橘 吉寿

大学院医学研究科 医科学専攻准教授
医学部 医学科

学位

  • 博士(歯学), 大阪大学

研究キーワード

  • 大脳基底核
  • 淡蒼球
  • 霊長類
  • パーキンソン病
  • 視床下核
  • 脳深部剌激
  • 随意運動
  • 大脳基底核疾患
  • 線条体

研究分野

  • ライフサイエンス / 医療薬学
  • ライフサイエンス / 生理学
  • ライフサイエンス / 神経科学一般

受賞

  • 2013年 日本生理学会奨励賞
    橘吉寿

  • 2006年 難病医学研究財団 医学研究奨励賞
    橘吉寿

  • 1999年 デンツプライ歯学賞
    橘吉寿

論文

  • Yumi Tsutsumi, Yayoi Morita, Fumihiko Sato, Takahiro Furuta, Katsuro Uchino, Jaerin Sohn, Tahsinul Haque, Yong Chul Bae, Hitoshi Niwa, Yoshihisa Tachibana, Atsushi Yoshida
    Proprioception from muscle spindles is necessary for motor function executed by the cerebellum. In particular, cerebellar nuclear neurons that receive proprioceptive signals and send projections to the lower brainstem or spinal cord play key roles in motor control. However, little is known about which cerebellar nuclear regions receive orofacial proprioception. Here, we investigated projections to the cerebellar nuclei from the supratrigeminal nucleus (Su5), which conveys the orofacial proprioception arising from jaw-closing muscle spindles (JCMSs). Injections of an anterograde tracer into the Su5 resulted in a large number of labeled axon terminals bilaterally in the dorsolateral hump (IntDL) of the cerebellar interposed nucleus (Int) and the dorsolateral protuberance (MedDL) of the cerebellar medial nucleus. In addition, a moderate number of axon terminals were ipsilaterally labeled in the vestibular group Y nucleus (group Y). We electrophysiologically detected JCMS proprioceptive signals in the IntDL and MedDL. Retrograde tracing analysis confirmed bilateral projections from the Su5 to the IntDL and MedDL. Furthermore, anterograde tracer injections into the external cuneate nucleus (ECu), which receives other proprioceptive input from forelimb/neck muscles, resulted in only a limited number of ipsilaterally labeled terminals, mainly in the dorsomedial crest of the Int and the group Y. Taken together, the Su5 and ECu axons almost separately terminated in the cerebellar nuclei (except for partial overlap in the group Y). These data suggest that orofacial proprioception is differently processed in the cerebellar circuits in comparison to other body-part proprioception, thus contributing to the executive function of orofacial motor control.
    2023年09月, Cerebellum (London, England), 英語, 国際誌
    研究論文(学術雑誌)

  • Daisuke Kato, Yuki Aoyama, Kazuki Nishida, Yutaka Takahashi, Takumi Sakamoto, Ikuko Takeda, Tsuyako Tatematsu, Shiori Go, Yutaro Saito, Shiho Kunishima, Jinlei Cheng, Lingnan Hou, Yoshihisa Tachibana, Shouta Sugio, Reon Kondo, Fumihiro Eto, Shumpei Sato, Andrew J Moorhouse, Ikuko Yao, Kenji Kadomatsu, Mitsutoshi Setou, Hiroaki Wake
    2023年07月, Glia
    [査読有り]

  • Yoko Hasegawa, Ayumi Sakuramoto, Tatsuya Suzuki, Joe Sakagami, Masako Shiramizu, Yoshihisa Tachibana, Hiromitsu Kishimoto, Yumie Ono, Takahiro Ono
    Distinct brain regions are known to be associated with various emotional states. Cortical activity may be modulated by emotional states that are triggered by flavors during food intake. We examined cortical activity during chewing with different flavors and assessed the emotional modulation of cortical activity using multichannel near-infrared spectroscopy. Thirty-six right-handed volunteers participated in this crossover trial. The participants experienced positive and negative emotions from chewing flavorful (palatable) or less flavorful (unpalatable) gums, respectively for 5 min. Participants rated the taste, odor, and deliciousness of each gum using a visual analog scale. Bilateral hemodynamic responses in the frontal and parietal lobes, bilateral masseter muscle activation, and heart rate were measured during gum chewing. Changes in all measured data during gum chewing were also evaluated. The ratings of the tastes and odors of each gum significantly differed among the participants (P < 0.001). Hemodynamic response changes were significantly elevated in the bilateral primary sensorimotor cortex during gum-chewing, in comparison to resting. The difference in hemodynamic responses between palatable and unpalatable gum conditions was detected in the left frontopolar/dorsolateral prefrontal cortex. Muscle activation and heart rate were not significantly different between different gum types. Our findings indicate that differential processing in the left prefrontal cortex might be responsible for the emotional states caused by palatable and unpalatable foods.
    Frontiers Media SA, 2022年11月, Frontiers in Neuroscience, 16
    研究論文(学術雑誌)

  • Yumi Tsutsumi, Fumihiko Sato, Takahiro Furuta, Katsuro Uchino, Masayuki Moritani, Yong Chul Bae, Takafumi Kato, Yoshihisa Tachibana, Atsushi Yoshida
    Proprioceptive sensory information from muscle spindles is essential for the regulation of motor functions. However, little is known about the motor control regions in the cerebellar cortex that receive proprioceptive signals from muscle spindles distributed throughout the body, including the orofacial muscles. Therefore, in this study, we investigated the pattern of projections in the rat cerebellar cortex derived from the supratrigeminal nucleus (Su5), which conveys orofacial proprioceptive information from jaw-closing muscle spindles (JCMSs). Injections of an anterograde tracer into the Su5 revealed that many bilateral axon terminals (rosettes) were distributed in the granular layer of the cerebellar cortex (including the simple lobule B, crus II and flocculus) in a various sized, multiple patchy pattern. We could also detect JCMS proprioceptive signals in these cerebellar cortical regions, revealing for the first time that they receive muscle proprioceptive inputs in rats. Retrograde tracer injections confirmed that the Su5 directly sends outputs to the cerebellar cortical areas. Furthermore, we injected an anterograde tracer into the external cuneate nucleus (ECu), which receives proprioceptive signals from the forelimb and neck muscle spindles, to distinguish between the Su5- and ECu-derived projections in the cerebellar cortex. The labeled terminals from the ECu were distributed predominantly in the vermis of the cerebellar cortex. Almost no overlap was seen in the terminal distributions of the Su5 and ECu projections. Our findings demonstrate that the rat cerebellar cortex receives orofacial proprioceptive input that is processed differently from the proprioceptive signals from the other regions of the body.
    2022年07月, Cerebellum (London, England), 22(4) (4), 663 - 679, 英語, 国際誌
    研究論文(学術雑誌)

  • Yuta Yoshioka, Yoshihisa Tachibana, Toshihiro Uesaka, Hiroyuki Hioki, Yuya Sato, Takumi Fukumoto, Hideki Enomoto
    Enteroendocrine cells (EECs) are the primary sensory cells that sense the gut luminal environment and secret hormones to regulate organ function. Recent studies revealed that vagal afferent neurons are connected to EECs and relay sensory information from EECs to the brain stem. To date, however, the identity of vagal afferent neurons connected to a given EEC subtype and the mode of their gene responses to its intestinal hormone have remained unknown. Hypothesizing that EEC-associated vagal afferent neurons change their gene expression in response to the microbiota-related extracellular stimuli, we conducted comparative gene expression analyses of the nodose-petrosal ganglion complex (NPG) using specific pathogen-free (SPF) and germ-free (GF) mice. We report here that the Uts2b gene, which encodes a functionally unknown neuropeptide, urotensin 2B (UTS2B), is expressed in a microbiota-dependent manner in NPG neurons. In cultured NPG neurons, expression of Uts2b was induced by AR420626, the selective agonist for FFAR3. Moreover, distinct gastrointestinal hormones exerted differential effects on Uts2b expression in NPG neurons, where cholecystokinin (CCK) significantly increased its expression. The majority of Uts2b-expressing NPG neurons expressed CCK-A, the receptor for CCK, which comprised approximately 25% of all CCK-A-expressing NPG neurons. Selective fluorescent labeling of Uts2b-expressing NPG neurons revealed a direct contact of their nerve fibers to CCK-expressing EECs. This study identifies the Uts2b as a microbiota-regulated gene, demonstrates that Uts2b-expressing vagal afferent neurons transduce sensory information from CCK-expressing EECs to the brain, and suggests potential involvement of UTS2B in a modality of CCK actions.
    2022年06月, Biochemical and biophysical research communications, 608, 66 - 72, 英語, 国際誌
    研究論文(学術雑誌)

  • Yu Hirata, Kazuhiro Nomura, Daisuke Kato, Yoshihisa Tachibana, Takahiro Niikura, Kana Uchiyama, Tetsuya Hosooka, Tomoaki Fukui, Keisuke Oe, Ryosuke Kuroda, Yuji Hara, Takahiro Adachi, Koji Shibasaki, Hiroaki Wake, Wataru Ogawa
    Whereas immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that KLF15 and IL-6 are up-regulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the down-regulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies to IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated by human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.
    2022年03月, The Journal of clinical investigation, 132(10) (10), 1 - 13, 英語, 国際誌
    研究論文(学術雑誌)

  • Atsushi Yoshida, Misaki Inoue, Fumihiko Sato, Yayoi Morita, Yumi Tsutsumi, Takahiro Furuta, Katsuro Uchino, Fatema Akhter, Yong Chul Bae, Yoshihisa Tachibana, Tomio Inoue
    The supratrigeminal nucleus (Su5) is a key structure for controlling jaw movements; it receives proprioceptive sensation from jaw-closing muscle spindles (JCMSs) and sends projections to the trigeminal motor nucleus (Mo5). However, the central projections and regulation of JCMS proprioceptive sensation are not yet fully understood. Therefore, we aimed to reveal the efferent and afferent connections of the Su5 using neuronal tract tracings. Anterograde tracer injections into the Su5 revealed that the Su5 sends contralateral projections (or bilateral projections with a contralateral predominance) to the Su5, basilar pontine nuclei, pontine reticular nucleus, deep mesencephalic nucleus, superior colliculus, caudo-ventromedial edge of the ventral posteromedial thalamic nucleus, parafascicular thalamic nucleus, zona incerta, and lateral hypothalamus, and ipsilateral projections (or bilateral projections with an ipsilateral predominance) to the intertrigeminal region, trigeminal oral subnucleus, dorsal medullary reticular formation, and hypoglossal nucleus as well as the Mo5. Retrograde tracer injections into the Su5 demonstrated that the Su5 receives bilateral projections with a contralateral predominance (or contralateral projections) from the primary and secondary somatosensory cortices, granular insular cortex, and Su5, and ipsilateral projections (or bilateral projections with an ipsilateral predominance) from the dorsal peduncular cortex, bed nuclei of stria terminalis, central amygdaloid nucleus, lateral hypothalamus, parasubthalamic nucleus, trigeminal mesencephalic nucleus, parabrachial nucleus, juxtatrigeminal region, trigeminal oral and caudal subnuclei, and dorsal medullary reticular formation. These findings suggest that the Su5, which receives JCMS proprioception, has efferent and afferent connections with multiple brain regions that are involved in emotional and autonomic functions as well as orofacial motor functions.
    2022年01月, Brain structure & function, 227(1) (1), 111 - 129, 英語, 国際誌
    研究論文(学術雑誌)

  • Yumi Tsutsumi, Yuka Mizuno, Tahsinul Haque, Fumihiko Sato, Takahiro Furuta, Ayaka Oka, Masayuki Moritani, Yong Chul Bae, Takashi Yamashiro, Yoshihisa Tachibana, Atsushi Yoshida
    The oval paracentral nucleus (OPC) was initially isolated from the paracentral nucleus (PC) within the intralaminar thalamic nuclei in rats. We have recently shown that the rat OPC receives proprioceptive inputs from jaw-closing muscle spindles (JCMSs). However, it remains unknown which cortical areas receive thalamic inputs from the OPC, and whether the cortical areas receiving the OPC inputs are distinct from those receiving inputs from the other intralaminar nuclei and sensory thalamic nuclei. To address this issue, we injected an anterograde tracer, biotinylated dextranamine (BDA), into the OPC, which was electrophysiologically identified by recording of proprioceptive inputs from the JCMSs. Many BDA-labeled axonal fibers and terminals from the OPC were ipsilaterally observed in the rostral and rostroventral regions of the primary somatosensory cortex (S1), the rostral region of the secondary somatosensory cortex (S2), and the most rostrocaudal levels of the granular insular cortex (GI). In contrast, a BDA injection into the caudal PC, which was located slightly rostral to the OPC, resulted in ipsilateral labeling of axonal fibers and terminals in the rostrolateral region of the medial agranular cortex and the rostromedial region of the lateral agranular cortex. Furthermore, injections of a retrograde tracer, Fluorogold, into these S1, S2, and GI regions, resulted in preferential labeling of neurons in the ipsilateral OPC among the intralaminar and sensory thalamic nuclei. These findings reveal that the rat OPC has widespread, but strong corticopetal projections, indicating that there exist divergent corticopetal pathways from the intralaminar thalamic nucleus, which process JCMS proprioceptive sensation.
    2021年05月, Brain structure & function, 226(4) (4), 1115 - 1133, 英語, 国際誌, 国際共著している
    [査読有り]
    研究論文(学術雑誌)

  • Takuya Okada, Daisuke Kato, Yuki Nomura, Norihiko Obata, Xiangyu Quan, Akihito Morinaga, Hajime Yano, Zhongtian Guo, Yuki Aoyama, Yoshihisa Tachibana, Andrew J Moorhouse, Osamu Matoba, Tetsuya Takiguchi, Satoshi Mizobuchi, Hiroaki Wake
    Sustained neuropathic pain from injury or inflammation remains a major burden for society. Rodent pain models have informed some cellular mechanisms increasing neuronal excitability within the spinal cord and primary somatosensory cortex (S1), but how activity patterns within these circuits change during pain remains unclear. We have applied multiphoton in vivo imaging and holographic stimulation to examine single S1 neuron activity patterns and connectivity during sustained pain. Following pain induction, there is an increase in synchronized neuronal activity and connectivity within S1, indicating the formation of pain circuits. Artificially increasing neuronal activity and synchrony using DREADDs reduced pain thresholds. The expression of N-type voltage-dependent Ca2+ channel subunits in S1 was increased after pain induction, and locally blocking these channels reduced both the synchrony and allodynia associated with inflammatory pain. Targeting these S1 pain circuits, via inhibiting N-type Ca2+ channels or other approaches, may provide ways to reduce inflammatory pain.
    2021年03月, Science advances, 7(12) (12), 英語, 国際誌
    [査読有り]
    研究論文(学術雑誌)

  • Yume Uemura, Tahsinul Haque, Fumihiko Sato, Yumi Tsutsumi, Haruka Ohara, Ayaka Oka, Takahiro Furuta, Yong Chul Bae, Takashi Yamashiro, Yoshihisa Tachibana, Atsushi Yoshida
    Proprioceptive signals from body muscles have historically been considered to project to the rostrodorsal shell of the ventrobasal thalamic complex [the ventral posterolateral nucleus (VPL) and ventral posteromedial nucleus (VPM)]. However, we have recently found that proprioception from rat jaw-closing muscle spindles (JCMSs) is conveyed via the supratrigeminal nucleus to the caudo-ventromedial edge of the VPM, but not to the rostrodorsal shell of the VPM. Therefore, proprioception from other body muscles may also project to thalamic regions other than the rostrodorsal shell of the VPL. We thus examined the thalamic projection from the rat external cuneate nucleus (ECu), which receives proprioceptive inputs from forelimb and neck muscles. After injection of anterograde tracer into the ECu, axon terminals were contralaterally labeled in the ventromedial part (VPLvm) of the VPL, but not in the rostrodorsal shell of the VPL. After anterograde tracer injection into the cuneate nucleus (Cu), axon terminals were widely labeled in the contralateral VPL including the VPLvm. In the VPLvm, we electrophysiologically confirmed the proprioceptive inputs responsive to electrical stimulation of the ECu or median nerve and to the pressure of forelimb/neck muscles or wrist flexion. After retrograde tracer injection into the VPLvm, neurons were contralaterally labeled in the ECu and Cu. After retrograde tracer injection into the VPL where no such proprioceptive inputs were recorded, no ECu neurons were labeled. These findings indicate that proprioception from forelimb/neck muscle spindles and JCMSs is somatotopically transmitted to the ventromedial floor of the ventrobasal thalamic complex, but not to its rostrodorsal shell.
    2020年09月, Brain structure & function, 225(7) (7), 2177 - 2192, 英語, 国際誌, 国際共著している
    [査読有り]
    研究論文(学術雑誌)

  • Fumihiko Sato, Seiya Kado, Yumi Tsutsumi, Yoshihisa Tachibana, Etsuko Ikenoue, Takahiro Furuta, Katsuro Uchino, Yong Chul Bae, Narikazu Uzawa, Atsushi Yoshida
    An invasive intralaminar thalamic stimulation and a non-invasive application of oral splint are both effective in treating tic symptoms of patients with Tourette syndrome (TS). Therefore, these two treatments may exert some influence on the same brain region in TS patients. We thus hypothesized that the proprioceptive input arising from the muscle spindles of jaw-closing muscles (JCMSs), known to be increased by the application of oral splint, is transmitted to the intralaminar thalamic nuclei. To test this issue, we morphologically and electrophysiologically examined the thalamic projections of proprioceptive input from the JCMSs to the intralaminar thalamic nuclei of rats. We first injected an anterograde tracer, biotinylated dextranamine, into the electrophysiologically identified supratrigeminal nucleus, which is known to receive proprioceptive inputs from the JCMSs via the trigeminal mesencephalic neurons. A moderate number of biotinylated dextranamine-labeled axon terminals were bilaterally distributed in the oval paracentral nucleus (OPC) of the intralaminar thalamic nuclei. We also detected electrophysiological responses to the electrical stimulation of bilateral masseter nerves and to sustained jaw-opening in the OPC. After injection of retrograde tracer (cholera toxin B subunit or Fluorogold) into the OPC, neuronal cell bodies were retrogradely labeled in the rostrodorsal portion of the bilateral supratrigeminal nucleus. Here, we show that proprioceptive inputs from the JCMSs are conveyed to the OPC in the intralaminar nuclei via the supratrigeminal nucleus. This study can help to understand previously unrecognized pathways of proprioception ascending inputs from the brainstem to the thalamus, which may contribute to treatments of TS patients.
    2020年07月, Brain research, 1739, 146830 - 146830, 英語, 国際誌, 国際共著している
    [査読有り]
    研究論文(学術雑誌)

  • Daisuke Kato, Hiroaki Wake, Philip R Lee, Yoshihisa Tachibana, Riho Ono, Shouta Sugio, Yukio Tsuji, Yasuyo H Tanaka, Yasuhiro R Tanaka, Yoshito Masamizu, Riichiro Hira, Andrew J Moorhouse, Nobuaki Tamamaki, Kazuhiro Ikenaka, Noriyuki Matsukawa, R Douglas Fields, Junichi Nabekura, Masanori Matsuzaki
    Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.
    2020年01月, Glia, 68(1) (1), 193 - 210, 英語, 国際誌, 国際共著している
    [査読有り]
    研究論文(学術雑誌)

  • Koichiro Haruwaka, Ako Ikegami, Yoshihisa Tachibana, Nobuhiko Ohno, Hiroyuki Konishi, Akari Hashimoto, Mami Matsumoto, Daisuke Kato, Riho Ono, Hiroshi Kiyama, Andrew J Moorhouse, Junichi Nabekura, Hiroaki Wake
    Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.
    2019年12月, Nature communications, 10(1) (1), 5816 - 5816, 英語, 国際誌, 国際共著している
    [査読有り]
    研究論文(学術雑誌)

  • Jumpei Murakami, Yoshihisa Tachibana, Shigehisa Akiyama, Takafumi Kato, Aya Taniguchi, Yoshiaki Nakajima, Mao Shimoda, Hiroaki Wake, Yukiko Kano, Masahiko Takada, Atsushi Nambu, Atsushi Yoshida
    2019年10月, Movement disorders : official journal of the Movement Disorder Society, 34(10) (10), 1577 - 1578, 英語, 国際誌
    [査読有り]

  • Hikosaka O, Kim HF, Amita H, Yasuda M, Isoda M, Tachibana Y, Yoshida A
    2019年03月, The European journal of neuroscience, 49(5) (5), 637 - 645, 国際共著している
    [査読有り]

  • Akiyoshi R, Wake H, Kato D, Horiuchi H, Ono R, Ikegami A, Haruwaka K, Omori T, Tachibana Y, Moorhouse AJ, Nabekura J
    Society for Neuroscience, 2018年09月, eNeuro, 5(5) (5), ENEURO.0088 - 18.2018
    [査読有り]
    研究論文(学術雑誌)

  • Etsuko Ikenoue, Fatema Akhter, Yumi Tsutsumi, Fumihiko Sato, Haruka Ohara, Katsuro Uchino, Takahiro Furuta, Yoshihisa Tachibana, Atsushi Yoshida
    Our motor behavior can be affected by proprioceptive information. However, little is known about which brain circuits contribute to this process. We have recently revealed that the proprioceptive information arising from jaw-closing muscle spindles (JCMSs) is conveyed to the supratrigeminal nucleus (Su5) by neurons in the trigeminal mesencephalic nucleus (Me5), then to the caudo-ventromedial edge of ventral posteromedial thalamic nucleus (VPMcvm), and finally to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2). Our next question is which brain areas receive the information from the dGIrvs2 for the jaw-movements. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the dGIrvs2, and analyzed the resultant distribution profiles of the labeled axon terminals. Anterogradely labeled axons were distributed in the pontomedullary areas (including the Su5) which are known to receive JCMS proprioceptive inputs conveyed directly by the Me5 neurons and to contain premotoneurons projecting to the jaw-closing motoneurons in the trigeminal motor nucleus (Mo5). They were also found in and around the VPMcvm. In contrast, no labeled axonal terminals were detected on the cell bodies of Me5 neurons and motoneurons in the Mo5. These data suggest that jaw-movements, which are evoked by the classically defined jaw-reflex arc originating from the peripheral JCMS proprioceptive information, could also be modulated by the transcortical feedback connections from the dGIrvs2 to the VPMcvm and Su5.
    Elsevier B.V., 2018年05月, Brain Research, 1687, 11 - 19, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Tsutsumi Y, Tachibana Y, Sato F, Furuta T, Ohara H, Tomita A, Fujita M, Moritani M, Yoshida A
    We have recently revealed that the proprioceptive signal from jaw-closing muscle spindles (JCMSs) is conveyed to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2) via the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM) in rats. However, it remains unclear to which cortical or subcortical structures the JCMS proprioceptive information is subsequently conveyed from the dGIrvs2. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the electophysiologically identified dGIrvs2, and analyzed the resultant distribution profiles of labeled axon terminals in rats. Labeled terminals were distributed with an ipsilateral predominance. In the cerebral cortex, they were seen in the primary and secondary somatosensory cortices, lateral and medial agranular cortices and dorsolateral orbital cortex. In the basal ganglia, they were found in the caudate putamen, core part of accumbens nucleus, lateral globus pallidus, subthalamic nucleus, and substantia nigra pars compacta and pars reticulata. They were also observed in the central amygdaloid nucleus and extended amygdala (the interstitial nucleus of posterior limb of anterior commissure and the juxtacapsular part of lateral division of bed nucleus of stria terminalis). In the thalamus, they were seen in the reticular nucleus, ventromedial nucleus, core VPM, parvicellular part of ventral posterior nucleus, oval paracentral nucleus, medial and triangular parts of posterior nucleus, and zona incerta as well as the VPMcvm. These data suggest that the JCMS proprioceptive information through the dGIrvs2 is transmitted to the emotional 'limbic' regions as well as sensorimotor regions.
    2018年, Neuroscience, 388, 317 - 329, 英語, 国際誌
    [査読有り]
    研究論文(学術雑誌)

  • Fumihiko Sato, Yume Uemura, Chiharu Kanno, Yumi Tsutsumi, Akiko Tomita, Ayaka Oka, Takafumi Kato, Katsuro Uchino, Jumpei Murakami, Tahsinul Haque, Yoshihisa Tachibana, Atsushi Yoshida
    Little is known about how proprioceptive signals arising from muscles reach to higher brain regions such as the cerebral cortex. We have recently shown that a particular thalamic region, the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM), receives the proprioceptive signals from jaw-closing muscle spindles (JCMSs) in rats. In this study, we further addressed how the orofacial thalamic inputs from the JCMSs were transmitted from the thalamus (VPMcvm) to the cerebral cortex in rats. Injections of a retrograde and anterograde neuronal tracer, wheat-germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), into the VPMcvm demonstrated that the thalamic pathway terminated mainly in a rostrocaudally narrow area in the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of the secondary somatosensory cortex (dGlrvs2). We also electrophysiologically confirmed that the dGlrvs2 received the proprioceptive inputs from JCMSs. To support the anatomical evidence of the VPMcvm-dGlrvs2 pathway, injections of aretrograde neuronal tracer Fluorogold into the dGlrvs2 demonstrated that the thalamic neurons projecting to the dGlrvs2 were confined in the VPMcvm and the parvicellular part of ventral posterior nucleus. In contrast, WGA-HRP injections into the lingual nerve area of core VPM demonstrated that axon terminals were mainly labeled in the core regions of the primary and secondary somatosensory cortices, which were far from the dGlrvs2. These results suggest that the dGlrvs2 is a specialized cortical region receiving the orofacial proprioceptive inputs. Functional contribution of the revealed JCMSs-VPMcvm-dGlrvs2 pathway to Tourette syndrome is also discussed. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
    PERGAMON-ELSEVIER SCIENCE LTD, 2017年12月, NEUROSCIENCE, 365, 158 - 178, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Hirokazu Iwamuro, Yoshihisa Tachibana, Yoshikazu Ugawa, Nobuhito Saito, Atsushi Nambu
    To understand how the information derived from different motor cortical areas representing different body parts is organized in the basal ganglia, we examined the neuronal responses in the subthalamic nucleus (STN), and the external (GPe) and internal (GPi) segments of the globus pallidus (input, relay and output nuclei, respectively) to stimulation of the orofacial, forelimb and hindlimb regions of the primary motor cortex (MI) and supplementary motor area (SMA) in macaque monkeys under the awake state. Most STN and GPe/GPi neurons responded exclusively to stimulation of either the MI or SMA, and one-fourth to one-third of neurons responded to both. STN neurons responding to the hindlimb, forelimb and orofacial regions of the MI were located along the medial-lateral axis in the posterolateral STN, while neurons responding to the orofacial region of the SMA were located more medially than the others in the anteromedial STN. GPe/GPi neurons responding to the hindlimb, forelimb and orofacial regions of the MI were found along the dorsal-ventral axis in the posterolateral GPe/GPi, and neurons responding to the corresponding regions of the SMA were similarly but less clearly distributed in more anteromedial regions. Moreover, neurons responding to the distal and proximal forelimb MI regions were found along the lateral-medial axis in the STN and the ventral-dorsal axis in the GPe/GPi. Most STN and GPe/GPi neurons showed kinaesthetic responses with similar somatotopic maps. These observations suggest that the somatotopically organized inputs from the MI and SMA are well preserved in the STN and GPe/GPi with partial convergence.
    WILEY, 2017年12月, EUROPEAN JOURNAL OF NEUROSCIENCE, 46(11) (11), 2684 - 2701, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Atsushi Yoshida, Takashi Fujio, Fumihiko Sato, Md Sams Sazzad Ali, Tahsinul Haque, Haruka Ohara, Masayuki Moritani, Takafumi Kato, Jonathan O. Dostrovsky, Yoshihisa Tachibana
    The ascending pathway mediating proprioception from the orofacial region is still not fully known. The present study elucidated the relay of jaw-closing muscle spindle (JCMS) inputs from brainstem to thalamus in rats. We injected an anterograde tracer into the electrophysiologically identified supratrigeminal nucleus (Su5), known to receive JCMS input. Many thalamic axon terminals were labeled and were found mainly contralaterally in a small, unpredicted area of the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM). Electrical stimulation of the masseter nerve and passive jaw movements induced large responses in the VPMcvm. The VPMcvm is far from the rostrodorsal part of ventral posterolateral thalamic nucleus (VPL) where proprioceptive inputs from the body are represented. After injection of a retrograde tracer into the electrophysiologically identified VPMcvm, many neurons were labeled almost exclusively in the contralateral Su5, whereas no labeled neurons were found in the principal sensory trigeminal nucleus (Pr5) and spinal trigeminal nucleus (Sp5). In contrast, after injection of a retrograde tracer into the core of VPM, many neurons were labeled contralaterally in the Pr5 and Sp5, but none in the Su5. We conclude that JCMS input excites trigeminothalamic projection neurons in the Su5 which project primarily to the VPMcvm in marked contrast to other pro-prioceptors and sensory receptors in the orofacial region which project to the core VPM. These findings suggest that lesions or deep brain stimulation in the human equivalent of VPMcvm may be useful for treatment of movement disorders (e.g., orofacial tremor) without affecting other sensations.
    SPRINGER HEIDELBERG, 2017年08月, BRAIN STRUCTURE & FUNCTION, 222(6) (6), 2655 - 2669, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Yoko Hasegawa, Yoshihisa Tachibana, Takahiro Ono, Hiromitsu Kishimoto
    There is some evidence to suggest that chewing gum reduces chronic stress. However, it remains controversial how the taste and odour properties of chewing gum influence stress. The present study was designed to investigate this issue in human subjects. Using an enzyme-linked immunosorbent assay, we tested salivary cortisol concentration, which is thought to be a stress marker, in 96 adults who chewed gum with different combinations of taste and odour. Subjects could discriminate between the types of gum without prior information. Salivary cortisol concentrations were highest and lowest for the subjects who chewed the most flavourful gum and the least flavourful gum, respectively. These findings suggest that the salivary cortisol level during gum chewing is not a marker of negative emotions (i.e., stressful conditions) as traditionally considered but, rather, an index of positive emotions that can facilitate biological responses to overcome stressful conditions.
    PUBLIC LIBRARY SCIENCE, 2017年04月, PLOS ONE, 12(4) (4), e0173475, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Osamu Shouno, Yoshihisa Tachibana, Atsushi Nambu, Kenji Doya
    Parkinson's disease is a movement disorder caused by dopamine depletion in the basal ganglia. Abnormally synchronized neuronal oscillations between 8 and 15 Hz in the basal ganglia are implicated in motor symptoms of Parkinson's disease. However, how these abnormal oscillations are generated and maintained in the dopamine-depleted state is unknown. Based on neural recordings in a primate model of Parkinson's disease and other experimental and computational evidence, we hypothesized that the recurrent circuit between the subthalamic nucleus (STN) and the external segment of the globus pallidus (GPe) generates and maintains parkinsonian oscillations, and that the cortical excitatory input to the STN amplifies them. To investigate this hypothesis through computer simulations, we developed a spiking neuron model of the STN-GPe circuit by incorporating electrophysiological properties of neurons and synapses. A systematic parameter search by computer simulation identified regions in the space of the intrinsic excitability of GPe neurons and synaptic strength from the GPe to the STN that reproduce normal and parkinsonian states. In the parkinsonian state, reduced firing of GPe neurons and increased GPe-STN inhibition trigger burst activities of STN neurons with strong post-inhibitory rebound excitation, which is usually subject to short-term depression. STN neuronal bursts are shaped into the 8-15 Hz, synchronous oscillations via recurrent interactions of STN and GPe neurons. Furthermore, we show that cortical excitatory input to the STN can amplify or suppress pathological STN oscillations depending on their phase and strength, predicting conditions of cortical inputs to the STN for suppressing oscillations.
    FRONTIERS MEDIA SA, 2017年03月, FRONTIERS IN NEUROANATOMY, 11, 21, 英語
    [査読有り]
    研究論文(学術雑誌)

  • T. Fujio, F. Sato, Y. Tachibana, T. Kato, A. Tomita, K. Higashiyama, T. Ono, Y. Maeda, A. Yoshida
    The supratrigeminal nucleus (Vsup), originally proposed as a premotoneuron pool in the trigeminal reflex arc, is a key structure of jaw movement control. Surprisingly, however, the location of the rat Vsup has not precisely been defined. In light of our previous cat studies, we made two hypotheses regarding the rat Vsup: (1) the Vsup is cytoarchitectonically distinguishable from its surrounding structures; (2) the Vsup receives central axon terminals of the trigeminal mesencephalic nucleus (Vmes) neurons which are primary afferents innervating muscle spindles of jaw-closing muscles and periodontal ligaments around the teeth. To test the first hypothesis, we examined the cytoarchitecture of the rat Vsup. The Vsup was identified as an area medially adjacent to the dorsomedial part of trigeminal principal sensory nucleus (Vp), and extended from the level just rostral to the caudal two-thirds of the trigeminal motor nucleus (Vmo) to the level approximately 150 mu m caudal to the Vmo. Our rat Vsup was much smaller and its location was considerably different in comparison to the Vsup reported previously. To evaluate the second hypothesis, we tested the distribution patterns of Vmes primary afferent terminals in the cytoarchitectonically identified Vsup. After transganglionic tracer applications to the masseter, deep temporal, and medial pterygoid nerves, a large number of axon terminals were observed in all parts of Vsup (especially in its medial part). After applications to the inferior alveolar, infraorbital, and lingual nerves, a small number of axon terminals were labeled in the caudolateral Vsup. The Vsup could also be identified electrophysiologically. After electrical stimulation of the masseter nerve, evoked potentials with slow negative component were isolated only in the Vsup. The present findings suggest that the rat Vsup can be cytoarchitectonically and electrophysiologically identified, receives somatotopic termination of the trigeminal primary afferents, and principally receives strong termination of the spindle Vmes primary afferents. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
    PERGAMON-ELSEVIER SCIENCE LTD, 2016年06月, NEUROSCIENCE, 324, 307 - 320, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Haruka Ohara, Yoshihisa Tachibana, Takashi Fujio, Rieko Takeda-Ikeda, Fumihiko Sato, Ayaka Oka, Takafumi Kato, Etsuko Ikenoue, Takashi Yamashiro, Atsushi Yoshida
    Trigeminal mesencephalic nucleus (Vmes) neurons are primary afferents conveying deep sensation from the masticatory muscle spindles or the periodontal mechanoreceptors, and are crucial for controlling jaw movements. Their cell bodies exist in the brain and receive descending commands from a variety of cortical and subcortical structures involved in limbic (emotional) systems. However, it remains unclear how the lateral habenula (LHb), a center of negative emotions (e.g., pain, stress and anxiety), can influence the control of jaw movements. To address this issue, we examined whether and how the LHb directly projects to the Vmes by means of neuronal tract tracing techniques in rats. After injections of a retrograde tracer Fluorogold in the rostral and caudal Vmes, a number of neurons were labeled in the lateral division of LHb (LHbl) bilaterally, whereas a few neurons were labeled in the medial division of LHb (LHbm) bilaterally. After injections of an anterograde tracer, biotinylated dextranamine (BDA) in the LHbl, a small number of labeled axons were distributed bilaterally in the rostral and caudal levels of Vmes, where some labeled axonal boutons contacted the cell body of rostral and caudal levels of Vmes neurons bilaterally. After the BDA injection into the LHbm, however, no axons were labeled bilaterally in the rostral and caudal levels of Vmes. Therefore, the present study for the first time demonstrated the direct projection from the LHbl to the Vmes and the detailed projection patterns, suggesting that jaw movements are modulated by negative emotions that are signaled by LHbl neurons. (C) 2015 Elsevier B.V. All rights reserved.
    ELSEVIER SCIENCE BV, 2016年01月, BRAIN RESEARCH, 1630, 183 - 197, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Atsushi Nambu, Yoshihisa Tachibana
    Accumulating evidence suggests that abnormal neuronal oscillations in the basal ganglia (BG) contribute to the manifestation of parkinsonian symptoms. In this article, we would like to summarize our recent work on the mechanism underlying abnormal oscillations in the parkinsonian state and discuss its significance in pathophysiology of Parkinson's disease. We recorded neuronal activity in the BG of parkinsonian monkeys treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Systemic administration of L-DOPA alleviated parkinsonian motor signs and decreased abnormal neuronal oscillations (8-15 Hz) in the internal (GPi) and external (GPe) segments of the globus pallidus and the subthalamic nucleus (STN). Inactivation of the STN by muscimol (GABAA receptor agonist) injection also ameliorated parkinsonian signs and suppressed GPi oscillations. The blockade of glutamatergic inputs to the STN by local microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (glutamatergic NMDA receptor antagonist) and 1, 2, 3, 4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline- 7-sulfonamide (glutamatergic AMPA/kainate receptor antagonist) suppressed neuronal oscillations in the STN. STN oscillations were also attenuated by the blockade of GABAergic neurotransmission from the GPe to the STN by muscimol inactivation of the GPe. These results suggest that cortical glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of GPe and STN neurons in the parkinsonian state. The oscillatory activity in the STN is subsequently transmitted to the GPi and may contribute to manifestation of parkinsonian symptoms. © 2014 Nambu and Tachibana.
    Frontiers Research Foundation, 2014年05月, Frontiers in Systems Neuroscience, 8(MAY) (MAY), 英語
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    研究論文(学術雑誌)

  • Yoko Hasegawa, Yoshihisa Tachibana, Joe Sakagami, Min Zhang, Masahiro Urade, Takahiro Ono
    Background:Flavor perception, the integration of taste and odor, is a critical factor in eating behavior. It remains unclear how such sensory signals influence the human brain systems that execute the eating behavior.Methods:We tested cerebral blood flow (CBF) in the frontal lobes bilaterally while subjects chewed three types of gum with different combinations of taste and odor: no taste/no odor gum (C-gum), sweet taste/no odor gum (T-gum), and sweet taste/lemon odor gum (TO-gum). Simultaneous recordings of transcranial Doppler ultrasound (TCD) and near infrared spectrometer (NIRS) were used to measure CBF during gum chewing in 25 healthy volunteers. Bilateral masseter muscle activity was also monitored.Results:We found that subjects could discriminate the type of gum without prior information. Subjects rated the TO-gum as the most flavorful gum and the C-gum as the least flavorful. Analysis of masseter muscle activity indicated that masticatory motor output during gum chewing was not affected by taste and odor. The TCD/NIRS measurements revealed significantly higher hemodynamic signals when subjects chewed the TO-gum compared to when they chewed the C-gum and T-gum.Conclusions:These data suggest that taste and odor can influence brain activation during chewing in sensory, cognitive, and motivational processes rather than in motor control. © 2013 Hasegawa et al.
    6, 2013年06月, PLoS ONE, 8(6) (6), 英語
    [査読有り]
    研究論文(学術雑誌)

  • Yoshihisa Tachibana, Okihide Hikosaka
    Motor actions are facilitated when expected reward value is high. It is hypothesized that there are neurons that encode expected reward values to modulate impending actions and potentially represent motivation signals. Here, we present evidence suggesting that the ventral pallidum (VP) may participate in this process. We recorded single neuronal activity in the monkey VP using a saccade task with a direction-dependent reward bias. Depending on the amount of the expected reward, VP neurons increased or decreased their activity tonically until the reward was delivered, for both ipsiversive and contraversive saccades. Changes in expected reward values were also associated with changes in saccade performance (latency and velocity). Furthermore, bilateral muscimol-induced inactivation of the VP abolished the reward-dependent changes in saccade latencies. These data suggest that the VP provides expected reward value signals that are used to facilitate or inhibit motor actions.
    CELL PRESS, 2012年11月, NEURON, 76(4) (4), 826 - 837, 英語
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    研究論文(学術雑誌)

  • Hiroki Nishibayashi, Atsuhi Nambu, Yoshihisa Tachibana, Toru Itakura
    2011年12月, Movement Disorders, 26(14) (14), 2583 - 2584, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Atsushi Nambu, Satomi Chiken, Pullanipally Shashidharan, Hiroki Nishibayashi, Mitsuhiro Ogura, Koji Kakishita, Satoshi Tanaka, Yoshihisa Tachibana, Hitoshi Kita, Toru Itakura
    Dystonia is a neurological disorder characterized by sustained or repetitive involuntary muscle contractions and abnormal postures. In the present article, we will introduce our recent electrophysiological studies in hyperkinetic transgenic mice generated as a model of DYT1 dystonia and in a human cervical dystonia patient, and discuss the pathophysiology of dystonia on the basis of these electrophysiological findings. Recording of neuronal activity in the awake state of DYT1 dystonia model mice revealed reduced spontaneous activity with bursts and pauses in both internal (GPi) and external (GPe) segments of the globus pallidus. Electrical stimulation of the primary motor cortex evoked responses composed of excitation and subsequent long-lasting inhibition, the latter of which was never observed in normal mice. In addition, somatotopic arrangements were disorganized in the GPi and GPe of dystonia model mice. In a human cervical dystonia patient, electrical stimulation of the primary motor cortex evoked similar long-lasting inhibition in the GPi and GPe. Thus, reduced GPi output may cause increased thalamic and cortical activity, resulting in the involuntary movements observed in dystonia. © 2011 Nambu, Chiken, Shashidharan, Nishibayashi, Ogura, Kakishita, Tanaka, Tachibana, Kita and Itakura.
    2011年11月, Frontiers in Systems Neuroscience, 5(2011) (2011), 89, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Yoshihisa Tachibana, Hirokazu Iwamuro, Hitoshi Kita, Masahiko Takada, Atsushi Nambu
    Parkinsons disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine-depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated parkinsonian monkeys. We found that systemic administration of l-3,4-dihydroxyphenylalanine (l-DOPA; dopamine precursor) decreased abnormal neuronal oscillations (815 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when parkinsonian signs were alleviated and during l-DOPA-induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABAA receptor agonist). Intrapallidal microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; N-methyl-d-aspartate receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine-depleted state, glutamatergic inputs to the STN and reciprocal GPeSTN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinsons disease.
    WILEY-BLACKWELL, 2011年11月, EUROPEAN JOURNAL OF NEUROSCIENCE, 34(9) (9), 1470 - 1484, 英語
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    研究論文(学術雑誌)

  • Hiroki Nishibayashi, Mitsuhiro Ogura, Koji Kakishita, Satoshi Tanaka, Yoshihisa Tachibana, Atsushi Nambu, Hitoshi Kita, Toru Itakura
    Responses of neurons in the globus pallidus (GP) to cortical stimulation were recorded for the first time in humans. We performed microelectrode recordings of GP neurons in 10 Parkinson's disease (PD) patients and 1 cervical dystonia (CD) patient during surgeries to implant bilateral deep brain stimulation electrodes in the GP. To identify the motor territories in the external (GPe) and internal (GPi) segments of the GP, unitary responses evoked by stimulation of the primary motor cortex were observed by constructing peristimulus time histograms. Neurons in the motor territories of the GPe and GPi responded to cortical stimulation. Response patterns observed in the PD patients were combinations of an early excitation, an inhibition, and a late excitation. In addition, in the CD patient, a long-lasting inhibition was prominent, suggesting increased activity along the cortico-striato-GPe/GPi pathways. The firing rates of GPe and GPi neurons in the CD patient were lower than those in the PD patients. Many GPe and GPi neurons of the PD and CD patients showed burst or oscillatory burst activity. Effective cathodal contacts tended to be located close to the responding neurons. Such unitary responses induced by cortical stimulation may be of use to target motor territories of the GP for stereotactic functional neurosurgery. Future findings utilizing this method may give us new insights into understanding the pathophysiology of movement disorders. (C) 2011 Movement Disorder Society
    WILEY-BLACKWELL, 2011年02月, MOVEMENT DISORDERS, 26(3) (3), 469 - 476, 英語
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    研究論文(学術雑誌)

  • Organization of motor cortical inputs in the globus pallidus via the subthalamic nucleus in monkeys
    Iwamuro Hirokazu, Tachibana Yoshihisa, Saito Nobuhito, Nambu Atsushi
    2008年, NEUROSCIENCE RESEARCH, 61, S241
    [査読有り]

  • Yoshihisa Tachibana, Hitoshi Kita, Satomi Chiken, Masahiko Takada, Atsushi Nambu
    The internal segment of the globus pallidus (GPi) receives motor-related cortical signals mainly through the striatum, the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). The GPi sends its outputs outside the basal ganglia and plays a key role in motor control. Extracellular unit recordings were performed in awake monkeys to explore how glutamatergic STN inputs and GABAergic striatal and GPe inputs control spontaneous activity and how these inputs contribute to motor cortex stimulation-induced responses of GPi neurons. The typical responses of GPi neurons to cortical stimulation consisted of an early excitation, an inhibition and a late excitation. Local applications of the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid and/or the AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide in the vicinity of recorded GPi neurons reduced the firing rate, and abolished or attenuated both early and late excitations following cortical stimulation. Local application of the GABA(A) receptor antagonist gabazine increased the firing rate, induced oscillatory firings and diminished the cortically induced inhibition. Muscimol or gabazine injection into the STN or GPe also altered the firing rate, and attenuated the late excitation of GPi neurons. The gabazine injection into the STN occasionally induced dyskinesia with significantly decreased GPi activity. These data suggest that the early and late excitations are glutamatergic and induced by the cortico-STN-GPi and cortico-striato-GPe-STN-GPi pathways, respectively. The inhibition is GABAergic and induced by the cortico-striato-GPi pathway. In addition, these inputs are the main factors governing the spontaneous activity of GPi neurons.
    WILEY-BLACKWELL, 2008年01月, EUROPEAN JOURNAL OF NEUROSCIENCE, 27(1) (1), 238 - 253, 英語
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    研究論文(学術雑誌)

  • Tachibana Yoshihisa, Iwamuro Hirokazu, Takada Masahiko, Nambu Atsushi
    2007年, NEUROSCIENCE RESEARCH, 58, S60
    [査読有り]

  • Hitoshi Kita, Satomi Chiken, Yoshihisa Tachibana, Atsushi Nambu
    Serotonin (5-HT)-containing neurons in the dorsal raphe project to the external and internal segments of the pallidum, which express several 5-HT receptors. Although the involvement of 5-HT in basal ganglia movement control has been suggested, little is known about the physiological action of 5-HT in the pallidum. Previous anatomical studies and in vitro physiological studies in other brain areas have suggested the following possibilities: (1) 5-HT suppresses GABAergic inhibition through presynaptic 5-HT1B receptors; (2) 5-HT decreases the firing of pallidal neurons through postsynaptic 5-HT1A receptors; and (3) 5-HT postsynaptically excites pallidal neurons through activation of 5-HT2C, 5-HT4, or 5-HT7 receptors. To test these possibilities, we examined the effects of locally applied agonists and antagonists of 5-HT on spontaneous neuronal firing and on excitatory and inhibitory responses of pallidal neurons to electrical stimulation of the motor cortex in awake monkeys. Although in vivo experiments could not conclusively determine the receptor types or the active sites involved in the observed effects, the results suggested the following possibilities: (1) 5-HT strongly suppresses GABAergic inhibition probably through 5-HT1B receptors; (2) in the external pallidal segment, the suppression may involve additional receptors or mechanisms; and (3) 5-HT suppresses glutamatergic excitation probably through 5-HT1A (and not 5-HT1B) receptors. The present study did not isolate or identify the existence of strong, direct postsynaptic inhibitory or excitatory effects of 5-HT. Thus, present results imply that 5-HT modulates synaptic inputs of both pallidal segments and exerts a significant role in movement control.
    SOC NEUROSCIENCE, 2007年01月, JOURNAL OF NEUROSCIENCE, 27(1) (1), 75 - 83, 英語
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    研究論文(学術雑誌)

  • H Kita, S Chiken, Y Tachibana, A Nambu
    The external and internal segments of the pallidum (GPe and GPi) receive heavy GABAergic innervations from the neostriatum, an input nucleus of the basal ganglia. The GPe neurons provide another major GABAergic innervation to the GPe itself and GPi. Although these GABAergic inputs are considered to play key roles in controlling the level and pattern of firing activity of pallidal neurons in both normal and pathophysiological conditions, these inputs have not been well characterized in vivo. Here, we characterized the responses of pallidal neurons to single and burst stimulation of the putamen (Put) in awake monkeys. Unit recordings in combination with local infusion of drugs and a chemical blockade of the subthalamic nucleus (STN), the major origin of excitatory afferents, revealed the following. Under STN blockade, the duration of single Put stimulation induced gabazine (a GABAA antagonist)-sensitive responses differed greatly in the GPe (similar to 400 ms long) and in the GPi (60 ms long). Burst stimulation of the Put induced CGP55845 [(2S)-3-{[(1S)-1-(3,4 dichlorophenyl)ethyl] amino-2-hydroxypropyl}(phenylmethyl) phosphinic acid] (a GABAB antagonist)- sensitive responses in the GPe and GPi. However, the data suggested that the origin of the GABAB responses was the GPe, not the Put. Local CGP55845 application increased the spontaneous firing of GPe and GPi neurons, suggesting that GABA released from the axons of GPe neurons effectively activates GABAB receptors in the GPe and GPi and contributes significantly to the control of the level of neuronal activity.
    SOC NEUROSCIENCE, 2006年06月, JOURNAL OF NEUROSCIENCE, 26(24) (24), 6554 - 6562, 英語
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    研究論文(学術雑誌)

  • Ionotropic glutamate receptor antagonism can reduce abnormal pallidal discharges in parkinsonian monkeys
    Tachibana Yoshihisa, Iwamuro Hirokazu, Takada Masahiko, Nambu Atsushi
    2006年, NEUROSCIENCE RESEARCH, 55, S200
    [査読有り]

  • K Kaneda, Y Tachibana, M Imanishi, H Kita, R Shigemoto, A Nambu, M Takada
    Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1 alpha, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1-related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1-related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down-regulation of pallidal and nigral mGluR1 alpha in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus-derived glutamatergic input that is generated in the disease.
    BLACKWELL PUBLISHING, 2005年12月, EUROPEAN JOURNAL OF NEUROSCIENCE, 22(12) (12), 3241 - 3254, 英語
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    研究論文(学術雑誌)

  • H Kita, Y Tachibana, A Nambu, S Chiken
    The subthalamic nucleus (STN) plays a pivotal role in controlling the activity of both the external and internal segments of the globus pallidus (GPe and GPi, respectively). Both nuclei receive monosynaptic excitatory and disynaptic GPe- mediated inhibitory inputs from the STN. Thus, we investigated the balance of these antagonistic inputs that may determine the overall response of pallidum to STN activation in monkeys. Single stimulation of the STN evoked a short-latency excitation followed by a weak inhibition in GPe neurons and a short-latency, very short-duration excitation followed by a strong inhibition in GPi neurons. Burst high-frequency stimulation (BHFS) ( 10 stimuli with 100 Hz) of the STN (STN-BHFS) evoked powerful excitatory responses in GPe neurons. Local injection of a mixture of 1, 2, 3, 4-tetrahydro-6-nitro-2, 3-dioxobenzo[f] quinoxaline-7-sulfonamide ( NBQX; AMPA/kainate receptor blocker) and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP;NMDA receptor blocker) greatly diminished or abolished excitatory responses to the STN stimulation. In contrast to the GPe, STN-BHFS evoked a predominantly inhibitory response in GPi neurons. The inhibition could be blocked either by a local application of the GABA(A) receptor antagonist gabazine or by an injection of an NBQX/CPP/ gabazine mixture into the GPe. STN-BHFS induced weak excitatory or inhibitory responses in a small number of phasically active putamen neurons. These data suggest that with single stimulation and during STN-BHFS, the STN-GPe excitatory response dominates over the STN-GPe-GPe recurrent inhibition in the GPe, whereas the STN-GPe-GPi inhibitory response dominates over the STN-GPi excitatory response in the GPi.
    SOC NEUROSCIENCE, 2005年09月, JOURNAL OF NEUROSCIENCE, 25(38) (38), 8611 - 8619, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Y Masuda, SK Kim, T Kato, S Iida, A Yoshida, Y Tachibana, T Morimoto
    The cortical masticatory area (CMA) elicits rhythmic jaw movements in response to repetitive stimulation and is involved in the control of mastication. Based on jaw movement patterns, the CMA is divided into two parts. One is the part of the CMA in which a T-pattern similar to jaw movements during food transport in natural mastication is evoked by electrical stimulation. The other is more dorsomedially located, and during chewing a C-pattern similar to jaw movements can be induced. However, it is still not known which region of the putamen receives projections from the CMA and whether projections originate from both parts of the CMA. In this study, electrophysiological and histological experiments were undertaken in rabbits to investigate projections from the CMA to the putamen. Both experiments showed that the ventral region of the putamen received projections from the CMA. The density of the projections from the CMA area inducing the T-pattern seemed to be higher than that from the area inducing the C-pattern. Furthermore, the peak latency of the evoked potentials from stimulation of the CMA area inducing the T-pattern was shorter than that from stimulation of the area inducing the C-pattern. The data obtained from the present study indicate the functional role of the ventral region of the putamen in the regulation of mastication, and further suggest that the corticostriatal pathway is involved in the transition between behavioral jaw movement patterns.
    SPRINGER, 2005年03月, EXPERIMENTAL BRAIN RESEARCH, 161(3) (3), 397 - 404, 英語
    [査読有り]
    研究論文(学術雑誌)

  • H Kita, A Nambu, K Kaneda, Y Tachibana, M Takada
    The neurons in the external segment of the pallidum (GPe) in awake animals maintain a high level of firing activity. The level and pattern of the activity change with the development of basal ganglia disorders including parkinsonism and hemiballism. The GPe projects to most of the nuclei in the basal ganglia. Thus exploring the mechanisms controlling the firing activity is essential for understanding basal ganglia function in normal and pathological conditions. To explore the role of ionotropic glutamatergic and GABAergic inputs to the GPe, unit recordings combined with local injections of receptor antagonists were performed in awake monkeys. Observations on the effects of local application of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate antagonist 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulfonamide, the N-methyl-D-aspartic acid (NMDA) antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, and the GABA(A) antagonist gabazine as well as the effects of muscimol blockade of the subthalamic nucleus on the spontaneous firing rate, firing patterns, and cortical stimulation induced responses in the GPe suggested the following: sustained glutamatergic and GABAergic inputs control the level of the spontaneous firing of GPe neurons; both AMPA/kainate and NMDA receptors are activated by glutamatergic inputs; some GPe neurons receive glutamatergic inputs originating from areas other than the subthalamic nucleus; no GPe neurons became silent after a combined application of glutamate and GABA antagonists, suggesting that GPe neurons have intrinsic properties or nonionotropic glutamatergic tonic inputs that sustain a fast oscillatory firing or a combination of a fast and a slow oscillatory firing in GPe neurons.
    AMER PHYSIOLOGICAL SOC, 2004年11月, JOURNAL OF NEUROPHYSIOLOGY, 92(5) (5), 3069 - 3084, 英語
    [査読有り]
    研究論文(学術雑誌)

  • M Takada, A Nambu, N Hatanaka, Y Tachibana, S Miyachi, M Taira, M Inase
    Linkage between the prefrontal cortex and the primary motor cortex is mediated by nonprimary motor-related areas of the frontal lobe. In an attempt to analyse the organization of the prefrontal outflow from area 46 toward the frontal motor-related areas, we investigated the pattern of projections involving the higher-order motor-related areas, such as the presupplementary motor area (pre-SMA) and the rostral cingulate motor area (CMAr). Tracer injections were made into these motor-related areas (their forelimb representation) on the medial wall that had been identified electrophysiologically. The following data were obtained from a series of tract-tracing experiments in Japanese monkeys. (i) Only a few neurons in area 46 were retrogradely labelled from the pre-SMA and CMAr; (ii) terminal labelling from area 46 occurred sparsely in the pre-SMA and CMAr; (iii) a dual labelling technique revealed that the sites of overlap of anterograde labelling from area 46 and retrograde labelling from the pre-SMA and CMAr were evident in the rostral parts of the dorsal and ventral premotor cortices (PMdr and PMvr); (iv) and tracer injections into the PMdr produced neuronal cell labelling in area 46 and terminal labelling in the pre-SMA and CMAr. The present results indicate that a large portion of the prefrontal signals from area 46 is not directly conveyed to the pre-SMA and CMAr, but rather indirectly by way of the PMdr and PMvr. This suggests that area 46 exerts its major influence on the cortical motor system via these premotor areas.
    BLACKWELL PUBLISHING LTD, 2004年06月, EUROPEAN JOURNAL OF NEUROSCIENCE, 19(12) (12), 3328 - 3342, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Y Tachibana, A Nambu, N Hatanaka, S Miyachi, M Takada
    Until recently, little was known about the rostral part of the dorsal premotor cortex (PMdr). In the present study, somatotopical representations of the PMdr were electrophysiologically identified in the macaque monkey, and the distribution of corticostriatal input from the forelimb region of the PMdr was analyzed in relation to its thalamocortical and intracortical (with the frontal lobe) connections. Results have revealed that (1) the forelimb is represented predominantly in the PMdr, while only a few sites representing other body parts are distributed as embedded within the forelimb representation; (2) the corticostriatal input zone is located in the striatal cell bridges and their surroundings; (3) the cells of origin of the thalamocortical projections to the PMdr are located mainly in the parvicellular division of the ventroanterior nucleus, the oral divison of the ventrolateral nucleus, area X, the caudal divison of the ventrolateral nucleus, the mediodorsal nucleus, and the intralaminar nuclear group; (4) the PMdr is interconnected primarily with higher-order motor-related areas and dorsal area 46. These data indicate that the input-output pattern of the PMdr resembles those of the presupplementary motor area and the rostral cingulate motor area, and that the PMdr may play critical roles in higher-order motor functions. (C) 2003 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved.
    ELSEVIER IRELAND LTD, 2004年01月, NEUROSCIENCE RESEARCH, 48(1) (1), 45 - 57, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Yuji Masuda, Yoshihisa Tachibana, Tomio Inoue, Koichi Iwata, Toshifumi Morimoto
    Abstract In order to study the role of sensory inputs to the cortical masticatory area (CMA) and plasticity in the CMA, the representation of sensory inputs and the change of sensory inputs and motor outputs in the CMA 16 days after trigeminal deafferentation in the rabbit were examined. Neuronal activity was recorded in response to mechanical and electrical stimulation of the oro-facial region and cortically-induced rhythmical jaw movements (CIRJMs) were analyzed. Cortical neurons with receptive fields in the deafferented region were not found in the CMA. However, the projection area of the intact lingual nerve extended both antero-posteriorly and medio-laterally in the CMA and included neurons with long latency responses to lingual nerve stimulation. In a previous study in the rabbit, CIRJMs were classified into two groups according to their similarity to normal masticatory patterns: one pattern resembled that occurring during the food transport stage (T-pattern), and the other resembled that occurring during the chewing stage (C-pattern). These two patterns of CIRJMs were evoked from different stimulation sites: T-patterns were induced from the dorsal CMA and C-patterns were induced from the ventral CMA. The relationship between the patterns of CIRJMs and the site of stimulation in the deafferented rabbits was similar to that observed in normal rabbits. This finding suggests that sensory inputs to the CMA may not directly influence the CMA motor outputs controlling jaw movements, despite a close spatial relationship between the input and output of this area.
    2002年, Experimental Brain Research, 146(4) (4), 501 - 510, 英語
    [査読有り]
    研究論文(学術雑誌)

  • Alteration of medullary dorsal horn neuronal activity following inferior alveolar nerve transection in rats
    K Iwata, T Imai, Y Tsuboi, A Tashiro, A Ogawa, T Morimoto, Y Masuda, Y Tachibana, J Hu
    The effects of inferior alveolar nerve (IAN) transection on escape behavior and MDH neuronal activity to noxious and nonnoxious stimulation of the face were precisely analyzed. Relative thresholds for escape from mechanical stimulation applied to the whisker pad area ipsilateral to the transection were significantly lower than that for the contralateral and sham-operated whisker pad until 28 days after the transection, then returned to the preoperative level at 40 days after transection. A total of 540 neurons were recorded from the medullary dorsal horn (MDH) of the nontreated naive rats [low-threshold mechanoreceptive (LTM), 27; wide dynamic range (WDR), 31; nociceptive specific (NS), 11] and sham-operated rats with skin incision (LTM, 34; WDR, 30; NS, 23) and from the ipsilateral (LTM, 82; WDR, 82; NS, 31) and contralateral MDH relative to the IAN transection (LTM, 77; WDR, 82; NS, 33). The electrophysiological properties of these neurons were precisely analyzed. Background activity of WDR neurons on the ipsilateral side relative to the transection was significantly increased at 2-14 days after the operation as compared with that of naive rats. Innocuous and noxious mechanical-evoked responses of LTM and WDR neurons were significantly enhanced at 2-14 days after IAN transection. The mean area of the receptive fields of WDR neurons was significantly larger on the ipsilateral MDH at 2-7 days after transection than that of naive rats. We could not observe any modulation of thermal responses of WDR and NS neurons following IAN transection. Also, no MDH neurons were significantly affected in the rats with sham operations. The present findings suggest that the increment of neuronal activity of WDR neurons in the MDH following IAN transection may play an important role in the development of the mechano-allodynia induced in the area adjacent to the area innervated by the injured nerve.
    AMER PHYSIOLOGICAL SOC, 2001年12月, JOURNAL OF NEUROPHYSIOLOGY, 86(6) (6), 2868 - 2877, 英語
    [査読有り]
    研究論文(学術雑誌)

MISC

  • 閉口筋筋紡錘感覚の小脳皮質への投射
    堤友美, 佐藤文彦, 古田貴寛, 孫在隣, 加藤隆史, 橘吉寿, 吉田篤, 吉田篤
    2023年, Journal of Oral Biosciences Supplement (Web), 2023

  • 味および香りがガム咀嚼時のストレスに及ぼす影響
    長谷川 陽子, 橘 吉寿, 小野 高裕
    (NPO)日本咀嚼学会, 2012年11月, 日本咀嚼学会雑誌, 22(2) (2), 144 - 145, 日本語

共同研究・競争的資金等の研究課題

  • 糖尿病網膜神経変性におけるアクアポリン9の役割の解明
    楠原 仙太郎, 淺原 俊一郎, 橘 吉寿
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日
    1.研究内容:遺伝子改変糖尿病マウスを安定的に得るためにInsCre;Pdkflox/+マウスとPdkflox/floxマウスを用いた体外受精を行い凍結受精卵を作成した。このことによって、任意の時期にInsCre;Pdkflox/flox(糖尿病マウス)およびPdkflox/floxマウス(コントロールマウス)を得ることができるようになった。遺伝子改変マウスCx3cr1-GFPマウス(ミクログリア標識)およびアデノ随伴ウイルス(アストロサイト、網膜神経節細胞)による標識を適宜利用し、糖尿病マウスでの2光子顕微鏡による生体イメージングを行った。ミクログリアの動きおよび形態変化を定量化する方法につき複数のアルゴリズムをトライし、安定して評価できる系が確立されつつある。また、AQP9の糖尿病網膜神経変性における役割の解明を進めるために、InsCre;Pdkflox/flox;Aqp9-/-マウスおよびPdkflox/flox;Aqp9+/-マウス(コントロール)の安定供給に向けマウスの交配を続けていると同時にAqp9-/-マウスにストレプトゾトシンを投与し高血糖を誘発して解析を進めている。 2.研究の意義:多面的な神経保護作用を有する乳酸のトランスポーターであるAQP9は糖尿病早期における糖尿病網膜神経変性に関与している可能性が高い。慢性炎症の際に早期から異常が認められるミクログリアの変化が2光子顕微鏡による生体イメージングで解析できていることから、この研究を続けることによって糖尿病網膜におけるAQP9の役割が明らかになるものと思われる。 3. 研究の重要性:本研究によって糖尿病早期におけるAQP9の役割が明らかになれば、乳酸をターゲットにした糖尿病網膜症への早期介入への道筋が示されることになり将来の失明予防に大いに貢献できると考える。

  • 神経回路可視化と光操作による薬物依存形成脳内機構の解明
    橘 吉寿, 金田 勝幸
    日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2021年04月01日 - 2024年03月31日

  • 行動の構造:比較認知神経科学によるアプローチ
    兎田 幸司, 櫻井 勝康, 橘 吉寿
    日本学術振興会, 科学研究費助成事業, 国際共同研究加速基金(国際共同研究強化(B)), 2018年10月09日 - 2021年03月31日
    本研究計画では、行動を担っている心理学的および神経生物学的基盤について解明することを目標として研究を行った。遺伝子改変マウスを利用可能な頭部固定を用いた実験系を用いて、様々な嗜好性および嫌悪性の古典的条件づけおよびオペラント条件づけ課題を新規に確立することができた。また、この課題を用いて、行動薬理学、光遺伝学、化学遺伝学の手法を用いて、神経細胞の活動を操作することにより、各種の行動に及ぼす影響について明らかにした。さらに、計算論的なアプローチを用いて、行動を変化させる要因について詳細に解明した。

  • 糖尿病網膜神経変性におけるneurovascular unitの役割の解明
    楠原 仙太郎, 淺原 俊一郎, 橘 吉寿
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2018年04月01日 - 2021年03月31日
    糖尿病(InsCreTg; Pdk1flox/flox)マウス網膜におけるneurovascular unit障害の評価とグリア細胞の2光子顕微鏡によるin vivoイメージングを行った。免疫染色では、糖尿病マウス網膜ではコントロールマウスに比べ、網膜神経節細胞軸索減少とラミニン菲薄化が先行するがその際にミクログリアが活性化されていることが明らかとなった。コンタクトレンズ等の光学系の改良により高解像度in vivo網膜イメージングが可能となった。この系を用いてミクログリアが突起を伸長させながら網膜血管とアストロサイトの周囲を遊走する様子および白血球がゆっくり血管腔内を移動する様子が観察された。

  • チック症の発現機序を紐解く-光イメージング法を用いたアプローチ-
    橘 吉寿
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2018年04月01日 - 2021年03月31日
    チックとは、反復性の動作を示す運動チックと奇声を発する音声チックから成るが、その病態に関しては明らかでない。線条体における異常興奮がチックの本態であるという仮説のもと、マウス線条体へのGABA受容体拮抗薬注入により、一過性の筋収縮を示すチック症状を呈するモデルマウスを作製することに成功した。さらに、c-Fos蛋白の免疫染色を行うことで、症状発現時の活性化脳部位を検討した結果、一次運動野に加え、扁桃体、帯状皮質、島皮質といった情動機能に関与する辺縁系脳部位の活性化を観察した。このことから、チックは運動のみならず情動に関連する脳領域のネットワーク異常に起因する疾患であることが明らかとなった。

  • 発振現象を基軸としたパーキンソン病の病態解明とオプトDBS開発
    橘 吉寿
    日本学術振興会, 科学研究費助成事業, 新学術領域研究(研究領域提案型), 神戸大学, 2018年04月01日 - 2020年03月31日
    パーキンソン病において、大脳基底核内の局所回路における異常リズム形成がパーキンソン病症状発現に深く関与するという報告がこれまでなされている。また、この異常リズムを是正する目的での視床下核もしくは淡蒼球内節(ともに大脳基底核の構成要素である)の高頻度電気刺激が、パーキンソン病症状を改善することが臨床的に知られている。しかしながら、パーキンソン病患者ならびにパーキンソン病モデル動物において、大脳基底核で異常発振が見られるものの、大脳皮質―大脳基底核―視床ループの一部である大脳皮質運動野において異常発振が起こるかどうか未だ明らかでない。これらの問題を解決するため、パーキンソン病モデルマウスにおいて、大脳基底核と密に連絡し最終的な運動出力を担う大脳皮質運動野で基底核と同様の異常リズムが観察されるかどうかを2光子顕微鏡イメージングにて検証した。その結果、パーキンソン病症状発現前に比べ、症状発現後において、大脳皮質一次運動野の同期発火は、大脳皮質浅層(II/III層)で有意に増加し、大脳皮質深層(V層)では有意な増加を示さないことが明らかとなった。また、大脳皮質一次運動野のII/III層は線条体に、V層は視床下核にそれぞれ投射することが解剖学的に確認されたので、ウイルスの二重感染により線条体もしくは視床下核にそれぞれ投射する大脳皮質運動野神経細胞を可視化することに成功し、さらに投射特異的な光遺伝学による人工神経活動操作法も確立したので、今後は、細胞種特異的に大脳皮質神経細胞の異常な同期化を是正することで、パーキンソン病症状が改善するかについて検証したい。

  • 口腔顔面機能にかかわる脳内回路を解明し、その重要性をコネクトーム研究に反映させる
    吉田 篤, 富田 章子, 加藤 隆史, 橘 吉寿, 佐藤 文彦
    日本学術振興会, 科学研究費助成事業, 挑戦的萌芽研究, 大阪大学, 2016年04月01日 - 2018年03月31日
    本研究で次の結果を得た。(1)意識に上らない閉口筋筋紡錘感覚は、三叉神経中脳路核ニューロンによって三叉神経上核に運ばれた後、視床後腹側内側核の尾腹内側部に伝達され、さらに顆粒性島皮質の小領域に伝達された。異常な咬合がこの経路によって、情動や自律神経機能に悪影響を与え得ると考えられる。(2)他のほとんど全ての口腔顔面感覚は、三叉神経節ニューロンによって三叉神経感覚核群に送られた後、視床後腹側内側核の中央部に伝達され、さらに感覚の弁別に関わる一次と二次体性感覚野に伝達された。(3)上記の2経路は交通せず別個であった。歯科領域での新発見が将来のコネクトーム研究に大きく貢献した。

  • 咀嚼する食品の味・香りがストレス反応に与える影響
    長谷川 陽子, 小野 高裕, 橘 吉寿
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 兵庫医科大学, 2013年04月01日 - 2016年03月31日
    本研究は,咀嚼する食品の味・香りとストレス反応との関連性を明らかにすることを目的に実験を行った.研究は,(1)ストレスを引き起こす咀嚼食品の味・香りについての検討,(2)食品に対する嗜好が脳高次機能に及ぼす影響について,(3)咀嚼食品に対する嗜好の違いが神経系・自律神経調節に与える影響,の3項目に分けて行った. その結果,咀嚼による刺激時唾液に含まれるコルチゾールは,美味しいガムを噛むことによって増え、生体の抗ストレス作用が高まる可能性が示唆された.また,美味しさを感じることによる脳高次機能の変化は明らかではなく,今後も検討を続ける必要性が示された.

  • ハイリスク・ハイリターン、ローリスク・ローリターンを選択する神経基盤と調節因子
    橘 吉寿
    日本学術振興会, 科学研究費助成事業, 新学術領域研究(研究領域提案型), 生理学研究所, 2012年04月01日 - 2014年03月31日
    本研究課題においては、(サル)がローリスク・ローリターン、ハイリスク・ハイリターンな状況におかれた際、どのような行動選択(意思決定)を行い、その際、大脳基底核にある視床下核ニューロンがどのように活動するかを電気生理学的に記録・解析することを目標とする。申請者が用いる行動課題(眼球運動課題)においては、視覚刺激の色情報に基づいた意思決定をサルは行わねばならない。具体的には、まず中央に四角形が現れ、サルが一定期間固視したあと、左右に二つの視覚刺激が呈示される。一つは緑色の視覚刺激で、研究期間を通して、ローリスク・ローリターンな報酬を予測させる刺激である。もう一つの刺激は、赤色の視覚刺激で、これは絶えずハイリスク・ハイリターンな報酬を予測させる刺激である。遅延期間のあと、固視点が消灯し、それを合図にサルは、左右のいずれかの視覚刺激に急速眼球運動を行わねばならない。ローリスク・ローリターンを示す緑色の刺激を選択した場合、例えば、ある決まった量の報酬を5回に4回の割合で得ることが出来る。一方、ハイリスク・ハイリターンを示す赤色の刺激を選んだ場合は、例えば、5回に1回の割合でしか報酬を得ることが出来ない。ただし、報酬を得ることが出来る試行においては、報酬量が緑色の刺激を選んだ際に得られる報酬量の4倍となる。このような眼球運動課題をサルに課した結果、ハイリスク・ハイリターンを示す刺激に対し、ローリスク・ローリターンとなる刺激をサルは好んで選択した。齧歯類は総じてハイリスク・ハイリターンとなる刺激を好むのに対し、サルはヒトと同様に、ローリスク・ローリターンを好んで選んだことは非常に興味深い結果と考えられる。また、その際に視床下核ニューロンから非常にユニークな関連神経活動が記録された。

  • 行動を安定化させる神経機構-大脳基底核の新たな機能を探る-
    橘 吉寿
    日本学術振興会, 科学研究費助成事業, 若手研究(B), 生理学研究所, 2012年04月01日 - 2014年03月31日
    行動制御系としてのアクセルとブレーキの機能を大脳基底核が担っているという仮説の下、眼球運動課題遂行中のサル視床下核から神経活動を記録した。その結果、ブレーキの機能を発現すると考えられてきた視床下核は運動が亢進する時にその神経活動を増大させていることが明らかとなった。従来の概念からすると運動が抑制される時に活動を増大させると予測されるが、実験結果は逆であった。他方、アクセルの機能と考えられる線条体の神経活動は運動が亢進する時に増大していることが分かっている。これらの事象から考えると、大脳基底核は行動制御系においてアクセルとブレーキを共働させることで安定した行動の発現を可能としていると考えられる。

  • 脳深部刺激療法がパーキンソン病を改善する神経生理学的基盤を探る
    橘 吉寿
    日本学術振興会, 科学研究費助成事業, 若手研究(B), 生理学研究所, 2007年 - 2008年
    パーキンソン病の病態生理を解明するために、MPTP神経毒誘発性パーキンソン病モデルサルを作製し、大脳基底核の神経活動を記録した。その結果、淡蒼球外節、淡蒼球内節ならびに視床下核において、過度のbeta帯域(13-17Hz)の発振現象を示す神経活動が多数観察された。これらの異常な神経活動はMPTP神経毒投与前においては認められなかったことから、この大脳基底核ニューロンにおけるbeta帯域の発振現象がパーキンソン症状を惹起している可能性が考えられる。モデル動物へのパーキンソン病治療薬であるL-DOPAの投与により、パーキンソン症状の消失と共に、beta帯域の異常発振は減弱した。つぎに、大脳基底核の出力核である淡蒼球内節の異常発振は、視床下核からのグルタミン酸作動性入力により惹起されるものであるという仮説のもと、視床下核にムシモールを注入し視床下核の神経活動を不活化したところ、パーキンソン症状の減弱と共に、淡蒼球内節の発振現象は消失した。また、視床下核の発振現象についてさらに詳細に調べたところ、淡蒼球外節からのGABA作動性入力と大脳皮質からのグルタミン酸作動性入力により視床下核の発振活動が増強されることが明らかとなった。本研究は、パーキンソン病患者に対して視床下核あるいは淡蒼球内節の脳深部刺激療法が奏功する作用メカニズムを考える上で、非常に重要な神経生理学的知見を与えるものであると考えられる。

  • 大脳皮質-大脳基底核ループによる動的運動制御機構の解明
    南部 篤, 畑中 伸彦, 橘 吉寿, 知見 聡美
    日本学術振興会, 科学研究費助成事業, 基盤研究(B), 生理学研究所, 2006年 - 2008年
    (1)正常な大脳基底核の機能に関する研究 線条体、淡蒼球外節・内節の活動を、覚醒下、課題遂行中のサルから記録し、大脳皮質刺激に対する応答や運動との相関を調べた。また、局所に薬剤を注入することにより、これらの神経活動が引き起こされるメカニズムについて検討した。 (2)大脳基底核疾患の病態に関する研究 MPTPを投与して作製したパーキンソン病モデルサルや、ヒト全身性ジストニアの原因遺伝子であるDYT1遺伝子を組み込んだジストニアモデルマウス、さらにはステレオ手術時に大脳基底核疾患患者などから大脳基底核の神経活動を記録することにより、これら大脳基底核疾患の病態について検討した。 その結果、ハイパー直接路・直接路・間接路が順にダイナミックに働くことにより、不必要な運動が抑制され、必要な運動のみが正確なタイミングで引き起こされるというモデルが妥当であり、これによってある程度、大脳基底核疾患の病態を説明できることが示された。