Faculty Profiles - SAKAMOTO Hirotaka

Papers - SAKAMOTO Hirotaka

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Identification of CNS Neurons Innervating the Levator Ani and Ventral Bulbospongiosus Muscles in Male Rats Reviewed

Amy D. Dobberfuhl, Takumi Oti, Hirotaka Sakamoto, Lesley Marson

JOURNAL OF SEXUAL MEDICINE 11 ( 3 ) 664 - 677 2014.3

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

IntroductionThe pelvic striated muscles play an important role in mediating erections and ejaculation, and together these muscles compose a tightly coordinated neuromuscular system that is androgen sensitive and sexually dimorphic.
AimTo identify spinal and brains neurons involved in the control of the levator ani (LA) and bulbospongiosus (BS) in the male adult and preadolescent rat.
MethodsRats were anesthetized, and the transsynaptic retrograde tracer pseudorabies virus (PRV) was injected into the LA muscle of adults or the ventral BS muscle in 30-day-old rats. After 3-5 days rats were sacrificed, and PRV-labeled neurons in the spinal cords and brains were identified using immunohistochemistry. The presence of gastrin-releasing peptide (GRP) in the lumbar spinal neurons was examined.
Main Outcomes MeasuresThe location and number of PRV-labeled neurons in the spinal cord and brain and GRP colocalization in the lumbar spinal cord.
ResultsPRV-labeled spinal interneurons were found distributed throughout T11-S1 of the spinal cord, subsequent to dorsal medial motoneuron infection. The majority of spinal interneurons were found in the lumbosacral spinal cord in the region of the dorsal gray commissure and parasympathetic preganglionic neurons. Preadolescent rats had more PRV-labeled spinal interneurons at L5-S1 where the motoneurons were located but relatively less spread rostrally in the spinal cord compared with adults. Lumbar spinothalmic neurons in medial gray of L3-L4 co-localized PRV and GRP. In the brain consistent labeling was seen in areas known to be involved in male sexual behavior including the ventrolateral medulla, hypothalamic paraventricular nucleus, and medial preoptic area.
ConclusionCommon spinal and brain pathways project to the LA and BS muscles in the rat suggesting that these muscles act together to coordinate male sexual reflexes. Differences may exist in the amount of synaptic connections/neuronal pathways in adolescents compared with adults. Dobberfuhl AD, Oti T, Sakamoto H, and Marson L. Identification of CNS neurons innervating the levator ani and ventral bulbospongiosus muscles in male rats. J Sex Med 2014;11:664-677.

DOI： 10.1111/jsm.12418

Androgen regulates development of the sexually dimorphic gastrin-releasing peptide neuron system in the lumbar spinal cord: Evidence from a mouse line lacking androgen receptor in the nervous system Reviewed

Hirotaka Sakamoto, Kazuhiro Saito, Clarisse Marie-Luce, Kalina Raskin, Takumi Oti, Keita Satoh, Kei Tamura, Tatsuya Sakamoto, Sakina Mhaouty-Kodja

NEUROSCIENCE LETTERS 558 109 - 114 2014.1

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Androgens including testosterone, organize the nervous system as well as masculine external and internal genitalia during the perinatal period. Androgen organization involves promotion of masculine body features, usually by acting through androgen receptors (ARs). We have recently demonstrated that the gastrin-releasing peptide (GRP) system in the lumbar spinal cord also mediates spinal centers promoting penile reflexes during male sexual behavior in rats. Testosterone may induce sexual differentiation of this spinal GRP system during development and maintain its activation in adulthood. In the present study, we examined the role of ARs in the nervous system regulating the development of the sexually dimorphic GRP system. For this purpose, we used a conditional mouse line selectively lacking the AR gene in the nervous system. AR foxed males carrying (mutants) or not (controls) the nestin-Cre transgene were castrated in adulthood and supplemented with physiological amounts of testosterone. Loss of AR expression in the nervous system resulted in a significant decrease in the number of GRP neurons compared to control littermates. Consequently, the intensity of GRP axonal projections onto the lower lumbar and upper sacral spinal cord was greater in control males than in mutant males. These results suggest that ARs expressed in the nervous system play a significant role in the development of the GRP system in the male lumbar spinal cord. The AR-deletion mutation may attenuate sexual behavior and activity of mutant males via spinal GRP system-mediated neural mechanisms. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2013.10.068

Sexually dimorphic nuclei in the spinal cord control male sexual functions Reviewed

Hirotaka Sakamoto

Frontiers in Neuroscience 8 ( 8 ) 184 2014

Authorship：Lead author,　Last author,　Corresponding author Language：English Publisher：Frontiers Research Foundation

Lower spinal cord injuries frequently cause sexual dysfunction in men, including erectile dysfunction and an ejaculation disorder. This indicates that the important neural centers for male sexual function are located within the lower spinal cord. It is interesting that the lumbar spinal segments contain several neural circuits, showing a clear sexually dimorphism that, in association with neural circuits of the thoracic and sacral spinal cord, are critical in expressing penile reflexes during sexual behavior. To date, many sex differences in the spinal cord have been discovered. Interestingly, most of these are male dominant. Substantial evidence of sexually dimorphic neural circuits in the spinal cord have been reported in many animal models, but major issues remain unknown. For example, it is not known how the different circuits cooperatively function during male sexual behavior. In this review, therefore, the anatomical and functional significance of the sexually dimorphic nuclei in the spinal cord corresponding to the expression of male sexual behavior is discussed. © 2014 Sakamoto.

DOI： 10.3389/fnins.2014.00184

The gastrin-releasing peptide receptor (GRPR) in the spinal cord as a novel pharmacological target Reviewed

Keiko Takanami, Hirotaka Sakamoto

CURRENT NEUROPHARMACOLOGY 12 ( 5 ) 434 - 443 2014

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BENTHAM SCIENCE PUBL LTD

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.

DOI： 10.2174/1570159X12666140923201432

Potential roles of arginine-vasotocin in the regulation of aggressive behavior in the mudskipper (Periophthalmus modestus) Reviewed

Nao Kagawa, Yudai Nishiyama, Kanoko Kato, Hideya Takahashi, Yasuhisa Kobayashi, Hirotaka Sakamoto, Tatsuya Sakamoto

General and Comparative Endocrinology 194 257 - 263 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Academic Press Inc.

The hypothalamic hormones, arginine-vasotocin (VT) and isotocin (IT), play central roles in osmoregulation and in the regulation of social behaviors including aggressive behavior in many vertebrates including fish. Here, we examined whether these hormones are associated with aggressive behavior in the mudskipper (Periophthalmus modestus). The mudskipper is an amphibious fish, which lives in the brackish water of river mouths and displays unique aggressive behavior. Upon introduction to each other in an experimental tank with aquatic and terrestrial areas, a pair of males can be classified as aggressive dominant or submissive subordinate based on the frequency of their aggressive acts, which is significantly higher in dominant male. Additionally, the length of stay in terrestrial area of dominant was longer than that of the subordinate. The latter remained in aquatic area almost throughout the period of behavioral observation. The expression of brain VT mRNA was significantly higher in subordinate than in dominant, whereas neither IT mRNA expression nor plasma cortisol level differed between subordinate and dominant male. On the other hand, an intracerebroventricular injection of VT increased aggressive behaviors in mudskippers. In addition to known roles of VT in mediation of aggressive behavior, these results may shed light on the role of endogenous VT toward water migration in submissive mudskippers. The amphibious fish is a valuable experimental model to observe the relationship between effects of central VT on the osmoregulation and social behavioral regulation in vertebrates. © 2013.

DOI： 10.1016/j.ygcen.2013.09.023

Ultrahigh voltage electron microscopy links neuroanatomy and neuroscience/neuroendocrinology. Reviewed

Sakamoto H, Kawata M

Anatomy Research International 2012 948704 2012.5

Brain-spinal cord neural circuits controlling male sexual function and behavior Reviewed

Hirotaka Sakamoto

NEUROSCIENCE RESEARCH 72 ( 2 ) 103 - 116 2012.2

Language：English Publisher：ELSEVIER IRELAND LTD

Men and women exhibit differences in sexual behavior. This indicates that neural circuits within the central nervous system (CNS) that control sexual behavior differ between the sexes, although differences in behavior are also influenced by sociocultural and hormonal factors. Sexual differentiation of the body and brain occurs during the embryonic and neonatal periods in humans and persists into adulthood with relatively low plasticity. Male sexual behavior is complex and depends on intrinsic and extrinsic factors, including olfactory, somatosensory and visceral cues. Many advances in our understanding of sexually dimorphic neural circuits have been achieved in animal models, but major issues are yet to be resolved. This review summarizes the sexually dimorphic nuclei controlling male sexual function in the rodent CNS and focuses on the interactions of the brain-spinal cord neural networks controlling male sexual behavior. Possible factors that relate findings from animal studies to human behavior are also discussed. (C) 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2011.11.002

Rapid signaling of steroid hormones in the vertebrate nervous system Reviewed

Hirotaka Sakamoto, Hideya Takahashi, Ken-Ichi Matsuda, Mayumi Nishi, Keiko Takanami, Maho Ogoshi, Tatsuya Sakamoto, Mitsuhiro Kawata

FRONTIERS IN BIOSCIENCE-LANDMARK 17 996 - 1019 2012.1

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS IN BIOSCIENCE INC

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.

DOI： 10.2741/3970

Immunohistochemical Analysis of the Effects of Estrogen on Intraarticular Neurogenic Inflammation in a Rat Anterior Cruciate Ligament Transection Model of Osteoarthritis Reviewed

Atsuhiko Yoshida, Toru Morihara, Ken-ichi Matsuda, Hirotaka Sakamoto, Yuji Arai, Yoshikazu Kida, Mitsuhiro Kawata, Toshikazu Kubo

CONNECTIVE TISSUE RESEARCH 53 ( 3 ) 197 - 206 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Synovitis is considered as one of the factors associated with the pathogenesis of osteoarthritis (OA). There is currently a significant amount of research linking estrogen deficiencies with the development of OA in estrogen-deficient women, including postmenopausal women; however, the exact etiology remains unclear. Various neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), have been shown to contribute to synovitis in OA joints, and the influence of estrogen on the expressions of SP and CGRP in the synovium of OA joints has been noted. After ovariectomy (OVX) followed by estradiol (E2) replacement, 24 female rats were divided into three groups: OVX group, OVX + E2 replacement group (E2 group), and a sham group. All rats underwent transection of the anterior cruciate ligament at the same time. After 30 days, the histological findings of knee joints by hematoxylin-eosin staining and immunofluorescence staining of protein gene product 9.5 (pan-neuronal marker), SP, and CGRP were compared among experimental groups. The degree of synovitis in the OVX group was higher than in the E2 and sham groups. No significant differences in the density of protein gene product 9.5-immunoreactive nerve fibers were observed among the three experimental groups, but the density of SP- or CGRP-immunoreactive nerve fibers in the OVX group was significantly higher than in the E2 and sham groups. These findings suggest that estrogen partly regulates intraarticular neurogenic inflammation in OA joints by modulating the expressions of neuropeptides in the synovium.

DOI： 10.3109/03008207.2011.628059

Corticosteroids stimulate the amphibious behavior in mudskipper: Potential role of mineralocorticoid receptors in teleost fish Reviewed

Tatsuya Sakamoto, Chie Mori, Shogo Minami, Hideya Takahashi, Tsukasa Abe, Daisuke Ojima, Maho Ogoshi, Hirotaka Sakamoto

PHYSIOLOGY & BEHAVIOR 104 ( 5 ) 923 - 928 2011.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

It has long been held that cortisol, a glucocorticoid in many vertebrates, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. However, 11-deoxycorticosterone (DOC) has been identified as a specific endogenous ligand for the teleostean mineralocorticoid receptor (MR). Furthermore, the expressions of MR mRNA are modest in the osmoregulatory organs, but considerably higher in the brain of most teleosts. These recent findings suggest that the mineralocorticoid system (DOC/MR) may carry out some behavioral functions in fish. To test this possibility, we examined the effects of cortisol and DOC administration in the amphibious behavior in mudskipper (Periophthalmus modestus) in vivo. It was found that mudskippers remained in the water for an increased period of time when they were immersed into 5 mu M DOC or cortisol for 8 h. Additionally, an exposure to 25 mu M DOC for 4 to 8 h caused a decreased migratory frequency of mudskippers to the water, reflected a tendency to remain in the water. It was further observed that after 8 h of intracerebroventricular (ICV) injection with 0.3 pmol DOC or cortisol the staying period in the water increased in fish. The migratory frequency was decreased after ICV DOC injection which indicated that fishes stayed in the water. Concurrent ICV injections of cortisol with RU486 [a specific glucocorticoid-receptor (GR) antagonist] inhibited only the partial effects of cortisol. Together with no changes in the plasma DOC concentrations under terrestrial conditions, these results indicate the involvement of brain MRs as cortisol receptors in the preference for an aquatic habitat of mudskippers. Although the role of GR signaling cannot be excluded in the aquatic preference, our data further suggest that the MR may play an important role in the brain dependent behaviors of teleost fish. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.physbeh.2011.06.002

The gastrin-releasing peptide system in the spinal cord mediates masculine sexual function Reviewed

Hirotaka Sakamoto*

ANATOMICAL SCIENCE INTERNATIONAL 86 ( 1 ) 19 - 29 2011.3

Authorship：Lead author,　Last author,　Corresponding author Language：English Publisher：SPRINGER

The lumbar spinal segments are of particular interest because they are sexually dimorphic and contain several neuronal circuits that are important in eliciting male sexual responses such as erection and ejaculation. Gastrin-releasing peptide (GRP) is a member of the bombesin-like peptide family first isolated from the porcine stomach. A collection of neurons in the lumbar spinal cord (L3-L4 level) of male rats projects to the lower lumbar spinal cord (L5-L6 level), releasing GRP onto somatic and autonomic centers known to regulate male sexual reflexes. All these target neurons express and localize specific receptors for GRP. This system of GRP neurons is sexually dimorphic, being prominent in male rats but vestigial in females. The system is completely feminine in genetically XY rats with a dysfunctional androgen receptor gene, demonstrating the androgen-dependent nature of the dimorphism. Pharmacological stimulation of GRP receptors in this spinal region remarkably restores sexual reflexes in castrated male rats. Exposure of male rats to a severe traumatic stress decreases the local content and the axonal distribution of GRP in the lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Administration of a specific agonist for GRP receptors restores penile reflexes in the traumatic stress-exposed male rats. This review summarizes findings on this recently identified spinal GRP system, which may be vulnerable to stress, that controls male reproductive function. The identification of a male-specific neuronal system regulating sexual functions offers new avenues for potential therapeutic approaches to masculine reproductive dysfunction.

DOI： 10.1007/s12565-010-0097-z

Biosynthesis, mode of action, and functional significance of neurosteroids in the purkinje cell Reviewed

Kazuyoshi Tsutsui, Kazuyoshi Ukena, Hirotaka Sakamoto, Shin-Ichiro Okuyama, Shogo Haraguchi

Frontiers in Endocrinology 2 ( OCT ) 61 2011

Language：English

The brain has traditionally been considered to be a target site of peripheral steroid hormones. In addition to this classical concept, we now know that the brain has the capacity to synthesize steroids de novo from cholesterol, the so-called "neurosteroids." In the middle 1990s, the Purkinje cell, an important cerebellar neuron, was identified as a major site for neurosteroid formation in the brain of mammals and other vertebrates. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis in the brain. In addition, biological actions of neurosteroids are becoming clear by the studies using the Purkinje cell, an excellent cellular model, which is known to play an important role in memory and learning processes. Based on the studies on mammals over the past decade, it is considered that the Purkinje cell actively synthesizes progesterone and estradiol from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions mediated by neurotrophic factors may contribute to the formation of cerebellar neuronal circuit during neonatal life. 3α,5α-Tetrahydroprogesterone (allopregnanolone), a progesterone metabolite, is also synthesized in the cerebellum and considered to act as a survival factor of Purkinje cells in the neonate. This review summarizes the current knowledge regarding the biosynthesis, mode of action, and functional significance of neurosteroids in the Purkinje cell during development in terms of synaptic formation of cerebellar neuronal networks. © 2011 Tsutsui, Ukena, Sakamoto, Okuyama and Haraguchi.

DOI： 10.3389/fendo.2011.00061

The neurobiology of psychogenic erectile dysfunction in the spinal cord Reviewed

Hirotaka Sakamoto*

JOURNAL OF ANDROLOGY 31 ( 6 ) 519 - 526 2010.11

Authorship：Lead author,　Last author,　Corresponding author Language：English Publisher：AMER SOC ANDROLOGY, INC

We recently reported a previously unknown peptider gic system within the lumbosacral spinal cord that uses gastrin releasing peptide (GRP) to trigger erection and ejaculation in male rats Many men suffering from stress including posttraumatic stress disorder (PTSD) and major depressive disorder report sexual dysfunction Sexual dysfunction in men suffering from stress and major depressive disorder is traditionally treated via psychological counseling To determine whether acute severe stress could alter the male specific GRP system, we used single prolonged stress (SPS) exposure in a putative rat model for PTSD Exposure of male rats to SPS decreases the local content and the axonal distribution of GRP in the lower lumbar spinal cord and results in an attenuation of penile reflexes in vivo Pharmacological stimulation of GRP receptors remarkably restores penile reflexes in SPS exposed male rats and in castrated male rats The administration of a GRP agonist to these animal models interestingly induces spontaneous ejaculation in a dose dependent manner Furthermore although the circulating level of androgens is normal 1 week after SPS exposure there is a significant decrease in the expression of androgen receptor protein in lumbar segments 3 and 4 of the spinal cord This might make the spinal center less responsive to androgens In this report I review findings on a recently identified spinal GRP system that could be vulnerable to stress and that controls male reproductive function This system provides new insights into the clinical treatment of psychogenic erectile dysfunction triggered by stress and psychiatric disorders

DOI： 10.2164/jandrol.110.010041

Induction of the arginine vasopressin-enhanced green fluorescent protein fusion transgene in the rat locus coeruleus Reviewed

Miwako Todoroki, Yoichi Ueta, Hiroaki Fujihara, Hiroki Otsubo, Minori Shibata, Hirofumi Hashimoto, Mizuki Kobayashi, Hirotaka Sakamoto, Mitsuhiro Kawata, Govindan Dayanithi, David Murphy, Hisanori Hiro, Ken Takahashi, Shoji Nagata

STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS 13 ( 4 ) 281 - 292 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

We examined the effects of intracerebroventricular (i.c.v.) administration of colchicine on the expression of the arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) fusion gene in rats. In rats administered i.c.v. vehicle ( control), eGFP fluorescence was observed in the supraoptic nucleus ( SON), the magnocellular division of the paraventricular nucleus (PVN), the suprachiasmatic nucleus (SCN), the median eminence ( ME) and the posterior pituitary. Two days after i.c.v. administration of colchicine, eGFP fluorescence was markedly increased in the SON, the magnocellular and parvocellular divisions of the PVN, the SCN, the ME and the locus coeruleus (LC). Immunohistochemical staining for eGFP confirmed the distribution of fluorescence in both groups. In the colchicines-administered groups, immunohistochemistry for tyrosine hydroxylase (TH) revealed that the eGFP fluorescence was co-localised with TH-immunoreactivity in the LC. Similarly, in situ hybridization histochemistry for eGFP mRNA revealed a significant increase in gene expression in the LC, the SON and the PVN 12-48 h after administration of colchicine. Our results indicate that the synthesis of AVP-eGFP is upregulated in noradrenergic neurones in the LC after colchicine administration. This implies that AVP and noradrenaline, originating from LC neurones, might play a role in response to chronic stress.

DOI： 10.3109/10253890903383406

Aldosterone-Sensitive Nucleus Tractus Solitarius Neurons Regulate Sensitivity of the Baroreceptor Reflex in High Sodium-Loaded Rats Reviewed

Tomoharu Masuda, Yasutoshi Hirabara, Yusuke Nakamura, Akiko Chishaki, Mai Tsuruhisa, Masayuki Miyakawa, Kenji Honda, Ryo Saito, Hirotaka Sakamoto, Mitsuhiro Kawata, Yukio Takano

JOURNAL OF PHARMACOLOGICAL SCIENCES 112 ( 4 ) 482 - 486 2010.4

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE PHARMACOLOGICAL SOC

We examined the role of aldosterone-sensitive neurons in the nucleus tractus solitarius (NTS) in the arterial baroreceptor reflex (baroreflex) function. Baroreflex sensitivity was induced by phenylephrine in high sodium-loaded rats and was significantly reduced. This baroreflex sensitivity was reversed by microinjection of the mineralocorticoid receptor (MR) antagonist eplerenone into the NTS. 11 beta-Hydroxysteroid dehydrogenase type 2 neurons and MR were also identified in the NTS. These data suggest that the aldosterone-sensitive neurons in the NTS may have an important role in baroreflex function.

DOI： 10.1254/jphs.09362SC

Expression of G protein-coupled receptor 30 in the spinal somatosensory system Reviewed

Keiko Takanami, Hirotaka Sakamoto, Ken-Ichi Matsuda, Koji Hosokawa, Mayumi Nishi, Eric R. Prossnitz, Mitsuhiro Kawata

BRAIN RESEARCH 1310 17 - 28 2010.1

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

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.

DOI： 10.1016/j.brainres.2009.11.004

High-Voltage Electron Microscopy Reveals Direct Synaptic Inputs from a Spinal Gastrin-Releasing Peptide System to Neurons of the Spinal Nucleus of Bulbocavernosus Reviewed

Hirotaka Sakamoto*, Tatsuo Arii, Mitsuhiro Kawata

ENDOCRINOLOGY 151 ( 1 ) 417 - 421 2010.1

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

The spinal nucleus of bulbocavernosus (SNB) is a sexually dimorphic motor nucleus located in the anterior horn of the fifth and sixth lumbar segments of the spinal cord that plays a significant role in male sexual function. We recently found that a sexually dimorphic expression of gastrin-releasing peptide (GRP) in the lumbar spinal cord regulates male copulatory reflexes. Although it is reported that these systems are both profoundly regulated by circulating androgen levels in male rats, no direct evidence has been reported regarding GRP synaptic inputs onto SNB motoneurons. The aim of the current study was to determine the axodendritic synaptic inputs of spinal GRP neurons to SNB motoneurons. Immunoelectron microscopy, combined with a retrograde tracing technique using high-voltage electron microscopy (HVEM), provided a three-dimensional visualization of synaptic contacts from the GRP system in the lumbar spinal cord onto SNB motoneurons. HVEM analysis clearly demonstrated that GRP-immunoreactive axon terminals directly contact dendrites that extend into the dorsal gray commissure from the SNB. These HVEM findings provide an ultrastructural basis for understanding how the spinal GRP system regulates male sexual behavior. (Endocrinology 151: 417-421, 2010)

DOI： 10.1210/en.2009-0485

Neurobiology of PTSD: Effects on the spinal cord

Hirotaka Sakamoto, S. Marc Breedlove, Mitsuhiro Kawata

Neurobiology of Post-Traumatic Stress Disorder 107 - 118 2010

Language：English Publishing type：Part of collection (book) Publisher：Nova Science Publishers, Inc.

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. To ask whether acute severe stress could alter the male-specific GRP system, we used a single-prolonged stress (SPS), a putative rat model for PTSD. Exposure of male rats to SPS 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 one week after SPS exposure, there is a significant decrease in the expression of androgen receptor protein in this spinal center, which may make the spinal center less responsive to circulating androgens. We conclude that the spinal GRP system for male reproductive function is vulnerable to stress, which may provide new insights into clinical treatment of erectile dysfunction triggered by stress and psychiatric disorders. © 2010 Nova Science Publishers, Inc. All rights reserved.

Characterization of In Vivo Effects of Platelet-Rich Plasma and Biodegradable Gelatin Hydrogel Microspheres on Degenerated Intervertebral Discs Reviewed

Kazuhide Sawamura, Takumi Ikeda, Masateru Nagae, Shin-ichi Okamoto, Yasuo Mikami, Hitoshi Hase, Kazuya Ikoma, Tetsuya Yamada, Hirotaka Sakamoto, Ken-ichi Matsuda, Yasuhiko Tabata, Mitsuhiro Kawata, Toshikazu Kubo

TISSUE ENGINEERING PART A 15 ( 12 ) 3719 - 3727 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：MARY ANN LIEBERT, INC

We have previously shown that administration of platelet-rich plasma-impregnated gelatin hydrogel microspheres (PRP-GHMs) into a degenerated intervertebral disc (IVD) markedly suppresses progression of IVD degeneration. In the current study, we characterized the in vivo effects of PRP-GHM treatment in a degenerated IVD model in rabbit. On magnetic resonance images, the IVD height was significantly greater after treatment with PRP-GHMs compared with phosphate-buffered saline-impregnated GHMs, PRP without GHMs, and needle puncture only. Water content was also preserved in PRP-GHM-treated IVDs. Consistent with this observation, the mRNA expression of proteoglycan core protein and type II collagen was significantly higher after PRP-GHM treatment compared with other treatment groups. No proliferating cells were found in the nucleus pulposus and inner annulus fibrosus in any groups, but the number of apoptotic cells in the nucleus pulposus after PRP-GHM treatment was significantly lower than that after other treatments. These results provide an improved understanding of the therapeutic effects of PRP-GHM treatment of degenerated IVDs.

DOI： 10.1089/ten.tea.2008.0697

バゾプレッシン(AVP)-eGFPトランスジェニックラットにおける青斑核での特異的なAVP-eGFPの合成

轟美和子, 上田陽一, 藤原広明, 大坪弘樹, 柴田美雅, 橋本弘史, 小林瑞, 坂本浩隆, 河田光博

日本病態生理学会雑誌 18 ( 2 ) 39 - 39 2009.12

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