Faculty Profiles - SAKAMOTO Hirotaka

Papers - SAKAMOTO Hirotaka

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Neuropeptidergic control circuits in the spinal cord for male sexual behaviour: Oxytocin-gastrin-releasing peptide systems. Reviewed International journal

Takumi Oti, Hirotaka Sakamoto

Journal of neuroendocrinology 35 ( 9 ) e13324 2023.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The neuropeptidergic mechanisms controlling socio-sexual behaviours consist of complex neuronal circuitry systems in widely distributed areas of the brain and spinal cord. At the organismal level, it is now becoming clear that "hormonal regulations" play an important role, in addition to the activation of neuronal circuits. The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord is an important component of the neural circuits that control penile reflexes in rats, circuits that are commonly referred to as the "spinal ejaculation generator (SEG)." Oxytocin, long known as a neurohypophyseal hormone, is now known to be involved in the regulation of socio-sexual behaviors in mammals, ranging from social bonding to empathy. However, the functional interaction between the SEG neurons and the hypothalamo-spinal oxytocin system remains unclear. Oxytocin is known to be synthesised mainly in hypothalamic neurons and released from the posterior pituitary into the circulation. Oxytocin is also released from the dendrites of the neurons into the hypothalamus where they have important roles in social behaviours via non-synaptic volume transmission. Because the most familiar functions of oxytocin are to regulate female reproductive functions including parturition, milk ejection, and maternal behaviour, oxytocin is often thought of as a "feminine" hormone. However, there is evidence that a group of parvocellular oxytocin neurons project to the lower spinal cord and control male sexual function in rats. In this report, we review the functional interaction between the SEG neurons and the hypothalamo-spinal oxytocin system and effects of these neuropeptides on male sexual behaviour. Furthermore, we discuss the finding of a recently identified, localised "volume transmission" role of oxytocin in the spinal cord. Findings from our studies suggest that the newly discovered "oxytocin-mediated spinal control of male sexual function" may be useful in the treatment of erectile and ejaculatory dysfunction.

DOI： 10.1111/jne.13324

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion. Reviewed International coauthorship International journal

Lora L Martucci, Jean-Marie Launay, Natsuko Kawakami, Cécile Sicard, Nathalie Desvignes, Mbarka Dakouane-Giudicelli, Barbara Spix, Maude Têtu, Franck-Olivier Gilmaire, Sloane Paulcan, Jacques Callebert, Cyrille Vaillend, Franz Bracher, Christian Grimm, Philippe Fossier, Sabine de la Porte, Hirotaka Sakamoto, John Morris, Antony Galione, Sylvie Granon, José-Manuel Cancela

Proceedings of the National Academy of Sciences of the United States of America 120 ( 7 ) e2213682120 2023.2

Language：English Publishing type：Research paper (scientific journal)

Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca2+ influx, but is also dependent on Ca2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca2+-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.

DOI： 10.1073/pnas.2213682120

Footedness for scratching itchy eyes in rodents Reviewed International journal

Yukitoshi Katayama, Ayane Miura, Tatsuya Sakamoto, Keiko Takanami, Hirotaka Sakamoto

Proceedings of the Royal Society B: Biological Sciences 289 ( 1985 ) 2022.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：The Royal Society

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.

DOI： 10.1098/rspb.2022.1126

Other Link： https://royalsocietypublishing.org/doi/full-xml/10.1098/rspb.2022.1126

Neuronal pentraxin 2 is required for facilitating excitatory synaptic inputs onto spinal neurons involved in pruriceptive transmission in a model of chronic itch. Reviewed International coauthorship International journal

Kensho Kanehisa, Keisuke Koga, Sho Maejima, Yuto Shiraishi, Konatsu Asai, Miho Shiratori-Hayashi, Mei-Fang Xiao, Hirotaka Sakamoto, Paul F Worley, Makoto Tsuda

Nature Communications 13 ( 1 ) 2367 - 2367 2022.5

Language：English Publishing type：Research paper (scientific journal)

An excitatory neuron subset in the spinal dorsal horn (SDH) that expresses gastrin-releasing peptide receptors (GRPR) is critical for pruriceptive transmission. Here, we show that glutamatergic excitatory inputs onto GRPR+ neurons are facilitated in mouse models of chronic itch. In these models, neuronal pentraxin 2 (NPTX2), an activity-dependent immediate early gene product, is upregulated in the dorsal root ganglion (DRG) neurons. Electron microscopy reveals that NPTX2 is present at presynaptic terminals connected onto postsynaptic GRPR+ neurons. NPTX2-knockout prevents the facilitation of synaptic inputs to GRPR+ neurons, and repetitive scratching behavior. DRG-specific NPTX2 expression rescues the impaired behavioral phenotype in NPTX2-knockout mice. Moreover, ectopic expression of a dominant-negative form of NPTX2 in DRG neurons reduces chronic itch-like behavior in mice. Our findings indicate that the upregulation of NPTX2 expression in DRG neurons contributes to the facilitation of glutamatergic inputs onto GRPR+ neurons under chronic itch-like conditions, providing a potential therapeutic target.

DOI： 10.1038/s41467-022-30089-x

A spinal microglia population involved in remitting and relapsing neuropathic pain. Reviewed International journal

Keita Kohno, Ryoji Shirasaka, Kohei Yoshihara, Satsuki Mikuriya, Kaori Tanaka, Keiko Takanami, Kazuhide Inoue, Hirotaka Sakamoto, Yasuyuki Ohkawa, Takahiro Masuda, Makoto Tsuda

Science (New York, N.Y.) 376 ( 6588 ) 86 - 90 2022.4

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1126/science.abf6805

Vasopressin-oxytocin-type signaling is ancient and has a conserved water homeostasis role in euryhaline marine planarians. Reviewed International coauthorship International journal

Aoshi Kobayashi, Mayuko Hamada, Masa-Aki Yoshida, Yasuhisa Kobayashi, Naoaki Tsutsui, Toshio Sekiguchi, Yuta Matsukawa, Sho Maejima, Joseph J Gingell, Shoko Sekiguchi, Ayumu Hamamoto, Debbie L Hay, John F Morris, Tatsuya Sakamoto, Hirotaka Sakamoto

Science Advances 8 ( 9 ) eabk0331 2022.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Vasopressin/oxytocin (VP/OT)-related peptides are essential for mammalian antidiuresis, sociosexual behavior, and reproduction. However, the evolutionary origin of this peptide system is still uncertain. Here, we identify orthologous genes to those for VP/OT in Platyhelminthes, intertidal planarians that have a simple bilaterian body structure but lack a coelom and body-fluid circulatory system. We report a comprehensive characterization of the neuropeptide derived from this VP/OT-type gene, identifying its functional receptor, and name it the "platytocin" system. Our experiments with these euryhaline planarians, living where environmental salinities fluctuate due to evaporation and rainfall, suggest that platytocin functions as an "antidiuretic hormone" and also organizes diverse actions including reproduction and chemosensory-associated behavior. We propose that bilaterians acquired physiological adaptations to amphibious lives by such regulation of the body fluids. This neuropeptide-secreting system clearly became indispensable for life even without the development of a vascular circulatory system or relevant synapses.

DOI： 10.1126/sciadv.abk0331

The gastrin-releasing peptide/bombesin system revisited by a reverse-evolutionary study considering Xenopus Reviewed

Asuka Hirooka, Mayuko Hamada, Daiki Fujiyama, Keiko Takanami, Yasuhisa Kobayashi, Takumi Oti, Yukitoshi Katayama, Tatsuya Sakamoto, Hirotaka Sakamoto

Scientific Reports 11 ( 1 ) 2021.12

Authorship：Last author,　Corresponding author Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title>Bombesin is a putative antibacterial peptide isolated from the skin of the frog, <italic>Bombina bombina</italic>. 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 (<italic>Xenopus tropicalis</italic>), 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 <italic>Xenopus</italic>. 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 <italic>Xenopus</italic>. 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 <italic>‘gut-brain peptide’</italic> systems.

DOI： 10.1038/s41598-021-92528-x

Other Link： http://www.nature.com/articles/s41598-021-92528-x

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons Reviewed International coauthorship

Keiko Takanami, Daisuke Uta, Ken Ichi Matsuda, Mitsuhiro Kawata, Earl Carstens, Tatsuya Sakamoto, Hirotaka Sakamoto

Proceedings of the National Academy of Sciences of the United States of America 118 ( 31 ) e2103536118 - e2103536118 2021.8

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences

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.

DOI： 10.1073/pnas.2103536118

Other Link： https://syndication.highwire.org/content/doi/10.1073/pnas.2103536118

Variation of pro-vasopressin processing in parvocellular and magnocellular neurons in the paraventricular nucleus of the hypothalamus: Evidence from the vasopressin-related glycopeptide copeptin. Reviewed International journal

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*

The Journal of Comparative Neurology 529 ( 7 ) 1372 - 1390 2021.5

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP) is synthesized in parvocellular- and magnocellular neuroendocrine neurons in the paraventricular nucleus (PVN) of the hypothalamus. Whereas magnocellular AVP neurons project primarily to the posterior pituitary, parvocellular AVP neurons project to the median eminence (ME) and to extrahypothalamic areas. The AVP gene encodes pre-pro-AVP that comprises the signal peptide, AVP, neurophysin (NPII), and a copeptin glycopeptide. In the present study, we used an N-terminal copeptin antiserum to examine copeptin expression in magnocellular and parvocellular neurons in the hypothalamus in the mouse, rat, and macaque monkey. Although magnocellular NPII-expressing neurons exhibited strong N-terminal copeptin immunoreactivity in all three species, a great majority (~90%) of parvocellular neurons that expressed NPII was devoid of copeptin immunoreactivity in the mouse, and in approximately half (~53%) of them in the rat, whereas in monkey hypothalamus, virtually all NPII-immunoreactive parvocellular neurons contained strong copeptin immunoreactivity. Immunoelectron microscopy in the mouse clearly showed copeptin-immunoreactivity co-localized with NPII-immunoreactivity in neurosecretory vesicles in the internal layer of the ME and posterior pituitary, but not in the external layer of the ME. Intracerebroventricular administration of a prohormone convertase inhibitor, hexa-d-arginine amide resulted in a marked reduction of copeptin-immunoreactivity in the NPII-immunoreactive magnocellular PVN neurons in the mouse, suggesting that low protease activity and incomplete processing of pro-AVP could explain the disproportionally low levels of N-terminal copeptin expression in rodent AVP (NPII)-expressing parvocellular neurons. Physiologic and phylogenetic aspects of copeptin expression among neuroendocrine neurons require further exploration.

DOI： 10.1002/cne.25026

In vivo electrophysiology of peptidergic neurons in deep layers of the lumbar spinal cord after optogenetic stimulation of hypothalamic paraventricular oxytocin neurons in rats. Reviewed International journal

Daisuke Uta*, Takumi Oti, Tatsuya Sakamoto, Hirotaka Sakamoto*

International Journal of Molecular Sciences 22 ( 7 ) 2021.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The spinal ejaculation generator (SEG) is located in the central gray (lamina X) of the rat lumbar spinal cord and plays a pivotal role in the ejaculatory reflex. We recently reported that SEG neurons express the oxytocin receptor and are activated by oxytocin projections from the paraventricular nucleus of hypothalamus (PVH). However, it is unknown whether the SEG responds to oxytocin in vivo. In this study, we analyzed the characteristics of the brain-spinal cord neural circuit that controls male sexual function using a newly developed in vivo electrophysiological technique. Optogenetic stimulation of the PVH of rats expressing channel rhodopsin under the oxytocin receptor promoter increased the spontaneous firing of most lamina X SEG neurons. This is the first demonstration of the in vivo electrical response from the deeper (lamina X) neurons in the spinal cord. Furthermore, we succeeded in the in vivo whole-cell recordings of lamina X neurons. In vivo whole-cell recordings may reveal the features of lamina X SEG neurons, including differences in neurotransmitters and response to stimulation. Taken together, these results suggest that in vivo electrophysiological stimulation can elucidate the neurophysiological response of a variety of spinal neurons during male sexual behavior.

DOI： 10.3390/ijms22073400

Oxytocin influences male sexual activity via non-synaptic axonal release in the spinal cord Reviewed International journal

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*

Current Biology 31 ( 1 ) 103 - 114.e5 2021.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Oxytocinergic neurons in the paraventricular nucleus of the hypothalamus that project to extrahypothalamic brain areas and the lumbar spinal cord play an important role in the control of erectile function and male sexual behavior in mammals. The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord is an important component of the neural circuits that control penile reflexes in rats, circuits that are commonly referred to as the "spinal ejaculation generator (SEG)." We have examined the functional interaction between the SEG neurons and the hypothalamo-spinal oxytocin system in rats. Here, we show that SEG/GRP neurons express oxytocin receptors and are activated by oxytocin during male sexual behavior. Intrathecal injection of oxytocin receptor antagonist not only attenuates ejaculation but also affects pre-ejaculatory behavior during normal sexual activity. Electron microscopy of potassium-stimulated acute slices of the lumbar cord showed that oxytocin-neurophysin-immunoreactivity was detected in large numbers of neurosecretory dense-cored vesicles, many of which are located close to the plasmalemma of axonal varicosities in which no electron-lucent microvesicles or synaptic membrane thickenings were visible. These results suggested that, in rats, release of oxytocin in the lumbar spinal cord is not limited to conventional synapses but occurs by exocytosis of the dense-cored vesicles from axonal varicosities and acts by diffusion-a localized volume transmission-to reach oxytocin receptors on GRP neurons and facilitate male sexual function.

DOI： 10.1016/j.cub.2020.09.089

Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity Reviewed International journal

Yuta Kohro, Tsuyoshi Matsuda, Kohei Yoshihara, Keita Kohno, Keisuke Koga, Ryuichi Katsuragi, Takaaki Oka, Ryoichi Tashima, Sho Muneta, Takuya Yamane, Shota Okada, Kazuya Momokino, Aogu Furusho, Kenji Hamase, Takumi Oti, Hirotaka Sakamoto, Kenichiro Hayashida, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Hidetoshi Tozaki-Saitoh, Katsuhiko Mikoshiba, Verdon Taylor, Kazuhide Inoue, Makoto Tsuda

Nature Neuroscience 23 ( 11 ) 1376 - 1387 2020.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5+ SDH astrocytes via α1A-adrenoceptors (α1A-ARs) through descending noradrenergic signaling from the locus coeruleus. Intrathecal norepinephrine induced mechanical pain hypersensitivity via α1A-ARs in Hes5+ astrocytes, and chemogenetic stimulation of Hes5+ SDH astrocytes was sufficient to produce the hypersensitivity. Furthermore, capsaicin-induced mechanical hypersensitivity was prevented by the inhibition of descending locus coeruleus-noradrenergic signaling onto Hes5+ astrocytes. Moreover, in a model of chronic pain, α1A-ARs in Hes5+ astrocytes were critical regulators for determining an analgesic effect of duloxetine. Our findings identify a superficial SDH-selective astrocyte population that gates descending noradrenergic control of mechanosensory behavior.

DOI： 10.1038/s41593-020-00713-4

Other Link： http://www.nature.com/articles/s41593-020-00713-4

Degradation of mutant protein aggregates within the endoplasmic reticulum of vasopressin neurons. Reviewed International journal

Takashi Miyata, Daisuke Hagiwara, Yuichi Hodai, Tsutomu Miwata, Yohei Kawaguchi, Junki Kurimoto, Hajime Ozaki, Kazuki Mitsumoto, Hiroshi Takagi, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Mami Matsumoto, Natsuko Kawakami, Nobuhiko Ohno, Hirotaka Sakamoto, Hiroshi Arima

iScience 23 ( 10 ) 101648 - 101648 2020.10

Language：English Publishing type：Research paper (scientific journal)

Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.

DOI： 10.1016/j.isci.2020.101648

Vasopressin gene products are colocalised with corticotrophin-releasing factor within neurosecretory vesicles in the external zone of the median eminence of the Japanese macaque monkey (Macaca fuscata). Reviewed International journal

Akito Otubo, Natsuko Kawakami, Sho Maejima, Yasumasa Ueda, John F Morris, Tatsuya Sakamoto, Hirotaka Sakamoto*

Journal of Neuroendocrinology 32 ( 8 ) e12875 2020.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP), when released into portal capillaries with corticotrophin-releasing factor (CRF) from terminals of parvocellular neurones of the hypothalamic paraventricular nucleus (PVH), facilitates the secretion of adrenocorticotrophic hormone (ACTH) in stressed rodents. The AVP gene encodes a propeptide precursor containing AVP, AVP-associated neurophysin II (NPII), and a glycopeptide copeptin, although it is currently unclear whether copeptin is always cleaved from the neurophysin and whether the NPII and/or copeptin have any functional role in the pituitary. Furthermore, for primates, it is unknown whether CRF, AVP, NPII and copeptin are all colocalised in neurosecretory vesicles in the terminal region of the paraventricular CRF neurone axons. Therefore, we investigated, by fluorescence and immunogold immunocytochemistry, the cellular and subcellular relationships of these peptides in the CRF- and AVP-producing cells in unstressed Japanese macaque monkeys (Macaca fuscata). Reverse transcription-polymerase chain reaction analysis showed the expression of both CRF and AVP mRNAs in the monkey PVH. As expected, in the magnocellular neurones of the PVH and supraoptic nucleus, essentially no CRF immunoreactivity could be detected in NPII-immunoreactive (AVP-producing) neurones. Immunofluorescence showed that, in the parvocellular part of the PVH, NPII was detectable in a subpopulation (approximately 39%) of the numerous CRF-immunoreactive neuronal perikarya, whereas, in the outer median eminence, NPII was more prominent (approximately 52%) in the CRF varicosities. Triple immunoelectron microscopy in the median eminence demonstrated the presence of both NPII and copeptin immunoreactivity in dense-cored vesicles of CRF-containing axons. The results are consistent with an idea that the AVP propeptide is processed and NPII and copeptin are colocalised in hypothalamic-pituitary CRF axons in the median eminence of a primate. The CRF, AVP and copeptin are all co-packaged in neurosecretory vesicles in monkeys and are thus likely to be co-released into the portal capillary blood to amplify ACTH release from the primate anterior pituitary.

DOI： 10.1111/jne.12875

Effects of Sex Steroids on the Spinal Gastrin-Releasing Peptide System Controlling Male Sexual Function in Rats Reviewed International journal

Takumi Oti, Keiko Takanami, Saya Ito, Takashi Ueda, Ken Ichi Matsuda, Mitsuhiro Kawata, Jintetsu Soh, Osamu Ukimura, Tatsuya Sakamoto, Hirotaka Sakamoto*

Endocrinology 159 ( 4 ) 1886 - 1896 2018.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

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.

DOI： 10.1210/en.2018-00043

Nemertean and phoronid genomes reveal lophotrochozoan evolution and the origin of bilaterian heads Reviewed

Yi-Jyun Luo, Miyuki Kanda, Ryo Koyanagi, Kanako Hisata, Tadashi Akiyama, Hirotaka Sakamoto, Tatsuya Sakamoto, Noriyuki Satoh

Nature Ecology and Evolution 2 ( 1 ) 141 - 151 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

Nemerteans (ribbon worms) and phoronids (horseshoe worms) are closely related lophotrochozoans - a group of animals including leeches, snails and other invertebrates. Lophotrochozoans represent a superphylum that is crucial to our understanding of bilaterian evolution. However, given the inconsistency of molecular and morphological data for these groups, their origins have been unclear. Here, we present draft genomes of the nemertean Notospermus geniculatus and the phoronid Phoronis australis, together with transcriptomes along the adult bodies. Our genome-based phylogenetic analyses place Nemertea sister to the group containing Phoronida and Brachiopoda. We show that lophotrochozoans share many gene families with deuterostomes, suggesting that these two groups retain a core bilaterian gene repertoire that ecdysozoans (for example, flies and nematodes) and platyzoans (for example, flatworms and rotifers) do not. Comparative transcriptomics demonstrates that lophophores of phoronids and brachiopods are similar not only morphologically, but also at the molecular level. Despite dissimilar head structures, lophophores express vertebrate head and neuronal marker genes. This finding suggests a common origin of bilaterian head patterning, although different heads evolved independently in each lineage. Furthermore, we observe lineage-specific expansions of innate immunity and toxin-related genes. Together, our study reveals a dual nature of lophotrochozoans, where conserved and lineage-specific features shape their evolution.

DOI： 10.1038/s41559-017-0389-y

Other Link： http://orcid.org/0000-0002-6224-4591

A sexually dimorphic peptidergic system in the lower spinal cord controlling penile function in non-human primates Reviewed

T. Ito, T. Oti, K. Takanami, K. Satoh, Y. Ueda, T. Sakamoto, H. Sakamoto

Spinal Cord 56 ( 1 ) 57 - 62 2018

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

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.

DOI： 10.1038/sc.2017.105

Other Link： http://orcid.org/0000-0002-6224-4591

Activation of supraoptic oxytocin neurons by secretin facilitates social recognition. Reviewed International journal

Yuki Takayanagi, Masahide Yoshida, Akihide Takashima, Keiko Takanami, Shoma Yoshida, Katsuhiko Nishimori, Ichiko Nishijima, Hirotaka Sakamoto, Takanori Yamagata, Tatsushi Onaka

Biological Psychiatry 81 ( 3 ) 243 - 251 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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.

DOI： 10.1016/j.biopsych.2015.11.021

Other Link： http://orcid.org/0000-0002-6224-4591

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 Reviewed

Takumi Oti, Keiko Takanami, Nao Katayama, Tomoca Edey, Keita Satoh, Tatsuya Sakamoto, Hirotaka Sakamoto*

BIOLOGY OF SEX DIFFERENCES 7 ( 1 ) 4 2016.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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.

DOI： 10.1186/s13293-016-0058-x

In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS. Reviewed International journal

Yuji Takihara, Masaru Inatani, Kei Eto, Toshihiro Inoue, Alexander Kreymerman, Seiji Miyake, Shinji Ueno, Masatoshi Nagaya, Ayami Nakanishi, Keiichiro Iwao, Yoshihiro Takamura, Hirotaka Sakamoto, Keita Satoh, Mineo Kondo, Tatsuya Sakamoto, Jeffrey L Goldberg, Junichi Nabekura, Hidenobu Tanihara

Proceedings of the National Academy of Sciences of the United States of America 112 ( 33 ) 10515 - 20 2015.8

Language：English

The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23-25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.

DOI： 10.1073/pnas.1509879112

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