 誠; 高浪景子; 越智拓海; 坂本竜哉; 坂本浩隆, 第27回日本行動神経内分泌研究会, 慢性ストレスによる雄の性機能と痒み感覚への影響の解析, Apr. 2017
• 高浪景子; 歌大介; 松田賢一; 河田光博; 坂本竜哉; 坂本浩隆, 第27回日本行動神経内分泌研究会, ホルモンによる知覚調節への影響, Apr. 2017
• 高浪景子, 奈良女子大学、こころとからだの健康シンポジウム, ホルモンによる知覚調節－ライフサイクルやストレス応答に着目して－, Feb. 2017
• 高浪景子; 長谷川功紀; 坂本浩隆, 第63回日本組織細胞化学会総会・学術集会、ワークショップ「組織細胞化学的研究技法の進展と応用」, リガンド誘導体染色と遺伝子改変動物を用いた特異細胞ターゲッティング―多様な生物を対象とする今後の可能性―, Invited oral presentation, Oct. 2022
• Keiko TAKANAMI; Yukitoshi KATAYAMA; Tatsuya SAKAMOTO; Hirotaka SAKAMOTO, Joint Conference of the European Society for Comparative Endocrinology and of the International Society for Fish Endocrinology, Symposia “Stress Axis: Molecular and Cellular Regulation of the HPI/HPA Axis”, Itch and its molecular/functional evolution, Invited oral presentation, Sep. 2022
• 高浪景子, 日本内分泌学会第40回内分泌代謝学サマーセミナー、シンポジウム, 環境要因により変動するかゆみと内分泌機構, Invited oral presentation, Jul. 2022
• Lalithadevi Mallarapu; Keiko Takanami; Akira Tanave; Yuji Imai; Tsuyoshi Koide, 36th International Mammalian Genome Conference: IMGC2023 (第36回国際哺乳類ゲノム会議), Effect of Esr1 gene polymorphisms on parental behavior in female mice, Oral presentation, Mar. 2023
• 高浪景子, 第128回日本解剖学会総会・学術集会、シンポジウム: 痛覚・痒覚の受容伝導システムの動作原理解明とその応用, 脳幹三叉神経知覚系における痒みセンシング機構, Invited oral presentation, Mar. 2023
• Somashekar Harsha; 高浪 景子; 平塚 理恵; 野々村 賢一, 日本育種学会第143回講演会, 減数分裂期のイネ葯室に蓄積するカロースのシンプラスト連絡とアポプラスト空間維持における役割, Oral presentation, Mar. 2023
• 高浪景子, 京都府立医科大学大学院特別講義, 女性ホルモンによる痒み閾値調節の神経機構, Invited oral presentation, Jan. 2023
• 高浪景子, 第96回日本内分泌学会学術集会、シンポジウム「神経ペプチドの最前線」, ガストリン放出ペプチド神経系による体性感覚調節機構, Invited oral presentation, Jun. 2023
• 高浪景子, 第70回日本実験動物学会、学術集会委員会企画シンポジウム「感覚研究の最前線と実験動物学の新展開」, 脳・脊髄が修飾する痒覚感受性とその伝達機構, Invited oral presentation, May 2023
• 高浪景子, 日本家政学会被服衛生学部会 第41回被服衛生学セミナー、公開シンポジウム 『被服とともに生活する〜新たな気づきと意識改革〜』, 生体防御システムとしての痒みとその破綻による知覚異常, Invited oral presentation, Aug. 2023
• 高浪景子, 第47回日本比較内分泌学会大会及びシンポジウム、大会実行委員会主催シンポジウム「内分泌が駆動する生命現象を多元的に俯瞰する」, かゆみの伝達を修飾する内分泌機構, Invited oral presentation, Nov. 2023
• 高浪景子, 第49回日本神経内分泌学会学術集会、川上賞受賞講演, 神経内分泌学からはじめた痒み研究, Invited oral presentation, Oct. 2023
• 高浪景子, 第32回国際痒みシンポジウム, エストロゲンによる脊髄GRP系を介した痒み閾値調節, Invited oral presentation, Oct. 2023
• 高浪景子, 第97回薬理学会学術集会、シンポジウム「性ホルモンを軸とした痛み・痒み研究の新展開」, エストロゲンによる痒み閾値調節機構, Invited oral presentation, Dec. 2023

Awards

• 国立遺伝学研究所 NIGINTERN2019 Best Instructor Award, 高浪 景子, Jul. 2019
• 若手研究者助成金, 日本神経内分泌学会, 高浪 景子, Oct. 2018
• NIGINTERN2018 Best Instructor Award, 国立遺伝学研究所, 高浪 景子, Aug. 2018
• 第19回Acta Histochemica et cytochemica論文賞, 日本組織細胞化学会, 高浪 景子, Sep. 2017
• 第14回若手研究者学術奨励賞, 日本組織細胞化学会, 高浪 景子, Sep. 2017
• 第16回女性研究者奨励OM賞, 日本動物学会, 高浪 景子, Nov. 2016
• Travel Award, 8th International Congress of Neuroendocrinology (Sydney), 高浪 景子, Aug. 2014
• 第12回若手研究奨励賞, 日本神経内分泌学会, 高浪 景子, Sep. 2012
• 第38回川上正澄賞, 日本神経内分泌学会, Oct. 2023
• クラブ賞（女性研究者賞）, 国際ソロプチミスト奈良, Dec. 2023

Research Projects

• Grant-in-Aid for Scientific Research (C), 2022, 2024, 22K06058, Principal investigator, 系統差から見出す痒みの個体差の遺伝的基盤, 高浪 景子, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), National Institute of Genetics, 4290000, 3300000, 990000
• 基盤研究(C), 2019, 2021, Principal investigator, 痒み中枢細胞制御による眼の痒み誘発および治療モデル動物の開発, 高浪 景子, 文部科学省, 科学研究費補助金, 0, 0, 0, Competitive research funding
• 国際共同研究加速基金（国際共同研究強化）, 2016, 2018, Principal investigator, 痒みを特異的に伝達する脳－脊髄神経ネットワークの同定（国際研究強化）, 高浪 景子, 文部科学省, 科学研究費補助金, 0, 0, 0, Competitive research funding
• 特別研究員奨励費, 2015, 2017, Principal investigator, 系統進化学的アプローチによる痒み感覚の獲得およびその生理機能の統合解明, 高浪 景子, 文部科学省, 科学研究費補助金, 0, 0, 0, Competitive research funding
• 若手研究(B), 2014, 2015, Principal investigator, 痒みを特異的に伝達する脳－脊髄神経ネットワークの同定, 高浪 景子, 文部科学省, 科学研究費補助金, 0, 0, 0, Competitive research funding
• 2012, 2013, Principal investigator, 感覚神経を標的としたホルモン制御による中枢性鎮痒薬の探索, 高浪 景子, 科学技術振興機構, 研究成果最適展開支援プログラムA-STEP FSステージ探索タイプ, 0, 0, 0, Competitive research funding
• 2011, 2012, Principal investigator, エストロゲンによる痒み調節機構の解明, 高浪 景子, 文部科学省, 科学研究費補助金（研究活動スタート支援）, 0, 0, 0, Competitive research funding
• 2019, 2021, Principal investigator
• 2019, 2021, Principal investigator
• 2016, 2018, Principal investigator
• 2016, 2018, Principal investigator
• 2015, 2017, Principal investigator
• 2015, 2017, Principal investigator
• 2014, 2015, Principal investigator
• 2011, 2012, Principal investigator
• 2022, 2026, Principal investigator, アトピー性皮膚炎の増悪に関わる脳内メカニズムの解明, 高浪景子, 武田科学振興財団, ライフサイエンス研究助成
• 01 Jul. 2022, 31 Mar. 2023, 22K06058, Principal investigator
• 2022, 2024, 22K06058, Principal investigator