Researchers Database


    DivisionofBrainandNeurophysiology,DepartmentofPhysiology Assistant Professor
Last Updated :2022/01/25

Researcher Information


J-Global ID

Research Interests

  • 遺伝子改変ラット   遺伝子改変マウス   肥満   バゾプレシン   セロトニン   幼若期   トランスジェニックラット   摂食   酸素消費量   母子愛着   RFRP   ACTH   オキシトシン   社会行動   

Research Areas

  • Life sciences / Neuroscience - general
  • Life sciences / Molecular biology
  • Life sciences / Physiology
  • Life sciences / Neuroscience - general

Academic & Professional Experience

  • 2012 - Today  Jichi Medical UniversitySchool of Medicine講師
  • 2007 - 2012  Jichi Medical UniversitySchool of Medicine助教
  • 2005 - 2007  Jichi Medical UniversitySchool of Medicine助手

Association Memberships

  • 日本神経内分泌学会   

Published Papers

  • Jun Watanabe, Yuki Takayanagi, Masahide Yoshida, Tatsuya Hattori, Michiko Saito, Kenji Kohno, Eiji Kobayashi, Tatsushi Onaka
    Journal of neuroendocrinology e13057  2021/10 
    Vasopressin-synthesizing neurons are located in several brain regions, including the hypothalamic paraventricular nucleus (PVN), supraoptic nucleus (SON) and suprachiasmatic nucleus (SCN). Vasopressin has been shown to have various functions in the brain, including social recognition memory, stress responses, emotional behaviors and circadian rhythms. The precise physiological functions of vasopressin-synthesizing neurons in specific brain regions remain to be clarified. Conditional ablation of local vasopressin-synthesizing neurons may be a useful tool for investigation of the functions of vasopressin neurons in the regions. In the present study, we characterized a transgenic rat line that expresses a mutated human diphtheria toxin receptor under control of the vasopressin gene promoter. Under a condition of salt loading, which activates the vasopressin gene in the hypothalamic PVN and SON, transgenic rats were i.c.v. injected with diphtheria toxin. Intracerebroventricular administration of diphtheria toxin after salt loading depleted vasopressin-immunoreactive cells in the hypothalamic PVN and SON, but not in the SCN. The number of oxytocin-immunoreactive cells in the hypothalamus was not significantly changed. The rats that received i.c.v. diphtheria toxin after salt loading showed polydipsia and polyuria, which were rescued by peripheral administration of 1-deamino-8-d-arginine vasopressin via an osmotic mini-pump. Intrahypothalamic administration of diphtheria toxin in transgenic rats under a normal hydration condition reduced the number of vasopressin-immunoreactive neurons, but not the number of oxytocin-immunoreactive neurons. The transgenic rat model can be used for selective ablation of vasopressin-synthesizing neurons and may be useful for clarifying roles of vasopressin neurons at least in the hypothalamic PVN and SON in the rat.
  • Tatsushi Onaka, Yuki Takayanagi
    Journal of neuroendocrinology e13049  2021/10 
    Early-life experience influences social and emotional behaviour in adulthood. Affiliative tactile stimuli in early life facilitate the development of social and emotional behaviour, whereas early-life adverse stimuli have been shown to increase the risk of various diseases in later life. On the other hand, oxytocin has been shown to have organizational actions during early-life stages. However, the detailed mechanisms of the effects of early-life experience and oxytocin remain unclear. Here, we review the effects of affiliative tactile stimuli during the neonatal period and neonatal oxytocin treatment on the activity of the oxytocin-oxytocin receptor system and social or emotional behaviour in adulthood. Both affiliative tactile stimuli and early-life adverse stimuli in the neonatal period acutely activate the oxytocin-oxytocin receptor system in the brain but modulate social behaviour and anxiety-related behaviour apparently in an opposite direction in adulthood. Accumulating evidence suggests that affiliative tactile stimuli and exogenous application of oxytocin in early-life stages induce higher activity of the oxytocin-oxytocin receptor system in adulthood, although the effects are dependent on experimental procedures, sex, dosages and brain regions examined. On the other hand, early-life stressful stimuli appear to induce reduced activity of the oxytocin-oxytocin receptor system, possibly leading to adverse actions in adulthood. It is possible that activation of a specific oxytocin system can induce beneficial actions against early-life maltreatments and thus could be used for the treatment of developmental psychiatric disorders.
  • Naoki Usui, Masahide Yoshida, Yuki Takayanagi, Naranbat Nasanbuyan, Ayumu Inutsuka, Hiroshi Kurosu, Hiroaki Mizukami, Yoshiyuki Mori, Makoto Kuro-O, Tatsushi Onaka
    Journal of neuroendocrinology e13026  2021/08 
    Fibroblast growth factor 21 (FGF21) modulates energy metabolism and neuroendocrine stress responses. FGF21 synthesis is increased after environmental or metabolic challenges. Detailed roles of FGF21 in the control of behavioural disturbances under stressful conditions remain to be clarified. Here, we examined the roles of FGF21 in the control of behavioural changes after social defeat stress in male rodents. Central administration of FGF21 increased the number of tyrosine hydroxylase-positive catecholaminergic cells expressing c-Fos protein, an activity marker of neurones, in the nucleus tractus solitarius and area postrema. Double in situ hybridisation showed that some catecholaminergic neurones in the dorsal medulla oblongata expressed β-Klotho, an essential co-receptor for FGF21, in male mice. Social defeat stress increased FGF21 concentrations in the plasma of male mice. FGF21-deficient male mice showed social avoidance in a social avoidance test with C57BL/6J mice (background strain of FGF21-deficient mice) and augmented immobility behaviour in a forced swimming test after social defeat stress. On the other hand, overexpression of FGF21 by adeno-associated virus vectors did not significantly change behaviours either in wild-type male mice or FGF21-deficient male mice. The present data are consistent with the view that endogenous FGF21, possibly during the developmental period, has an inhibitory action on stress-induced depression-like behaviour in male rodents.
  • Wataru Nishimura, Yuki Takayanagi, Munkhtuya Tumurkhuu, Ruyun Zhou, Harukata Miki, Yasuko Noda
    Physiology & behavior 234 113386 - 113386 2021/05 
    Long-term and mild confinement or isolation in an enclosed environment can occur in situations such as disasters, specific political, economic or social events, nuclear shelters, seabed exploration, polar expeditions, and space travel. To investigate the effects of stress caused by long-term confinement in an enclosed environment in mammals, we divided 8-week-old C57BL/6J mice into four groups that were housed in a closed environment with a narrow metabolic cage (stress group), normal metabolic cage (control group), conventional cage (conventional group) or conventional cage with wire mesh floor (wire mesh group). The phenotypes of the mice were examined for four weeks, followed by behavioral tests. Weight gain suppression was observed in the stress group. Continuous analysis of these mice every two minutes for four weeks using an implanted measuring device showed a significantly decreased amount of spontaneous activity and subcutaneous temperature in the stress group. After housing in each environment for four weeks, the behavioral tests of mice in the stress group also revealed a shorter latency to fall off in the rotarod test and shorter stride length and interstep distance in the footprint test. Interestingly, the lower spontaneous activity of mice in the stress group was rescued by housing in conventional cages. These results suggest a temporary effect of long-term confinement in an enclosed environment as a chronic and mild stress on homeostasis in mammals.
  • Makiya Matsumoto, Masahide Yoshida, Buddhini Wimarsha Jayathilake, Ayumu Inutsuka, Katsuhiko Nishimori, Yuki Takayanagi, Tatsushi Onaka
    Journal of neuroendocrinology 33 (6) e12980  2021/05 
    Social contact reduces stress responses in social animals. Mice have been shown to show allogrooming behaviour toward distressed conspecifics. However, the precise neuronal mechanisms underlying allogrooming behaviour remain unclear. In the present study, we examined whether mice show allogrooming behaviour towards distressed conspecifics in a social defeat model and we also determined whether oxytocin receptor-expressing neurons were activated during allogrooming by examining the expression of c-Fos protein, a marker of neurone activation. Mice showed allogrooming behaviour toward socially defeated conspecifics. After allogrooming behaviour, the percentages of oxytocin receptor-expressing neurones expressing c-Fos protein were significantly increased in the anterior olfactory nucleus, cingulate cortex, insular cortex, lateral septum and medial amygdala of female mice, suggesting that oxytocin receptor-expressing neurones in these areas were activated during allogrooming behaviour toward distressed conspecifics. The duration of allogrooming was correlated with the percentages of oxytocin receptor-expressing neurones expressing c-Fos protein in the anterior olfactory nucleus, insular cortex, lateral septum and medial amygdala. In oxytocin receptor-deficient mice, allogrooming behaviour toward socially defeated cage mates was markedly reduced in female mice but not in male mice, indicating the importance of the oxytocin receptor for allogrooming behaviour in female mice toward distressed conspecifics. The results suggest that the oxytocin receptor, possibly in the anterior olfactory nucleus, insular cortex, lateral septum and/or medial amygdala, facilitates allogrooming behaviour toward socially distressed familiar conspecifics in female mice.
  • Shota Okabe, Yuki Takayanagi, Masahide Yoshida, Tatsushi Onaka
    Scientific reports 11 (1) 3805 - 3805 2021/02 
    Gentle touch contributes to affiliative interactions. We investigated the effects of gentle stroking in female rats on the development of affiliative behaviors toward humans and we exploratively examined brain regions in which activity was influenced by stroking. Rats that had received stroking stimuli repeatedly after weaning emitted 50-kHz calls, an index of positive emotion, and showed affiliative behaviors toward the experimenter. Hypothalamic paraventricular oxytocin neurons were activated in the rats after stroking. The septohypothalamic nucleus (SHy) in the post-weaningly stroked rats showed decreased activity in response to stroking stimuli compared with that in the non-stroked control group. There were negative correlations of neural activity in hypothalamic regions including the SHy with the number of 50-kHz calls. These findings revealed that post-weaning stroking induces an affiliative relationship between female rats and humans, possibly via activation of oxytocin neurons and suppression of the activity of hypothalamic neurons.
  • Yoshie Kurokawa, Hitoshi Osaka, Takeshi Kouga, Eriko Jimbo, Kazuhiro Muramatsu, Sachie Nakamura, Yuki Takayanagi, Tatsushi Onaka, Shin-Ichi Muramatsu, Takanori Yamagata
    Human gene therapy 2020/11 [Refereed]
    Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a CMV promotor (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μl) and cisterna magna (10 μl) of Npc1 homo-knockout (Npc1-/-) mice. Each mouse received total 1.35×1011 vector genome on day 4 or 5 of life. AAV-treated Npc1-/- mice (n=11) had an average survival of >28 weeks, while all saline-treated Npc1-/- mice (n=11) and untreated Npc1-/- mice (n=6) died within 16 weeks. Saline-treated and untreated Npc1-/- mice lost body weight from seven weeks until death. However, the average body weight of AAV-treated Npc1-/- mice increased until 15 weeks. AAV-treated Npc1-/- mice also showed a significant improvement in Rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1-/- mice. In contrast, untreated Npc1-/- mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports with injection into the lateral ventricles or veins alone. In AAV-treated Npc1-/- mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in liver was reduced in the AAV-treated Npc1-/- mice. Our results suggest the feasibility of gene therapy for patients with NPC1.
  • Shoko Takei, Shuichi Nagashima, Akihito Takei, Daisuke Yamamuro, Tetsuji Wakabayashi, Akiko Murakami, Masayo Isoda, Hisataka Yamazaki, Chihiro Ebihara, Manabu Takahashi, Ken Ebihara, Katsuya Dezaki, Yuki Takayanagi, Tatsushi Onaka, Ken Fujiwara, Takashi Yashiro, Shun Ishibashi
    Diabetes 69 (11) 2352 - 2363 2020/11 [Refereed]
    Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes. To investigate the role of HMGCR in the development of β-cells and glucose homeostasis, we deleted Hmgcr in a β-cell-specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in β-cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β-cell mass and insulin secretion. Ki67-positive cells were reduced in β-KO mice at P9; thus, β-cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of β-cell-associated genes, such as insulin, pancreatic and duodenal homeobox 1 (Pdx1), and MAF BZIP transcription factor A (Mafa) in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β-cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β-cells in mice.
  • Shota Okabe, Yuki Takayanagi, Masahide Yoshida, Tatsushi Onaka
    Scientific reports 10 (1) 9135 - 9135 2020/06 [Refereed][Not invited]
    Gentle tactile stimuli have been shown to play an important role in the establishment and maintenance of affiliative social interactions. Oxytocin has also been shown to have similar actions. We investigated the effects of gentle stroking on affiliative relationships between humans and rats and the effects of gentle stroking on activation of oxytocin neurons. Male rats received 5-min stroking stimuli from an experimenter every other day for 4 weeks between 3 and 6 weeks of age (S3-6 group), for 4 weeks between 7 and 10 weeks of age (S7-10 group), or for 8 weeks between 3 and 10 weeks of age (S3-10 group). Control rats did not receive stroking stimuli. Rats in the S7-10 and S3-10 groups emitted 50-kHz calls, an index of positive emotion, more frequently during stroking stimuli. Rats in the S3-6, S7-10, and S3-10 groups showed affiliative behaviors toward the experimenter. Oxytocin neurons in the hypothalamic paraventricular nucleus of rats in the S3-6, S7-10, and S3-10 groups were activated following stroking stimuli. These findings revealed that post-weaning repeated stroking stimuli induce an affiliative relationship between rats and humans and activation of oxytocin neurons.
  • Yoshida M, Takayanagi Y, Ichino-Yamashita A, Sato K, Sugimoto Y, Kimura T, Nishimori K
    Endocrinology 160 (12) 2800 - 2810 0013-7227 2019/12 [Refereed][Not invited]
  • Tatsushi Onaka, Yuki Takayanagi
    Journal of neuroendocrinology 31 (3) e12700  0953-8194 2019/03 [Refereed][Not invited]
    Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information-processing cerebral cortex; the cognitive information-processing prefrontal cortex; reward-related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress-related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis-controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.
  • Naranbat Nasanbuyan, Masahide Yoshida, Yuki Takayanagi, Ayumu Inutsuka, Katsuhiko Nishimori, Akihiro Yamanaka, Tatsushi Onaka
    Endocrinology 159 (2) 763 - 775 0013-7227 2018/02 [Refereed][Not invited]
    Social stress has deteriorating effects on various psychiatric diseases. In animal models, exposure to socially dominant conspecifics (i.e., social defeat stress) evokes a species-specific defeat posture via unknown mechanisms. Oxytocin neurons have been shown to be activated by stressful stimuli and to have prosocial and anxiolytic actions. The roles of oxytocin during social defeat stress remain unclear. Expression of c-Fos, a marker of neuronal activation, in oxytocin neurons and in oxytocin receptor‒expressing neurons was investigated in mice. The projection of oxytocin neurons was examined with an anterograde viral tracer, which induces selective expression of membrane-targeted palmitoylated green fluorescent protein in oxytocin neurons. Defensive behaviors during double exposure to social defeat stress in oxytocin receptor‒deficient mice were analyzed. After social defeat stress, expression of c-Fos protein was increased in oxytocin neurons of the bed nucleus of the stria terminalis, supraoptic nucleus, and paraventricular hypothalamic nucleus. Expression of c-Fos protein was also increased in oxytocin receptor‒expressing neurons of brain regions, including the ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray. Projecting fibers from paraventricular hypothalamic oxytocin neurons were found in the ventrolateral part of the ventromedial hypothalamus and in the ventrolateral periaqueductal gray. Oxytocin receptor‒deficient mice showed reduced defeat posture during the second social defeat stress. These findings suggest that social defeat stress activates oxytocin-oxytocin receptor systems, and the findings are consistent with the view that activation of the oxytocin receptor in brain regions, including the ventrolateral part of the ventromedial hypothalamus and the ventrolateral periaqueductal gray, facilitates social defeat posture.
  • Yuki Takayanagi, Masahide Yoshida, Akihide Takashima, Keiko Takanami, Shoma Yoshida, Katsuhiko Nishimori, Ichiko Nishijima, Hirotaka Sakamoto, Takanori Yamagata, Tatsushi Onaka
    Biological psychiatry 81 (3) 243 - 251 0006-3223 2017/02 [Refereed][Not invited]
    BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. CONCLUSIONS: The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits.
  • Shota Okabe, Masahide Yoshida, Yuki Takayanagi, Tatsushi Onaka
    Neuroscience letters 600 22 - 7 0304-3940 2015/07 [Refereed][Not invited]
    Gentle touching or stroking has anxiolytic actions and contributes to the establishment of an intimate relationship between individuals. Oxytocin administration also has anxiolytic actions and facilitates social behaviors. In this study, we examined effects of stroking stimuli on activation of oxytocin neurons and emission of 50-kHz ultrasonic vocalizations, an index of positive emotion, in rats. The number of oxytocin neurons expressing Fos protein was increased in the hypothalamus, especially in the dorsal zone of the medial parvicellular part of the paraventricular nucleus. The number of 50-kHz ultrasonic vocalizations was also increased. These findings suggest that pleasant sensory stimuli activate hypothalamic oxytocin neurons.
  • ONAKA Tatsushi, OKABE Shota, TAKAYANAGI Yuki, YOSHIDA Masahide
    Interdisciplinary Information Sciences 21 (3) 189-195 (J-STAGE)  1340-9050 2015 [Not refereed][Not invited]
  • Masahide Yoshida, Yuki Takayanagi, Tatsushi Onaka
    Endocrinology 155 (8) 2996 - 3004 0013-7227 2014/08 [Refereed][Not invited]
    Fear responses play evolutionarily beneficial roles, although excessive fear memory can induce inappropriate fear expression observed in posttraumatic stress disorder, panic disorder, and phobia. To understand the neural machineries that underlie these disorders, it is important to clarify the neural pathways of fear responses. Contextual conditioned fear induces freezing behavior and neuroendocrine responses. Considerable evidence indicates that the central amygdala plays an essential role in expression of freezing behavior after contextual conditioned fear. On the other hand, mechanisms of neuroendocrine responses remain to be clarified. The medial amygdala (MeA), which is activated after contextual conditioned fear, was lesioned bilaterally by infusion of N-methyl-d-aspartate after training of fear conditioning. Plasma oxytocin, ACTH, and prolactin concentrations were significantly increased after contextual conditioned fear in sham-lesioned rats. In MeA-lesioned rats, these neuroendocrine responses but not freezing behavior were significantly impaired compared with those in sham-lesioned rats. In contrast, the magnitudes of neuroendocrine responses after exposure to novel environmental stimuli were not significantly different in MeA-lesioned rats and sham-lesioned rats. Contextual conditioned fear activated prolactin-releasing peptide (PrRP)-synthesizing neurons in the medulla oblongata. In MeA-lesioned rats, the percentage of PrRP-synthesizing neurons activated after contextual conditioned fear was significantly decreased. Furthermore, neuroendocrine responses after contextual conditioned fear disappeared in PrRP-deficient mice. Our findings suggest that the MeA-medullary PrRP-synthesizing neuron pathway plays an important role in neuroendocrine responses to contextual conditioned fear.
  • Yoshiyuki Kasahara, Keisuke Sato, Yuki Takayanagi, Hiroaki Mizukami, Keiya Ozawa, Shizu Hidema, Kyoung-Ha So, Teruo Kawada, Nao Inoue, Ikuo Ikeda, Sang-Gun Roh, Keiichi Itoi, Katsuhiko Nishimori
    ENDOCRINOLOGY 154 (11) 4305 - 4315 0013-7227 2013/11 [Refereed][Not invited]
    Oxytocin (OXT) and OXT receptor (OXTR) have been implicated in the regulation of energy homeostasis, but the detailed mechanism is still unclear. We recently showed late-onset obesity and impaired cold-induced thermogenesis in male OXTR knockout (Oxtr(-/-)) mice. Here we demonstrate that the OXTR in the hypothalamus has important functions in thermoregulation. Male Oxtr(-/-) mice failed to maintain their body temperatures during exposure to a cold environment. Oxtr(-/-) mice also showed decreased neuronal activation in the thermoregulatory hypothalamic region during cold exposure. Normal cold-induced thermogenesis was recovered in Oxtr (/) mice by restoring OXTR to the hypothalamus with an adeno-associated virus-Oxtr vector. In addition, brown adipose tissue (BAT) in Oxtr(-/-) mice contained larger lipid droplets in both 10- and 20-week-old compared with BAT from age-matched Oxtr(-/-) control mice. In BAT, the expression level of beta 3-adrenergic receptor at normal temperature was lower in Oxtr(-/-) mice than that in control mice. In contrast, alpha 2A-adrenergic receptor expression level was higher in BAT from Oxtr(-/-) mice in both normal and cold temperatures. Because beta 3- and alpha 2A-adrenergic receptors are known to have opposite effects on the thermoregulation, the imbalance of adrenergic receptors is suspected to affect this dysfunction in the thermoregulation. Our study is the first to demonstrate that the central OXT/OXTR system plays important roles in the regulation of body temperature homeostasis.
  • M. Yamashita, Y. Takayanagi, M. Yoshida, K. Nishimori, M. Kusama, T. Onaka
    JOURNAL OF NEUROENDOCRINOLOGY 25 (5) 455 - 465 0953-8194 2013/05 [Refereed][Not invited]
    Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCKPrRPoxytocin pathway plays an important role in the control of the termination of each meal.
  • T. Onaka, Y. Takayanagi, M. Yoshida
    JOURNAL OF NEUROENDOCRINOLOGY 24 (4) 587 - 598 0953-8194 2012/04 [Refereed][Invited]
    Oxytocin neurones are activated by stressful stimuli, food intake and social attachment. Activation of oxytocin neurones in response to stressful stimuli or food intake is mediated, at least in part, by noradrenaline/prolactin-releasing peptide (PrRP) neurones in the nucleus tractus solitarius, whereas oxytocin neurones are activated after social stimuli via medial amygdala neurones. Activation of oxytocin neurones induces the release of oxytocin not only from their axon terminals, but also from their dendrites. Oxytocin acts locally where released or diffuses and acts on remote oxytocin receptors widely distributed within the brain, resulting in anxiolytic, anorexic and pro-social actions. The action sites of oxytocin appear to be multiple. Oxytocin shows anxiolytic actions, at least in part, via serotoninergic neurones in the median raphe nucleus, has anorexic actions via pro-opiomelanocortin neurones in the nucleus tractus solitarius and facilitates social recognition via the medial amygdala. Stress, obesity and social isolation are major risk factors for mortality in humans. Thus, the oxytocinoxytocin receptor system is a therapeutic target for the promotion of human health.
  • Maroot Kaewwongse, Yuki Takayanagi, Tatsushi Onaka
    Journal of neuroendocrinology 23 (1) 20 - 7 0953-8194 2011/01 [Refereed][Not invited]
    RFamide-related peptides (RFRP-1 and RFRP-3) are localised in neurones of the dorsomedial hypothalamus in rats. The dorsomedial hypothalamus plays an essential role in neuroendocrine and behavioural stress responses. In the present study, we examined the role of RFRP in the control of neuroendocrine and behavioural responses in rats. Stressful stimuli increased expression of Fos protein in RFRP-immunoreactive neurones of the dorsomedial hypothalamus, suggesting that stressful stimuli activate RFRP neurones. Intracerebroventricular injection of RFRPs increased the expression of Fos protein in oxytocin neurones in the hypothalamus and plasma concentrations of adrenocorticotrophic hormone and oxytocin. The hypothalamic paraventricular and supraoptic nuclei expressed mRNA of GPR147, the putative RFRP receptor, and application of RFRPs to isolated supraoptic nuclei facilitated oxytocin release, suggesting that RFRPs activate oxytocin neurones directly. Furthermore, the administration of RFRPs induced anxiety-related behaviour in rats in open-field tests. All these data taken together suggest that RFRPs play a role in the control of neuroendocrine and behavioural stress responses in rats.
  • Yuki Takayanagi, Tatsushi Onaka
    The FEBS journal 277 (24) 4998 - 5005 1742-464X 2010/12 [Refereed][Invited]
    Subsequent to the isolation of the first recognized RFamide neuropeptide, FMRFamide, from the clam, a large number of these peptides have been identified. There are now five groups of RFamide peptides identified in mammals. RFamide peptides show diversity with respect to their N-terminal sequence and biological activity. RFamide peptides have been implicated in a variety of roles, including energy metabolism, stress and pain modulation, as well as effects in the neuroendocrine and cardiovascular systems. In the present minireview, we focus on prolactin-releasing peptide (PrRP) and RFamide related peptide (RFRP) with respect to their roles in the control of energy metabolism and stress responses. Both food intake and stressful stimuli activate PrRP neurons. The administration of PrRP affects energy metabolism and neuroendocrine systems. PrRP-deficient or PrRP receptor-deficient mice show abnormal energy metabolism and/or stress responses. On the other hand, RFRP neurons are activated by stressful stimuli and the administration of RFRP induces neuroendocrine and behavioral stress responses. Taken together, these data suggests that PrRP and RFRP neurons play a role in the control of energy metabolism and/or stress responses.
  • Yuki Takayanagi, Eriko Fujita, Zhiling Yu, Takanori Yamagata, Mariko Y. Momoi, Takashi Momoi, Tatsushi Onaka
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 396 (3) 703 - 708 0006-291X 2010/06 [Refereed][Not invited]
    Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates synaptic cell adhesion. Missense mutations in the CADM1 gene have been identified in autism spectrum disorder (ASD) patients. In the present study, we examined emotional behaviors, social behaviors and motor performances in Cadm1-knockout (KO) mice. Cadm1-KO mice showed increased anxiety-related behavior in open-field and light-dark transition tests. Social behaviors of Cadm1-KO mice were impaired in social interaction, resident-intruder and social memory/recognition tests. Furthermore, motor coordination and gait of Cadm1-MO mice were impaired in rotarod and footprint tests. Our study demonstrates that CADM1 plays roles in regulating emotional behaviors, social behaviors and motor performances, and that CADM1 has important implications for psychiatric disorders with disruptions in social behavior, such as autism. (C) 2010 Elsevier Inc. All rights reserved.
  • Tatsushi Onaka, Yuki Takayanagi, Gareth Leng
    TRENDS IN ENDOCRINOLOGY AND METABOLISM 21 (5) 287 - 293 1043-2760 2010/05 [Refereed][Invited]
    In the modern world, improvements in human health can be offset by unhealthy lifestyle factors, including the deleterious consequences of stress and obesity. For energy homeostasis, humoral factors and neural afferents from the gastrointestinal tract, in combination with long-term nutritional signals, communicate information to the brain to regulate energy intake and expenditure. Energy homeostasis and stress interact with each other, and stress affects both food intake and energy expenditure. Prolactin-releasing peptide, synthesized in discrete neuronal populations in the hypothalamus and brain-stem, plays an important role in integrating these responses. This review describes how prolactin-releasing peptide neurons receive information concerning both internal metabolic states and environmental conditions, and play a key role in energy homeostasis and stress responses.
  • Vicky A. Tobin, Hirofumi Hashimoto, Douglas W. Wacker, Yuki Takayanagi, Kristina Langnaese, Celine Caquineau, Julia Noack, Rainer Landgraf, Tatsushi Onaka, Gareth Leng, Simone L. Meddle, Mario Engelmann, Mike Ludwig
    NATURE 464 (7287) 413 - U110 0028-0836 2010/03 [Refereed][Not invited]
    Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours(1). In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders and obsessive-compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism(2,3). Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.
  • Yuki Takayanagi, Hirokazu Matsumoto, Masanori Nakara, Takashi Mera, Shoji Fukusumi, Shuji Hinuma, Yoichi Ueta, Toshihiko Yada, Gareth Leng, Tatsushi Onaka
    JOURNAL OF CLINICAL INVESTIGATION 119 (2) 422 - 422 0021-9738 2009/02 [Refereed][Not invited]
  • Masahide Yoshida, Yuki Takayanagi, Kiyoshi Inoue, Tadashi Kimura, Larry J. Young, Tatsushi Onaka, Katsuhiko Nishimori
    JOURNAL OF NEUROSCIENCE 29 (7) 2259 - 2271 0270-6474 2009/02 [Refereed][Not invited]
    The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT(2A/2C) receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.
  • Yuki Takayanagi, Hirokazu Matsumoto, Masanori Nakata, Takashi Mera, Shoji Fukusumi, Shuji Hinuma, Yoichi Ueta, Toshihiko Yada, Gareth Leng, Tatsushi Onaka
    JOURNAL OF CLINICAL INVESTIGATION 118 (12) 4014 - 4024 0021-9738 2008/12 [Refereed][Not invited]
    Food intake is regulated by a network of signals that emanate from the gut and the brainstem. The peripheral satiety signal cholecystokinin is released from the gut following food intake and acts on fibers of the vagus nerve, which project to the brainstem and activate neurons that modulate both gastrointestinal function and appetite. In this study, we found that neurons in the nucleus tractus solitarii of the brainstern that express prolactin-releasing peptide (PrRP) are activated rapidly by food ingestion. To further examine the role of this peptide in the control of food intake and energy metabolism, we generated PrRP-deficient mice and found that they displayed late-onset obesity and adiposity, phenotypes that reflected an increase in meal size, hyperphagia, and attenuated responses to the anorexigenic signals cholecystokinin and leptin. Hypothalamic expression of 6 other appetite-regulating peptides remained unchanged in the PrRP-deficient mice. Blockade of endogenous PrRP signaling in WT rats by central injection of PrRP-specific mAb resulted in an increase in food intake, as reflected by an increase in meal size. These data suggest that PrRP relays satiety signals within the brain and that selective disturbance of this system can result in obesity and associated metabolic disorders.
  • Yuki Takayanagi, Yoshiyuki Kasahara, Tatsushi Onaka, Nobuyuki Takahashi, Teruo Kawada, Katsuhiko Nishimori
    NEUROREPORT 19 (9) 951 - 955 0959-4965 2008/06 [Refereed][Not invited]
    The oxytocin receptor has been suggested to be involved in energy metabolism, such as food intake and energy consumption. Here, we demonstrate that oxytocin receptor-deficient (Oxtr(-/-)) male mice exhibited late-onset obesity with increases in abdominal fat pads and fasting plasma triglycerides. Daily food intake and spontaneous motor activity of Oxtr(-/-) mice were not significantly different as compared with wild-type mice. In contrast, brown adipose tissue in Oxtr(-/-) mice contained large lipid droplets and cold-induced thermogenesis was impaired. This study demonstrates that oxytocin receptor plays essential roles in the regulation of energy homeostasis.
  • Masaki Kawamata, Masahide Yoshida, Yukihiko Sugimoto, Tadashi Kimura, Yutaka Tonomura, Yuki Takayanagi, Teruyuki Yanagisawa, Katsuhiko Nishimori
    MOLECULAR AND CELLULAR ENDOCRINOLOGY 283 (1-2) 32 - 37 0303-7207 2008/02 [Refereed][Not invited]
    The dramatic increase of oxytocin (OT) receptor (OTR) in the myometrium as well as circulating progesterone withdrawal has been thought to be the most important factor in the induction and accomplishment of parturition since delivery fails in prostaglandin F-2 alpha receptor (FP) knockout (FP KO) mice. The expression levels of OTR mRNA/protein were not dramatically increased in the near-term uteri of FP KO mice. However, OT-induced myometrial contractions and the concentration-response curves in FP KO in vitro were almost similar to those in wild-type (WT) mice. OT-infusion (0.3 U/day) enabled FP KO mice to experience successful delivery, and furthermore the duration until the onset was hastened by a higher dose of OT (3 U/day). The plasma progesterone levels of FP KO females were maintained at high levels, but decreased during labor by OT-infusion Q U/day). These results suggest that OT has potentials to induce strong myometrial contractions in uterus with low expression levels of OTR and luteolysis in ovary, which enabled Fl? KO females to undergo successful delivery. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Katsuhiko Nishimori, Yuki Takayanagi, Masahide Yoshida, Yoshiyuki Kasahara, Larry J. Young, Masaki Kawamata
    To further define the function of the oxytocin receptor (OXTR) in vivo, we generated mice deficient in the Oxtr gene (Oxtr-/-). Oxtr-/- mice had no obvious deficits in fertility or sexual behaviour, but displayed several aberrations in social behaviours, including male aggression, and mother-offspring interaction. In addition, they showed novel physiological defects including obesity, and dysfunction in body temperature control when exposed to cold. We review here our new findings with Oxtr-/- mice, and introduce newly generated Oxtr-Venus knockin mice as a potential tool for examining molecular physiology of Oxtr-neurons.
  • Gareth Leng, Tatsushi Onaka, Celine Caquineau, Nancy Sabatier, Vicky A. Tobin, Yuki Takayanagi
    Oxytocin has potent central effects on feeding behaviour, as well as on social and sexual behaviours, and one likely substrate for its anorectic effect is the ventromedial nucleus of the hypothalamus. This nucleus expresses a high density of oxytocin receptors, but contains very few oxytocin-containing fibres, hence it is a likely target of 'neurohormonal' actions of oxytocin, including possibly oxytocin released from the dendrites of magnocellular oxytocin neurones. As oxytocin release from dendrites is regulated independent of electrical activity and of secretion from the neurohypophysis, exactly how this release is regulated by metabolic and reproduction-related signals remains to be established fully. Intriguingly though, it looks as though this central release of oxytocin from magnocellular neurons might be instrumental in a fundamental shift in motivational behaviour - switching behaviour from being driven by the need to find and consume food, to the need to reproduce.
  • Takayanagi Yuki, Matsumoto Hirokazu, Mera Takashi, Hashimoto Hirofumi, Fukusumi Shoji, Hinuma Shuji, Ueta Yoichi, Onaka Tatsushi
    Proceedings of Annual Meeting of the Physiological Society of Japan 日本生理学会 2008 (0) 106 - 106 2008 
    Food intake is controlled by signals from the brainstem that mediate signals from the gut. Prolactin-releasing peptide (PrRP) neurons are localized in the brainstem. In the present study, we investigated whether food intake activates PrRP neurons. We examined expression of phospho-CREB in PrRP neurons after food intake. The percentage of phospho-CREB-positive PrRP neurons in the nucleus of tractus solitarii was increased by food intake, suggesting that food intake activates PrRP neurons in the nucleus tractus solitarii. To further study the role of endogenous PrRP in food intake, we generated PrRP-deficient mice. PrRP-deficient mice developed late onset obestity associated with metabolic disorders due to hyperphagia but not to energy expenditure, and showed an attenuated response to the peripheral satiety signal, cholecystokinin. Blockade of endogenous PrRP signaling by a central injection of monoclonal anti-PrRP neutralizing antibodies increased food intake, reflecting an increase in meal size. Furthermore, we demonstrated that leptin-induced reduction in food intake and body weight was impaired in PrRP-deficient mice. All these data suggest that PrRP relays satiety signals within the brain and that disturbance of this system can result in obesity and associated metabolic disorders. [J Physiol Sci. 2008;58 Suppl:S106]
  • Yoshiyuki Kasahara, Yuki Takayanagi, Teruo Kawada, Keiichi Itoi, Katsuhiko Nishimori
    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 71 (12) 3122 - 3126 0916-8451 2007/12 [Refereed][Not invited]
    We analyzed temperature homeostasis in oxytocin-deficient (Oxt(-/-)) mice and found that Oxt(-/-) mice exhibited lower body temperatures than wild-type animals when they were exposed to cold. Oxt(-/-) mice also showed slightly more weight gain, but there were no obvious differences in the morphology of white and brown adipose tissues as between wild-type and Oxt(-/-) mice. In cold-exposed conditions, oxytocin neurons containing c-Fos immunoreactivity existed in the para-ventricular nucleus of the hypothalamus. These results suggest that the central oxytocin neurons constitute part of the thermoregulatory system involved in maintaining body temperature in cold environments.
  • Yuki Sato, Yuki Takayanagi, Tatsushi Onaka, Eiji Kobayashi
    TRANSPLANTATION 83 (10) 1365 - 1370 0041-1337 2007/05 [Refereed][Not invited]
    Background. Cyclosporine induces psychological side effects but its mechanisms of action remain to be elucidated. Methods. Mice were injected with cyclosporine (0, 10, 60 mg/kg intraperitoneal) and indexes of both anxiety-related and social behaviors were examined. Release of serotonin and dopamine in the prefrontal cortex was also investigated by microdialysis. Results. Intraperitoneal administration of cyclosporine increased cyclosporine concentrations in the blood and brains in mice. Cyclosporine administration at a higher-dose reduced motor activity, increased indexes of anxiety-related behavior, and decreased an index of social interaction. The administration reduced release of serotonin and dopamine in the prefrontal cortex. Clozapine administration abolished the reduced release of dopamine and partially restored the index of social behavior in cyclosporine-injected mice. Conclusions. This in vivo model suggests that cyclosporine at a high dose induced hypo-function of the prefrontal. cortex as a result of reduced release of serotonin and dopamine, increased anxiety-related behavior, and disturbed social behavior. Clozapine partially restored an index of social behavior. The present findings are pathologically relevant in patients who take cyclosporine.
  • Tadatoshi Tanino, Akihiro Nawa, Eisaku Kondo, Fumitaka Kikkawa, Tohru Daikoku, Tatsuya Tsurumi, ChenHong Luo, Yukihiro Nishiyama, Yuki Takayanagi, Katuhiko Nishimori, Seiji Ichida, Tetsuyuki Wada, Yasuyoshi Miki, Masahiro Iwaki
    PHARMACEUTICAL RESEARCH 24 (3) 555 - 565 0724-8741 2007/03 [Refereed][Not invited]
    Purpose: The aim of the study was to investigate whether 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et) circumvents P-glycoprotein (P-gp)-mediated cellular efflux and cytotoxicity enhanced by TAX-2'-Et activation within human culture cells transfected with a rabbit liver carboxylesterase (Ra-CES) cDNA. Materials and Methods: TAX-2'-Et transport was characterized in a human colon carcinoma cell line (Caco-2) and paclitaxel (TAX)-resistant ovarian carcinoma cells (SKOV3/TAX60). Expression of P-gp, multidrug resistance protein (MRP) 2 and Ra-CES was detected by Western blotting. Cytotoxicity against Ra-CES-expressing cells and cellular amount of TAX produced were determined by MTT assay and using HPLC, respectively. Results: Unlike rhodamine123 and TAX, TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells in the absence or presence of verapamil. P-gp levels were expressed much higher in the SKOV3/TAX60 cells than in the Caco-2 cells. MRP2 protein was not detectable in the SKOV3/TAX60 cells. Uptake by the SKOV3/TAX60 cells was similar in quantity to the amount internalized by P-gp-negative SKOV3 cells. In the SKOV3/TAX60 cells, cellular uptake of TAX-2'-Et was not altered regardless of the absence or presence of verapamil. The cytotoxicity to the untransfected SKOV3 cells induced by TAX-2'-Et was significantly lower than that induced by TAX. In the Ra-CES-expressing SKOV3 line, the EC50 value of TAX (10.6 nM) was approximately four-fold higher than that of TAX-2'-Et (2.5 nM). Transfection of Ra-CES into another TAX-resistant ovarian carcinoma cells (KOC-7c) conferred a high level of TAX-2'-Et cytotoxicity via prodrug activation. The intracellular levels of TAX produced from TAX-2'-Et in the Ra-CES-positive KOC-7c cells significantly increased compared with the levels seen in exposure of the untransfected KOC-7c cells to TAX. Conclusions: TAX-2'-Et can circumvent P-gp-associated cellular efflux of TAX. TAX-2'-Et is converted into TAX by the Ra-CES, supporting its potential use as a theoretical GDEPT strategy for cancer cells expressing high levels of P-gp. The TAX-2'-Et prodrug efficiently increased the amount of intracellular TAX, which mediates tumor cell death.
  • Y Takayanagi, K Nishimori, T Onaka
    NEUROSCIENCE LETTERS 391 (1-2) 22 - 27 0304-3940 2005/12 [Refereed][Not invited]
    Salt loading reduces neuroendocrine responses to stressful stimuli. Noxious stimuli facilitate noradrenaline release in the hypothalamus and, as a result, activate oxytocin neurones. Here, we examined effects of salt loading upon plasma oxytocin concentrations and noradrenaline release in the hypothalamus after footshocks. Male rats were allowed to drink 2% NaCl for 7 days. Salt loading reduced the footshock- induced increase in plasma oxytocin concentrations and noradrenaline release in the supraoptic nucleus (SON). Acute administration of hypertonic saline also attenuated the footshock-induced noradrenaline increase in the supraoptic nucleus. In contrast, salt loading did not significantly change activation of Al catecholaminergic neurones in the medulla oblongata, as measured by expression of Fos protein. These data suggest that salt loading presynaptically Suppresses noradrenaline release in the hypothalamus and oxytocin release into the blood after footshocks. (C) 2005 Elsevier Ireland Ltd. All rights reserved.
  • Y Takayanagi, M Yoshida, IF Bielsky, HE Ross, M Kawamata, T Onaka, T Yanagisawa, T Kimura, MM Matzuk, LJ Young, K Nishimori
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 (44) 16096 - 16101 0027-8424 2005/11 [Refereed][Not invited]
    The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr(-/-)) and compared them with OXT-deficient (Oxt(-/-)) mice. Oxtr(-/-) mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr(-/-) dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr(-/-) males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr(-/-) males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt(-/-) males from Oxt(-/-) dams, but not from Oxt(+/-) dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT/OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior.
  • 荻田 和秀, 木村 正, 中村 仁美, 香山 晋輔, 下屋 浩一郎, 古山 将康, 村田 雄二, 高柳 友紀, 川又 理樹, 西森 克彦
    日本内分泌学会雑誌 (一社)日本内分泌学会 80 (1) 192 - 192 0029-0661 2004/04 [Refereed][Not invited]
  • M Kawamata, M Mitsui-Saito, T Kimura, Y Takayanagi, T Yanagisawa, K Nishimori
    EUROPEAN JOURNAL OF PHARMACOLOGY 472 (3) 229 - 234 0014-2999 2003/07 [Refereed][Not invited]
    In the non-pregnant mouse myometrium, both arginine vasopressin and oxytocin induced contractions (pD(2) = 8.55 +/- 0.13 and 9.23 +/- 0.09, respectively). The effect of oxytocin was the most potent, while the maximum contractions induced by these two peptides were almost of the same magnitude. Both vasopressin- and oxytocin-induced contractions were strongly inhibited by an oxytocin receptor antagonist, CL-12-42 (d(CH2)(5)[Tyr(Me)(2),Thr(4),Tyr-NH29]OVT), and weakly inhibited by a vasopressin V-1a receptor antagonist, SR49059 ((2s)1-[2R,3s)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide). Similar results were obtained in the pregnant mouse myometrium. These results suggest that not only oxytocin- but also vasopressin-induced contraction is mediated by the activation of oxytocin receptors in the mouse myometrium. A reverse transcription polymerase chain reaction study failed to reveal mRNA of the vasopressin V-1a receptor in the mouse myometrium. In contrast, in the non-pregnant human myometrium, vasopressin-induced contraction was inhibited by SR49059. Oxytocin showed no effect on the myometrium. These results suggest that there are significant differences in the functional receptors and contractile responses to vasopressin and oxytocin in the human and mouse uteri. (C) 2003 Elsevier B.V. All rights reserved.
  • K Nishimori, M Kawamata, Y Takayanagi

Conference Activities & Talks

  • 社会行的敗北ストレスにおけるオキシトシンの役割  [Invited]
    高柳 友紀
    第92回日本内分泌学会学術総会  2019/05
  • 社会行動におけるオキシトシンの働き  [Invited]
    高柳 友紀
    第122回日本解剖学会総会・全国学術集会  2017/03
  • エネルギー代謝とストレスにおけるオキシトシンの働き  [Invited]
    高柳 友紀
    第43回日本神経内分泌学会学術集会  2016/10
  • オキシトシンによる情動・社会行動の制御  [Invited]
    高柳 友紀
    第92回日本生理学会大会  2015/03
  • エネルギー代謝とストレスにおけるPrRP-オキシトシン系の働き  [Invited]
    高柳 友紀
    第39回日本神経内分泌学会学術集会  2012/09
  • PrRP-オキシトシン系による摂食調節  [Invited]
    高柳 友紀
    第89回日本生理学会大会  2012/03
  • PrRPによる摂食とストレスの調節  [Invited]
    高柳 友紀
    第88回日本生理学会大会(誌上開催)  2011/03
  • 下垂体後葉ホルモンとストレス・社会行動:バゾプレシン発現ニューロン選択的破壊法による解析  [Invited]
    高柳 友紀
    第87回日本生理学会大会  2010/05


Industrial Property Rights

Awards & Honors

  • 2021/10 日本神経内分泌学会 川上賞
  • 2019/07 第12回資生堂女性研究者サイエンスグラント
    受賞者: 高柳 友紀
  • 2018/11 平成30年度自治医科大学医学部最優秀論文賞
    受賞者: 高柳 友紀
  • 2014/11 平成26年度自治医科大学医学部優秀論文賞
    受賞者: 高柳 友紀
  • 2009/11 The Best Paper Award-2009 Jichi Medical University
     Endogenous prolactin-releasing peptide regulates food intake in rodents. 
    受賞者: Yuki Takayanagi
  • 2008/02 (財)井上科学振興財団 井上研究奨励賞
    受賞者: 高柳友紀
  • 2007/09 The 7th World Congress on Neurohypophysial Hormones Armin Ermisch Memorial Award 2007
     「Effects of secretin upon oxytocin release」 
    受賞者: Yuki Takayanagi
  • 2006/04 自治医科大学医学部研究奨励賞
    受賞者: 高柳 友紀
  • 1999/06 東北大学 ヨシ・エス・クノ奨学賞
    受賞者: 高柳 友紀

Research Grants & Projects

  • Promoting social development through social play: Roles of oxytocin neural pathways.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 高柳 友紀
  • ストレスレジリエンスの獲得・強化に関わる神経基盤の解明
    公益財団法人 小柳財団:2021年度研究助成金
    Date (from‐to) : 2021/04 -2022/03
  • 幼少期社会的親和行動によるレジリエンス強化の神経基盤解明
    Date (from‐to) : 2020/10
  • 思春期社会的ストレスが成熟後の社会行動に与える影響とその機序の解明
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : 高柳 友紀
    思春期の社会的遊びは社会性の発達に重要であるが、この神経基盤は明らかではない。これまでに、ラットの遊び行動時にオキシトシン産生ニューロンが活性化されること、遊びを阻害すると成体で社会的相互作用が阻害されることを示してきた。本研究の目的は、「思春期に遊びが阻害されると、オキシトシン神経回路が可塑的に変化して、成体で社会行動の障害が起こる」という仮説を検証することである。 オキシトシン産生ニューロンの投射先を探るために、オキシトシン遺伝子プロモーター制御下で蛍光タンパク質tdTomatoとDNA組換え酵素Flippaseを発現するトランスジェニックラットを作製し、ラインの選定を行った。オキシトシン産生ニューロンの存在する分界条床核、視床下部室傍核、視索上核の全てにおいて、オキシトシン産生ニューロンの90%程度でtdTomatoの発現が観察され、トランスジーンの特異的な発現が確認できた。現在、この動物に対して、Flippase依存的に膜移行性緑色蛍光タンパク質を発現するアデノ随伴ウイルスベクターを投与し、検討を始めている。 遊び行動におけるオキシトシンーオキシトシン受容体システムの機能を明らかにする目的で、CRISPR-Cas9系を用いてオキシトシン受容体遺伝子欠損ラットを作製し、ゲノム配列の確認を行ってラインの選定をした。また、この遺伝子欠損ラットにおけるオキシトシン受容体の発現を確認するため、ラット脳における受容体オートラジオグラフィマッピングの系を構築した。 さらに、遊び行動時に活性化されるオキシトシン産生ニューロンの役割解析のために、オキシトシンプロモーター制御下でヒト改変ジフテリア毒素受容体を発現するトランスジェニックラットを用いることを計画した。この動物に対して乳児期にジフテリア毒素を脳室内投与し、オキシトシン産生ニューロンが破壊される条件を検討した。
  • 思春期の社会的遊び行動の神経回路解明
    Date (from‐to) : 2019 -2020 
    Author : 高柳 友紀
  • 幼少期の社会的遊び行動による社会性神経回路発達の分子基盤解明
    公益財団法人 内藤記念科学振興財団:内藤記念女性研究者研究助成金
    Date (from‐to) : 2017 -2019 
    Author : 高柳 友紀
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    Date (from‐to) : 2013/06 -2018/03 
    Author : Onaka Tatsushi, NAGASAWA Miho
    Roles of oxytocin-oxytocin receptor systems in the control of empathetic behaviors were investigated. We found that supraoptic oxytocin neurons extend their dendrites into the medial amygdala and that this dendritic oxytocin system mediates social recognition. We also found that distinct oxytocin systems facilitate both expression of social defeat postures and consolidation-like behaviors. Affective touches or playing behaviors were also found to activate oxytocin neurons in the hypothalamus, and to modulate development of social behaviors. We also found that oxytocin facilitates bonding between humans and dogs.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : Takayanagi Yuki
    We examined the effects of early-life social stress (deprivation of social play) upon food intake and body weight in adulthood of rats. Social play induced the activation of oxytocin neurons in the paraventricular hypothalamic nucleus. Oxytocin neurons in the paraventricular hypothalamic nucleus were also activated in the observer rats (which observed playing cagemates). Contrary to our expectations, food intake and body weight of chronic social stressed rats were not significantly different from control rats. We generated two transgenic rat strains that express human diphtheria toxin receptor under the control of the oxytocin promoter and express human interleukin-2 receptor alpha-subunit under the control of the prolactin-releasing peptide (PrRP) promoter. We succeeded in site-specific destruction of oxytocin neurons or PrRP neurons by local injection of diphtheria toxin or immunotoxin in transgenic rats.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2014/04 -2017/03 
    Author : Onaka Tatsushi, TAKAYANAGI Yuki, YOSHIDA Masahide, INUTSUKA Ayumu, OKABE Shota
    I have previously shown that the medullary prolactin releasing peptide (PrRP)-producing neuron-hypothalamic oxytocin-producing neuron system is activated by food intake and that activation of the PrRP-oxytocin system terminates food intake. In the preset study, I investigated physiological roles of the PrRP-oxytocin system in the control of conditioned fear or social stress-related responses. The PrRP-oxytocin system was activated following conditioned fear and social defeat stimuli. PrRP deficiency facilitated freezing behavior during conditioned fear stimuli, suggesting inhibitory roles of PrRP in conditioned fear-induced freezing behavior. On the other hand, oxytocin receptor deficiency attenuated defeat posture during social defeat stress, suggesting facilitative roles of oxytocin in the social defeat posture. All these data are consistent with a view that the PrRP-oxytocin system plays different roles in the control of stress responses dependent upon stressful stimuli used.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2012/04 -2014/03 
    Author : TAKAYANAGI Yuki
    Secretin activated oxytocin neurons of the supraoptic nucleus and facilitated oxytocin release centrally. Local application of secretin into the supraoptic nucleus facilitated social recognition/ memory. The facilitative effects of secretin upon social recognition/ memory were inhibited by an oxytocin receptor antagonist injected into the medial amygdala or in oxytocin receptor-deficient mice. Furthermore, oxytocin treatment restored social recognition/ memory in secretin receptor-deficient mice. All these results suggest that newly defined secretin-oxytocin system plays a critical role in regulating social memory/ recognition.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2011/04 -2014/03 
    Author : ONAKA Tatsushi, TAKAYANAGI Yuki
    Epidemiological studies have suggested interactions between food intake and social behaviors. This study show that food intake and social stimuli activated oxytocin-synthesizing neurons in the hypothalamus, that activation of oxytocin-synthesizing neurons following food intake was caused by activation of prolactin releasing peptide-synthesizing neurons in the medulla oblongata, and that oxytocin released following food intake played an important role in termination of food intake. Considering the data that oxytocin modulates both food intake and social behavior, it is possible to consider that oxytocin plays a role in interaction between food intake and social behavior.
  • 幼若期ストレスによる情動障害:オキシトシン―セロトニン神経回路の可塑的変容
    Date (from‐to) : 2013/09 -2014/03 
    Author : 高柳 友紀
  • 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)
    Date (from‐to) : 2011/04 -2013/03 
    Author : 高柳 友紀
    本研究の目的は、幼若期に形成されるPrRP産生ニューロン-オキシトシン産生ニューロン-セロトニン作動性ニューロン回路が、幼若期ストレスによって可塑的に変化し、将来の摂食行動を規定しているという仮説の検証を行うことである。 まず、成体においてPrRP産生ニューロン-オキシトシン産生ニューロン回路が摂食を抑制するかを検討した。PrRP遺伝子欠損マウスとオキシトシン受容体遺伝子欠損マウスでは、野生型と比較して一回摂食量が暗期特異的に増大していた。また、一回摂食量を決定する末梢の満腹物質であるコレシストキニン(CCK)を投与すると、野生型では視床下部室傍核、視索上核、分界条床核に存在するオキシトシン産生ニューロンが活性化されたが、PrRP遺伝子欠損マウスではこの活性化が抑制された。これらのことから、暗期においてCCKはPrRP-オキシトシン系を介して満腹信号を伝達している可能性が示唆された。更に、成体においてオキシトシン産生ニューロン-セロトニン作動性ニューロン回路が摂食を抑制するかを、オキシトシン受容体遺伝子座にVenusをノックインしたマウスを利用して検討した。摂食あるいはCCK投与によって、オキシトシン受容体を発現するセロトニン作動性ニューロンの活性化が確認された。 一方で、母仔分離ストレスによって、仔のオキシトシン産生ニューロンが活性化されることを明らかにした。昨年度の結果とあわせると、幼若期ストレスによるオキシトシン系の活性化が将来の肥満に影響を与える可能性が示唆された。 さらに、PrRP産生ニューロン-オキシトシン産生ニューロン-セロトニン作動性ニューロン回路を詳細に明らかにする目的で、PrRP産生ニューロンあるいはオキシトシン産生ニューロンを部位・時間特異的に破壊できるトランスジェニックラットを作製した。
  • 摂食とストレスの接点分子:PrRP−オキシトシン系の働きの解明
    サントリー生命科学財団:SUNBOR GRANT
    Date (from‐to) : 2010 -2012 
    Author : 高柳 友紀
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2010 -2011 
    Author : TAKAYANAGI Yuki
    To examine effects of time-or site-specific inhibition of oxytocin system upon social behaviors, we generated transgenic rats expressing human diphtheria toxin receptor under the control of the oxytocin promoter. We screened for germ-line transmission of the transgene and established six lines of transgenic rats expressing human diphtheria toxin receptor in oxytocin-synthesizing neurons. On the other hand, to examine effects of the activation of oxytocin receptor during the neonatal period upon social behaviors in adulthood, we injected mice with oxytocin over the first five postnatal days. Contrary to our expectations, social, emotional and depression-related behaviors in adulthood of oxytocin-injected mice were not significantly different from control mice.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2008 -2010 
    Author : ONAKA Tatsushi, TAKAYANAGI Yuki
    Not only stressful stimuli but also food intake activated PrRP-synthesizing neurons and oxytocin-synthesizing neurons. Social stimuli activated oxytocin-synthesizing neurons. PrRP-synthesizing neurons were suggested to have stress-modulating and anorexic actions. Oxytocin-synthesizing neurons were suggested to have anti-stress, anorexic and social memory-enhancing actions. Downstream neurons of oxytocin-synthesizing neurons were suggested to be serotoninergic.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2008 -2009 
    Author : TAKAYANAGI Yuki
    Maternal separation induced the activation of oxytocin-producing neurons in the supraoptic nucleus of mouse pups. Injection of oxytocin receptor antagonist in the neonatal period modulated anxiety-related and social behaviors in adulthood. On the other hand, to examine effects of increased oxytocin release at parturition upon fetal brain, we investigated the behavior of mice delivered by Cesarean section. Mice delivered by Cesarean section and then injected with oxytocin exhibited increased anxiety-related behavior as compared to mice delivered naturally. These results suggest that the activation of oxytocin receptor in neonatal brain during mother-infant interaction or parturition affects emotional and social behaviors in adulthood.
  • 日本学術振興会:科学研究費助成事業 特定領域研究
    Date (from‐to) : 2008 -2009 
    Author : 尾仲 達史, 高柳 友紀
    本研究の目的は、プロラクチン放出ペプチド(PrRP)ニューロンの異常によりストレス反応の異常をきたすことを証明し、さらに、PrRPがストレス反応を維持する機構を明らかにすることであった。本年度は、まず、ストレス反応における内因性のPrRPの働きを明らかにする目的で、PrRP遺伝子欠損マウスを用いてストレス反応に異常があるかを検討した。PrRP遺伝子欠損動物は、条件恐怖刺激に対するオキシトシンの分泌反応が減弱していた。また、ストレス刺激負荷によるエネルギー消費量上昇反応が、PrRP遺伝子欠損動物では減弱していた。さらに、ストレスに対する摂食抑制反応もPrRP遺伝子欠損動物で減弱していた。一方、条件刺激に対するすくみ行動が促進していた。また、PrRP遺伝子欠損動物に慢性ストレスを負荷すると、野生型の動物に比較して欝様行動が強く観察された。従って、PrRPは急性と慢性のストレス反応に重要な因子であることが示唆された。 PrRを脳室内に投与すると不安行動が減弱する。そこで、次に、PrRPの不安行動減弱作用における作用部位を明らかにする目的で、PrRPを分界条床核、視床下部室傍核、視床下部背内側核、扁桃体の脳内各部位に投与する実験を行った。その結果、視床下部背内側核がPrRPの抗不安作用の作用部位の候補であることが示唆された。さらに、PrRPを投与すると視床下部のオキシトシン産生ニューロが活性化されることがわかった。さらに、オキシトシン産生ニューロンの下流を探索する目的で、オキシトシン受容体を発現する細胞の探索を行った。その結果、縫線核のセロトニン産生ニューロンの多くがオキシトシン受容体を発現することを見出した。さらに、オキシトシンの抗不安行動作用がセロトニン受容体アンタゴニストで阻害された。これらのデータは、オキシトシン産生ニューロンの下流にセロトニン産生ニューロンがあるという考えに矛盾しないデータである。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    Date (from‐to) : 2006 -2007 
    Author : 高柳 友紀
    下垂体後葉ホルモンのオキシトシンとその受容体は、社会行動と親和行動に重要であることが示されている。オキシトシン受容体遺伝子欠損マウスには母性行動低下が認められた。一方で幼若期のオキシトシン受容体遺伝子欠損マウスでは、母親から隔離したときの超音波発声がほとんど認められなかった。これらの結果は母仔親和行動において、母仔共にオキシトシン受容体が重要な因子であることを示している。また一方で、仔の成長後の行動は幼若期に母親から受けた愛着行動に強く影響をうけることが知られている。そこで、本研究では(1)母仔愛着行動においてオキシトシン系が活性化される脳部位の同定を行うこと、(2)幼若期のオキシトシン系活性化が仔の将来の行動を形成するという仮説を検証することを目的とした。 母性行動誘発時にオキシトシン系が機能する脳部位を明らかにする目的で、神経活動マーカーであるc-Fosの免疫組織化学による解析を行った。仔に曝露して母性行動誘発刺激を与えたオキシトシン受容体遺伝子欠損マウスでは、外側中隔野、内側視索前野における神経活動が野生型に比べて顕著に少なく、これが母性行動低下に影響していることが示唆された。また、母仔分離をして仔が母への求愛行動を示す時にオキシトシン系が機能する脳部位を同定する目的で、オキシトシンとc-Fosの二重免疫染色による解析を行った。母と同腹仔から隔離した生後七日目のC57BL/6Jマウスにおいて、視索上核で神経活動マーカー陽性のオキシトシン産生ニューロンが多い傾向が認められ、室傍核のオキシトシン産生ニューロンにその傾向は見られなかった。 また、C57BL/6J仔マウスに対して出生日から生後5日目までオキシトシン受容体アンタゴニストを連続投与し、成熟後の行動を解析した。Vehicle投与群と比較して情動行動には差が見られなかったが、社会行動において差が認められた。
  • 農芸化学研究奨励会:第33回 農芸化学会研究奨励金
    Date (from‐to) : 2005 
    Author : 高柳 友紀
  • 遺伝子欠損マウスを用いたオキシトシン/オキシトシン受容体システムの解析
    日本学術振興会:科学研究費助成事業 特別研究員奨励費
    Date (from‐to) : 2003 -2004 
    Author : 高柳 友紀
    1.オキシトシン(OT)と同様に子宮収縮に働くプロスタグランジンF_<2α>の受容体(FP)とOTの両遺伝子欠損マウス(fp-/-・ot-/-)では、分娩直前に卵巣黄体ホルモンであるプロゲステロンの低下が起こらないために自然分娩が誘起されなかった。そこで、これらに対して分娩直前にプロゲステロン受容体アンタゴニストのRU486を投与したところ、分娩が正常に誘導される事が明らかとなった。これによって、子宮収縮に最も重要と考えられてきたFP,OTの二つの因子がなくともプロゲステロン受容体の効果が減少する事で分娩が開始されるという興味深い結果が得られた。ところが一方で、fp-/-・ot-/-では分娩の完了に24時間以上を要する個体が70%程度と非常に高い割合で認められた。これによって、FP,OTは分娩時の子宮筋収縮に相補的に働き、重要な役割を果たす事が示唆された。 2.OT/OTRは摂食行動の抑制に働く事が以前より示されていたため、雄otr-/-の示す肥満は摂食行動異常に起因する可能性が最も高いと予測された。そこで、雄otr-/-について摂食量と活動量の測定を行った。肥満を示すより以前の週齢で24時間の摂食行動をモニターし、その摂食量と摂食パターンの検討を行った。しかし、otr-/-の摂食行動は慨日リズムも含めて正常である事が明らかとなった。また、同様に活動量についても変化がなかったため、otr-/-の肥満の原因はこれら以外にある事が明らかとなった。一方で、雄otr-/-は内臓脂肪型肥満を呈するため、代謝に異常をきたしている可能性が考えられた。そこで、20週齢の雄について血糖値や血中トリグリセライド値・コレステロール値・遊離脂肪酸値などを各々測定し、更に経口糖負荷試験も行った。ところが、これら全てにおいてotr-/-は正常値を示し、また耐糖能も正常である事が明らかとなった。

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