Updated on 2025/04/10

写真a

 
MIYAZONO Sadaharu
 
Organization
Center Research technology support center
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Degree

  • 理学博士 ( 大阪大学 )

Research Interests

  • グリア細胞

  • 神経科学

  • 脳機能

  • 脳科学

  • 感覚生理

  • 「次世代脳」プロジェクト

  • 炎症

  • 記憶

  • 情動

  • 天敵

  • 視覚

  • 包括脳ネットワーク

  • 分子生理学

  • 電気生理学

  • 嗅覚

  • アルツハイマー病

Research Areas

  • Life Science / Basic brain sciences

  • Life Science / Animal physiological chemistry, physiology and behavioral biology

Education

  • 大阪大学大学院   生命機能研究科

    - 2008

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Research History

  • Asahikawa Medical College   Assistant Professor

    2011

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  • Harvard Medical School, Postdoctoral fellow

    2008 - 2011

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Professional Memberships

Committee Memberships

  • 日本味と匂学会   評議員  

    2016   

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    Committee type:Academic society

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  • Frontiers in Molecular Neuroscience   Review Editor  

    2016   

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    Committee type:Academic society

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Papers

  • Oregano leaf odor regulates sodium chloride consumption in mice Reviewed

    Kazumi Osada, Nanako Akiyama, Akira Hosono, Motoko Ohata, Issei Yokoyama, Sadaharu Miyazono, Michio Komai

    Bioscience, Biotechnology, and Biochemistry   2025.2

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    Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Abstract

    This study explores how the odor of oregano and its active component, carvacrol, influence salt preference in mice. Using a 2-bottle choice test (distilled water vs 0.15 m NaCl), 66 C57BL/6J mice were exposed to oregano odor. Female mice showed a significant reduction in saline intake with oregano or carvacrol exposure, while the effect was lower in males. Carvacrol was identified in dried oregano using gas chromatography–mass spectrometry (GC–MS) with headspace–solid-phase microextraction (HS–SPME). Neurologically, oregano odor increased c-Fos immunoreactivity in the ventral bed nucleus of the stria terminalis, a region regulating salt appetite. These results suggest that oregano odor decreases salt preference, partly due to carvacrol, which stimulates brain areas controlling salt appetite. This study highlights the role of olfactory cues in modulating dietary behavior and suggests potential applications for managing salt consumption in health contexts.

    DOI: 10.1093/bbb/zbaf014

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  • Changes in gaseous concentration of alkylpyrazine analogs affect mouse avoidance behavior. Reviewed International journal

    Kazumi Osada, Sadaharu Miyazono, Motoko Ohata, Tomohiro Noguchi, Makoto Kashiwayanagi

    Bioscience, biotechnology, and biochemistry   2021.10

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    The Y-maze is often used to detect subtle differences between similar odor sources; however, very little information is available about the dispersion of odor plumes in the Y-maze. Using headspace solid-phase microextraction (HS-SPME) in conjunction with a GC-MS system, we quantified alkylpyrazine analogs in the Y-maze. Rapid extraction of volatile compounds in the vapor phase enabled accurate quantitative analysis of temporal changes in the levels of gaseous alkylpyrazine analogs at several locations in the Y-maze. We conducted behavioral tests of mice in response to these volatiles and identified a positive relationship between the rate of increase in gaseous concentration and the induced avoidance rate. Our results demonstrate that the Y-maze is a simple but reliable apparatus for behavioral studies of olfaction. Our findings show that the HS-SPME fast extraction method could quantify how gaseous concentrations of alkylpyrazine analogs change over time, and that temporal increases in alkylpyrazine concentration were correlated with induction of aversive behavior in mice.

    DOI: 10.1093/bbb/zbab178

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  • Thallium-201 Imaging in Intact Olfactory Sensory Neurons with Reduced Pre-Synaptic Inhibition In Vivo. Reviewed International journal

    Hideaki Shiga, Hiroshi Wakabayashi, Kohshin Washiyama, Tomohiro Noguchi, Tomo Hiromasa, Sadaharu Miyazono, Masami Kumai, Kazuma Ogawa, Junichi Taki, Seigo Kinuya, Takaki Miwa

    Molecular neurobiology   57 ( 12 )   4989 - 4999   2020.8

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    In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6-7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 μg rotenone, p = 0.0012; 20 μg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 μg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 μg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.

    DOI: 10.1007/s12035-020-02078-y

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  • Stimulus dynamics-dependent information transfer of olfactory and vomeronasal sensory neurons in mice. Reviewed International journal

    Noguchi T, Miyazono S, Kashiwayanagi M

    Neuroscience   400   48 - 61   2019.2

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    The parallel processing of chemical signals by the main olfactory system and the vomeronasal system has been known to control animal behavior. The physiological significance of peripheral parallel pathways consisting of olfactory sensory neurons and vomeronasal sensory neurons is not well understood. Here, we show complementary characteristics of the information transfer of the olfactory sensory neurons and vomeronasal sensory neurons. A difference in excitability between the sensory neurons was revealed by patch-clamp experiments. The olfactory and vomeronasal sensory neurons showed phasic and tonic firing, respectively. Intrinsic channel kinetics determining firing patterns was demonstrated by a Hodgkin-Huxley-style computation. Our estimation of the information carried by action potentials during one cycle of sinusoidal stimulation with variable durations revealed distinct characteristics of information transfer between the sensory neurons. Phasic firing of the olfactory sensory neurons was suitable to carry information about rapid changes in a shorter cycle (<200 ms). In contrast, tonic firing of the vomeronasal sensory neurons was able to convey information about smaller stimuli changing slowly with longer cycles (>500 ms). Thus, the parallel pathways of the two types of sensory neurons can convey information about a wide range of dynamic stimuli. A combination of complementary characteristics of olfactory information transfer may enhance the synergy of the interaction between the main olfactory system and the vomeronasal system.

    DOI: 10.1016/j.neuroscience.2018.12.043

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  • Oxytocin receptor signaling contributes to olfactory avoidance behavior induced by an unpleasant odorant. Reviewed International journal

    Osada K, Ohta T, Takai R, Miyazono S, Kashiwayanagi M, Hidema S, Nishimori K

    Biology open   7 ( 9 )   2018.9

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    Oxytocin (OXT) and its receptor (OXTR) regulate reproductive physiology (i.e. parturition and lactation), sociosexual behavior, learned patterns of behavior and olfactory behavior in social contexts. To characterize the function of OXTR in basic olfactory behavior, the present study compared the behavioral responses of homozygous, heterozygous and wild-type mice when these mice were confronted with an unpleasant odorant (butyric acid) in a custom-made Y-maze in the absence of a social context. Wild-type mice avoided the first encounter with the butyric acid odorant, whereas homozygous and heterozygous mice did not. However, both heterozygous and wild-type mice habituated when confronted with the butyric odorant again on the following 2 days. By contrast, homozygous mice failed to habituate and instead avoided the location of the odorant for at least 3 days. These data suggest that homozygous and heterozygous mice display abnormal olfactory responses to the presentation of an unpleasant odorant. Our studies demonstrate that OXTR plays a critical role in regulating olfactory behavior in the absence of a social context.

    DOI: 10.1242/bio.029140

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  • Etizolam attenuates the reduction in cutaneous temperature induced in mice by exposure to synthetic predator odor Reviewed

    Sadaharu Miyazono, Kaede Hasegawa, Seri Miyazaki, Hikari Sakakima, Shun Konno, Saori Meguro, Hitoshi Sasajima, Tomohiro Noguchi, Kazumi Osada, Makoto Kashiwayanagi

    European Journal of Pharmacology   824   157 - 162   2018.4

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    Anxiety- and stress-related disorders can be debilitating psychiatric conditions in humans. To prevent or ameliorate these conditions, reliable animal models are needed to evaluate the effects of anxiolytic drugs. Previously, we found that a mixture of three pyrazine analogues (P-mix) that were present at high levels in wolf urine induced fear-related responses in mice, rats and deer. A change in cutaneous temperature was shown to be induced by acute stress simultaneously with changes in heart rate, arterial pressure and freezing behavior, raising the possibility that cutaneous temperature could be used as an index of stress. In the present study, using infrared thermography, we showed that exposure of mice to P-mix induced a decrease in cutaneous temperature. We then examined the dose-dependent effects of an anxiolytic drug, etizolam (0–20 mg/kg), on the temperature decrease. Pre-administration of etizolam (5 mg/kg or higher) inhibited the P-mix-induced decrease in cutaneous temperature. Exposure to P-mix induced Fos-immunoreactivity, a marker of neuronal excitation, at the mouse amygdala and hypothalamus, and etizolam (5 mg/kg) attenuated that immunoreactivity. The present results suggested that the measurement of cutaneous P-mix-induced temperature changes in mice could be used as an animal model for evaluating the effects of anxiolytic drugs.

    DOI: 10.1016/j.ejphar.2018.02.015

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  • Pyrazine analogues from wolf urine induced unlearned fear in rats Reviewed

    Makoto Kashiwayanagi, Sadaharu Miyazono, Kazumi Osada

    Heliyon   3 ( 8 )   e00391   2017.8

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    Urine excreted from the common grey wolf (Canis lupus) contains a kairomone, inducing fear-related behaviors in various mammals. Numerous fear-inducing substances activate neurons at the main and/or accessory olfactory bulb (AOB), medial and central amygdala, and hypothalamus. Our previous study showed that the mixture of pyrazine analogues (P-mix) contained in wolf urine induced avoidance and fear-related behaviors in laboratory mice and Hokkaido deer (Cervus nippon yesoensis), a species native to Japan. Exposure to wolf urine or P-mix induced expression of Fos, a marker of neuronal excitation, in the AOB of mice. In the present study, we explored the effects of P-mix on fear-related behaviors and Fos-expression in rats. Exposure to P-mix induced avoidance and immobilization in rats, while that to a mixture of i-amyl acetate, linalool and R(+)-limonene (O-mix), which generate floral and fruity odors, induced avoidance but not immobilization. P-mix but not O-mix increased Fos-immunoreactivity of the AOB, medial and central amygdala, and hypothalamus of rats. The present results suggest that P-mix odor induces unlearned fear-related behaviors in rats.

    DOI: 10.1016/j.heliyon.2017.e00391

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  • Structure-Activity Relationships of Alkylpyrazine Analogs and Fear-Associated Behaviors in Mice Reviewed

    Kazumi Osada, Sadaharu Miyazono, Makoto Kashiwayanagi

    JOURNAL OF CHEMICAL ECOLOGY   43 ( 3 )   263 - 272   2017.3

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    Our previous studies identified alkyl pyrazine analogs in wolf urine that act as novel kairomones and induce a series of fear-associated behaviors in mice. A mixture of these alkyl pyrazines also effectively suppressed the approach of deer to a feeding area, and animals that did approach the marked area exhibited fear-associated behaviors. To investigate structure-activity relationships of alkyl pyrazines, four fear-associated behaviors - freezing, locomotion activity, odor investigation, and avoidance - were measured in experiments on female C57BL/6 J mice. Of the 17 compounds tested, 2,3-diethylpyrazine, 3-ethyl-2,5-dimethylpyrazine, and 3-ethyl-2,5-dimethylpyrazine induced all four fear-associated behaviors. 2,3,5-Trimethylpyrazine also induced three of the fear-associated behaviors, but did not decrease locomotion. Multivalent analysis of behaviors clearly demonstrated that these four compounds formed an independent cluster and were the most active. Structure-activity relationships revealed that active alkyl pyrazines inducing all four fear-associated behaviors had methyl or ethyl group(s), but not longer carbon chains, and alkyl side chains consisting of four carbon atoms in total were present in the most potent analogs. This study is the first experimental investigation of structure-activity relationships between alkyl pyrazine analogs and fear-associated behaviors in mice.

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  • Intranasal Administration of Rotenone to Mice Induces Dopaminergic Neurite Degeneration of Dopaminergic Neurons in the Substantia Nigra Reviewed

    Hitoshi Sasajima, Sadaharu Miyazono, Tomohiro Noguchi, Makoto Kashiwayanagi

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   40 ( 1 )   108 - 112   2017.1

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    Exposure to environmental neurotoxins is suspected to be a risk factor for sporadic progressive neurodegenerative diseases. Parkinson's disease has been associated with exposure to the pesticide rotenone, a mitochondrial respiration inhibitor. We previously reported that intranasal administration of rotenone in mice induced dopaminergic (DA) neurodegeneration in the olfactory bulb (OB) and reduced olfactory functions. In the present study, we investigated the DA neurons in the brains of mice that were administered rotenone intranasally for an extended period. We found that the olfactory function of mice was attenuated by rotenone administration. Electrophysiological analysis of the mitral cells, which are output neurons in the OB, revealed that the inhibitory input into the mitral cells was retarded. In the immunohistochemical analysis, neurite degeneration of DA neurons in the substantia nigra was observed in rotenone -administered mice, indicating that rotenone progressively initiated the degeneration of cerebral DA neurons via the nasal route.

    DOI: 10.1248/bpb.b16-00654

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  • Intranasal administration of rotenone in mice attenuated olfactory functions through the lesion of dopaminergic neurons in the olfactory bulb Reviewed

    Hitoshi Sasajima, Sadaharu Miyazono, Tomohiro Noguchi, Makoto Kashiwayanagi

    NEUROTOXICOLOGY   51   106 - 115   2015.12

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    Many environmental chemicals are thought to affect brain function. It was reported that chemicals-in the nasal cavity directly reach the brain through the connection between olfactory neurons and the olfactory bulb (OB). In this 'olfactory transport,' xenobiotics absorbed at the nasal mucosa reach the brain by bypassing some physical barriers and defenses, and thus olfactory transport is suspected to be a vulnerable mechanism of the brain against invasion threats of environmental chemicals. In this study, we focused on the neuronal toxicity of rotenone administered intranasally to mice. The results showed that the mice that were administered rotenone had attenuated olfactory functions. We also found that intranasally administered rotenone induced acute mitochondrial stress at the OB. The repeated administration of rotenone resulted in a decrease in the number of dopaminergic neurons, which are inhibitory interneurons in the OB. Taken together, our findings suggest that the inhalation of environmental toxins induces the neurodegeneration of cranial neurons through olfactory transport, and that olfactory dysfunction may be induced as an earliest symptom of neurodegeneration caused by inhaled neurotoxins. (C) 2015 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.neuro.2015.10.006

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  • The scent of wolves: pyrazine analogs induce avoidance and vigilance behaviors in prey Reviewed

    Kazumi Osada, Sadaharu Miyazono, Makoto Kashiwayanagi

    FRONTIERS IN NEUROSCIENCE   9   363   2015.10

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    The common gray wolf (Canis lupus) is an apex predator located at the top of the food chain in the Northern Hemisphere. It preys on rodents, rabbits, ungulates, and many other kinds of mammal. However, the behavioral evidence for, and the chemical basis of, the fear inducing impact of wolf urine on prey are unclear. Recently, the pyrazine analogs 2, 6-dimethylpyrazine, 2, 3, 5-trimethylpyrazine and 3-ethyl-2, 5-dimethyl pyrazine were identified as kairomones in the urine of wolves. When mice were confronted with a mixture of purified pyrazine analogs, vigilance behaviors, including freezing and excitation of neurons at the accessory olfactory bulb, were markedly increased. Additionally, the odor of the pyrazine cocktail effectively suppressed the approach of deer to a feeding area, and for those close to the feeding area elicited fear-related behaviors such as the "tail-flag," "flight," and "jump" actions. In this review, we discuss the transfer of chemical information from wolf to prey through the novel kairomones identified in wolf urine and also compare the characteristics of wolf kairomones with other predator-produced kairomones that affect rodents.

    DOI: 10.3389/fnins.2015.00363

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  • RDH13L, an Enzyme Responsible for the Aldehyde-Alcohol Redox Coupling Reaction (AL-OL Coupling Reaction) to Supply 11-cis Retinal in the Carp Cone Retinoid Cycle Reviewed

    Shinya Sato, Sadaharu Miyazono, Shuji Tachibanaki, Satoru Kawamura

    JOURNAL OF BIOLOGICAL CHEMISTRY   290 ( 5 )   2983 - 2992   2015.1

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    Background: In carp cones, 11-cis retinal is formed with the AL-OL coupling reaction. Results: We identified RDH13L which catalyzes both the AL-OL coupling reaction with tightly-bound NADP(+) and the conventional RDH activity with exogenous NADP(+). Mouse RDH14 showed similar activity. Conclusion: Cones have effective mechanisms to regenerate the pigment. Significance: Molecular bases of effective pigment regeneration in cones are uncovered.
    Cone photoreceptors require effective pigment regeneration mechanisms to maintain their sensitivity in the light. Our previous studies in carp cones suggested the presence of an unconventional and very effective mechanism to produce 11-cis retinal, the necessary component in pigment regeneration. In this reaction (aldehyde-alcohol redox coupling reaction, AL-OL coupling reaction), formation of 11-cis retinal, i.e. oxidation of 11-cis retinol is coupled to reduction of an aldehyde at a 1:1 molar ratio without exogenous NADP(H) which is usually required in this kind of reaction. Here, we identified carp retinol dehydrogenase 13-like (RDH13L) as an enzyme catalyzing the AL-OL coupling reaction. RDH13L was partially purified from purified carp cones, identified as a candidate protein, and its AL-OL coupling activity was confirmed using recombinant RDH13L. We further examined the substrate specificity, subcellular localization, and expression level of RDH13L. Based on these results, we concluded that RDH13L contributes to a significant part, but not all, of the AL-OL coupling activity in carp cones. RDH13L contained tightly bound NADP(+) which presumably functions as a cofactor in the reaction. Mouse RDH14, a mouse homolog of carp RDH13L, also showed the AL-OL coupling activity. Interestingly, although carp cone membranes, carp RDH13L and mouse RDH14 all showed the coupling activity at 15-37 degrees C, they also showed a conventional NADP(+)-dependent 11-cis retinol oxidation activity above 25 degrees C without addition of aldehydes. This dual mechanism of 11-cis retinal synthesis attained by carp RDH13L and mouse RDH14 probably contribute to effective pigment regeneration in cones that function in the light.

    DOI: 10.1074/jbc.M114.629162

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  • Impaired mastication reduced newly generated neurons at the accessory olfactory bulb and pheromonal responses in mice Reviewed

    Chizuru Utsugi, Sadaharu Miyazono, Kazumi Osada, Mitsuyoshi Matsuda, Makoto Kashiwayanagi

    ARCHIVES OF ORAL BIOLOGY   59 ( 12 )   1272 - 1278   2014.12

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    Objectives: A large number of neurons are generated at the subventricular zone (SVZ) even during adulthood. In a previous study, we have shown that a reduced mastication impairs both neurogenesis in the SVZ and olfactory functions. Pheromonal signals, which are received by the vomeronasal organ, provide information about reproductive and social states. Vomeronasal sensory neurons project to the accessory olfactory bulb (AOB) located on the dorso-caudal surface of the main olfactory bulb. Newly generated neurons at the SVZ migrate to the AOB and differentiate into granule cells and periglomerular cells. This study aimed to explore the effects of changes in mastication on newly generated neurons and pheromonal responses.
    Design: Bromodeoxyuridine-immunoreactive (BrdU-ir; a marker of DNA synthesis) and Fosir (a marker of neurons excited) structures in sagittal sections of the AOB after exposure to urinary odours were compared between the mice fed soft and hard diets.
    Results: The density of BrdU-ir cells in the AOB in the soft-diet-fed mice after 1 month was essentially similar to that of the hard-diet-fed mice, while that was lower in the soft-diet-fed mice for 3 or 6 months than in the hard-diet-fed mice. The density of Fos-ir cells in the soft-diet-fed mice after 2 months was essentially similar to that in the hard-diet-fed mice, while that was lower in the soft-diet-fed mice for 4 months than in the hard-diet-fed mice.
    Conclusions: The present results suggest that impaired mastication reduces newly generated neurons at the AOB, which in turn impairs olfactory function at the AOB. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.archoralbio.2014.07.018

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  • Pyrazine analogs are active components of wolf urine that induce avoidance and fear-related behaviors in deer Reviewed

    Kazumi Osada, Sadaharu Miyazono, Makoto Kashiwayanagi

    FRONTIERS IN BEHAVIORAL NEUROSCIENCE   8   276   2014.8

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    Our previous studies Indicated that a cocktail of pyrazine analogs, identified in wolf urine, induced avoidance and fear behaviors in mice. The effects of the pyrazine cocktail on Hokkaido deer (Cervus nipper, yesoensis) were investigated in field bioassays at a deer park in Hokkaido, Japan. A set of feeding bioassay trials tested the effects of the pyrazine cocktail odor on the behavior of the deer located around a feeding area in August and September 2013. This odor effectively suppressed the approach of the deer to the feeding area In addition, the pyrazine cocktail odor provoked fear-related behaviors, such as "tail-flag': "flight" and "jump" actions, of the deer around the feeding area. This study is the first experimental demonstration that the pyrazine analogs in wolf urine have robust and continual fearful aversive effects on ungulates as well as mice. The pyrazine cocktail might be suitable for a chemical repellent that could limit damage to forests and agricultural crops by wild ungulates.

    DOI: 10.3389/fnbeh.2014.00276

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  • Similar rate of information transfer on stimulus intensity in accessory and main olfactory bulb output neurons Reviewed

    Tomohiro Noguchi, Hitoshi Sasajima, Sadaharu Miyazono, Makoto Kashiwayanagi

    NEUROSCIENCE LETTERS   576   56 - 61   2014.7

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    Recently, evidence has accumulated that the vomeronasal system cooperates with the main olfactory system to process volatile cues that regulate the animal's behavior. This is contradictory to the traditional view that the vomeronasal system is quite different from the main olfactory system in the time scale of information processing. Particularly, the firing rate of mitral/tufted cells in the accessory olfactory bulb (MTAOB) is known to be significantly lower than that of mitral cells in the main olfactory bulb (MCMOB). To address this question of whether the low-frequency firing in MTAOB carries less information than the high-frequency firing in MCMOB in the early stages of stimulation, we compared MTAOB and MCMOB for their firing mechanisms and information transfer characteristics. A model computation demonstrated that the inherent channel kinetics of MTAOB was responsible for their firing at a lower frequency than MCMOB. Nevertheless, our analysis suggested that MTAOB were comparable to MCMOB in both the amount and speed of information transfer about depolarizing current intensity immediately after current injection onset (&lt;200 ms). Our results support a hypothesis of simultaneous processing of common cues in both systems. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2014.05.058

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  • Hard-Diet Feeding Recovers Neurogenesis in the Subventricular Zone and Olfactory Functions of Mice Impaired by Soft-Diet Feeding Reviewed

    Chizuru Utsugi, Sadaharu Miyazono, Kazumi Osada, Hitoshi Sasajima, Tomohiro Noguchi, Mitsuyoshi Matsuda, Makoto Kashiwayanagi

    PLOS ONE   9 ( 5 )   e97309   2014.5

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    The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB.

    DOI: 10.1371/journal.pone.0097309

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  • Modulating the phototransduction cascade with small molecules Reviewed

    Isayama Tomoki, Wu Junchao, Miyazono Sadaharu, Lee Vanessa, Levine Emily, Makino Elina, Zimmerman Anita, Makino Clint

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   54 ( 15 )   2013.6

  • ロテノンの経鼻投与によるマウス嗅覚機能の低下

    柏柳 誠, 笹島 仁, 宮園 貞治, 野口 智弘

    日本鼻科学会会誌   51 ( 3 )   429 - 429   2012.9

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  • Vitamin A activates rhodopsin and sensitizes it to ultraviolet light Reviewed

    Sadaharu Miyazono, Tomoki Isayama, Francois C. Delori, Clint L. Makino

    VISUAL NEUROSCIENCE   28 ( 6 )   485 - 497   2011.11

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    The visual pigment, rhodopsin, consists of opsin protein with 11-cis retinal chromophore, covalently bound. Light activates rhodopsin by isomerizing the chromophore to the all-trans conformation. The activated rhodopsin sets in motion a biochemical cascade that evokes an electrical response by the photoreceptor. All-trans retinal is eventually released from the opsin and reduced to vitamin A. Rod and cone photoreceptors contain vast amounts of rhodopsin, so after exposure to bright light, the concentration of vitamin A can reach relatively high levels within their outer segments. Since a retinal analog, b-ionone, is capable of activating some types of visual pigments, we tested whether vitamin A might produce a similar effect. In single-cell recordings from isolated dark-adapted salamander green-sensitive rods, exogenously applied vitamin A decreased circulating current and flash sensitivity and accelerated flash response kinetics. These changes resembled those produced by exposure of rods to steady light. Microspectrophotometric measurements showed that vitamin A accumulated in the outer segments and binding of vitamin A to rhodopsin was confirmed in in vitro assays. In addition, vitamin A improved the sensitivity of photoreceptors to ultraviolet ( UV) light. Apparently, the energy of a UV photon absorbed by vitamin A transferred by a radiationless process to the 11-cis retinal chromophore of rhodopsin, which subsequently isomerized. Therefore, our results suggest that vitamin A binds to rhodopsin at an allosteric binding site distinct from the chromophore binding pocket for 11-cis retinal to activate the rhodopsin, and that it serves as a sensitizing chromophore for UV light.

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  • Do vertebrate rhodopsins contain an allosteric binding site(s) for retinoids? Reviewed

    Tomoki Isayama, Sadaharu Miyazono, Tetsuji Okada, Masahiro Kono, Rosalie Crouch, Anita Zimmerman, Clint Makino

    FASEB JOURNAL   24   2010.4

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  • Highly efficient retinal metabolism in cones Reviewed

    Sadaharu Miyazono, Yoshie Shimauchi-Matsukawa, Shuji Tachibanaki, Satoru Kawamura

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   105 ( 41 )   16051 - 16056   2008.10

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    After bleaching of visual pigment in vertebrate photoreceptors, all-trans retinal is reduced to all-trans retinol by retinol dehydrogenases (RDHs). We investigated this reaction in purified carp rods and cones, and we found that the reducing activity toward all-trans retinal in the outer segment (OS) of cones is &gt; 30 times higher than that of rods. The high activity of RDHs was attributed to high content of RDH8 in cones. In the inner segment (IS) in both rods and cones, RDH8L2 and RDH13 were found to be the major enzymes among RDH family proteins. We further found a previously undescribed and effective pathway to convert 11-cis retinol to 11-cis retinal in cones: this oxidative conversion did not require NADP(+) and instead was coupled with reduction of all-trans retinal to all-trans retinol. The activity was &gt; 50 times effective than the oxidizing activity of RDHs that require NADP(+). These highly effective reactions of removal of all-trans retinal by RDH8 and production of 11-cis retinal by the coupling reaction are probably the underlying mechanisms that ensure effective visual pigment regeneration in cones that function under much brighter light conditions than rods.

    DOI: 10.1073/pnas.0806593105

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  • Reduction of all-trans retinal to retinol in rods and cones Reviewed

    Sadaharu Miyazono, Yoshie Matsukawa, Shuji Tachibanaki, Satoru Kawamura

    ZOOLOGICAL SCIENCE   23 ( 12 )   1199 - 1199   2006.12

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  • Function of fatty acid-binding protein (FBP) in the Drosophila retina Reviewed

    Koichi Ozaki, Sadaharu Miyazono, Noboru Gombi, Daichi Ohno

    ZOOLOGICAL SCIENCE   23 ( 12 )   1199 - 1199   2006.12

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  • Metabolic pathways of retinoid in the pigment cells of Drosophila retina Reviewed

    Koichi Ozaki, Sadaharu Miyazono, Noboru Gombi, Daichi Ohno

    COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY   145 ( 3-4 )   420 - 420   2006.11

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    Language:English   Publisher:ELSEVIER SCIENCE INC  

    DOI: 10.1016/j.cbpb.2006.10.079

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  • Functional analysis of the proteins localized on pigment granules in the Drosophila retinal pigment cells Reviewed

    Sadaharu Miyazono, Satoru Kawamura, Koichi Ozaki

    ZOOLOGICAL SCIENCE   22 ( 12 )   1474 - 1474   2005.12

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MISC

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Presentations

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Awards

  • F1000Prime

    2012   F1000 Faculty  

    宮園 貞治

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  • F1000Prime

    2009   F1000 Faculty  

    宮園 貞治

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  • 楠本賞

    2003   大阪大学  

    宮園 貞治

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Research Projects

  • 中枢性嗅覚障害における嗅球ドパミン神経細胞死と匂い嗅ぎ呼吸調節の因果関係

    Grant number:23K08904  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    野口 智弘, 志賀 英明, 佐藤 元, 笹島 仁, 宮園 貞治

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    Grant amount:\4,680,000 ( Direct Cost: \3,600,000 、 Indirect Cost:\1,080,000 )

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  • 幼少期ストレスによる精神・身体変容の性差を生み出す脳内神経基盤の包括的理解

    Grant number:20K06734  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    宮園 貞治

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    Grant amount:\4,420,000 ( Direct Cost: \3,400,000 、 Indirect Cost:\1,020,000 )

    幼少期に虐待やネグレクト(育児放棄)などの大きなストレスを経験すると、将来、うつ病や心的外傷後ストレス症候群(Post Traumatic Stress Disorder;PTSD)などの精神疾患の発症率が高くなるだけでなく、心臓病や肺がんといった身体の異常の発症率も上昇すると言われている。このような将来的に精神だけでなく身体までにも引き起こされる異常は、成長過程における脳内神経回路の不可逆的な変容が長期にわたって継続したためと考えられるが、その機序の詳細は明らかではない。本研究では、幼少期に母仔分離ストレスを継続的に経験したマウスを用いて、幼少期ストレスによって精神と身体の両方に異常を引き起こす脳内神経回路の変容機序の解明を目的とし、その性差についても検討することとした。
    令和2年度は次のような成果を得た。嗅覚による先天的恐怖反応試験時における、内分泌性のストレス耐性の指標である血中コルチコステロン濃度を調べた。その結果、幼少期ストレスによって、オスでは先天的恐怖刺激がなくてもコルチコステロン濃度が高レベルで維持され、試験時にはそれ以上の大きな上昇は見られなかった。一方、メスでは通常とは異なる変化は見られなかった。以上のことから、オスではメスに比べて、幼少期ストレスが継続的な内分泌性の異常をもたらし、それが身体に悪影響を与え続けることが示唆された。今後、この機序の解明に取り組んでいくと共に、内分泌性だけでなく自律神経性のストレス耐性についても検討を行っていく予定である。

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  • Spatiotemporal control of synapse formation on dopaminergic interneurons in mouse olfactory bulbs during recovery from olfactory impairments.

    Grant number:20K09683  2020.4 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

    Grant amount:\4,030,000 ( Direct Cost: \3,100,000 、 Indirect Cost:\930,000 )

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  • アルツハイマー病最初期における嗅覚障害を引き起こす脳内異常の予防

    2018

    旭川医科大学  抗加齢医学プロジェクト 

    宮園貞治

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  • 幼少期ストレスによる神経回路変容が引き起こす心身異常の総合的理解

    2017 - 2021

    文部科学省  科学研究費補助金(基盤研究(C)) 

    宮園貞治

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  • Elucidation of neural and molecular mechanisms regulating brain function by oral sensation

    Grant number:15K07962  2015.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kashiwayanagi Makoto

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    Authorship:Coinvestigator(s) 

    Grant amount:\4,810,000 ( Direct Cost: \3,700,000 、 Indirect Cost:\1,110,000 )

    In this study, the neural pathway where oral sensory information is transmitted to the substantia nigra parenchyma were investigated when mouse ingested chow. For example, neurons at the cerebral cortex somatosensory area, lateral reticular body, pontine nucleus, trigeminal spinal cord tract were excited. In addition, at the olfactory bulb where nerve cells newly generated in the subventricular zone migrated, the activity of interneurons such as the change of GABA release was affected. These results directly indicate that the decrease in migration of newly generated cells to the olfactory bulb associated with the decrease in neurogenesis in the subventricular zone of mice fed a powder diet affects the mitral cell, output cells of the olfactory bulb, activity.

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  • Neural circuits mediating behavioral and physiological changes in fear response to odor stimulus

    Grant number:15K18573  2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    MIYAZONO Sadaharu

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4,290,000 ( Direct Cost: \3,300,000 、 Indirect Cost:\990,000 )

    For animal survival, it is important to respond appropriately to danger by feeling fear. When mice sniff the predator odor, they show behavioral, autonomic, and endocrine fear responses. In this study, we attempted to understand the induction and control mechanism of the fear reactions, using pyrazine compounds involved in wolf urine we identified previously. The pyrazine odor information simultaneously induced a set of fear reactions by activating neural circuits in both the main olfactory and vomeronasal systems in the brain. Also, the odor information was suggested to cause the region-specific activation in the bed nucleus of the stria terminalis and the anterior hypothalamic nucleus in these olfactory systems.

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  • 本能的に恐怖を感じる匂いを応用した野生動物に対する忌避剤の開発

    2015

    秋山記念生命科学振興財団  研究助成(奨励) 

    宮園貞治

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  • においに対する恐怖反応を制御する脳内神経回路の解明とその応用

    2014

    ノーステック財団研究開発助成事業  若手研究人材・ネットワーク育成補助金 

    宮園貞治

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  • 新規抗不安薬の恐怖情動に対する定量的評価系の確立

    2013 - 2014

    旭川医科大学  独創性のある生命科学研究 

    宮園貞治

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  • Olfactory dysfunction in early Alzheimer's disease

    Grant number:24770064  2012 - 2014

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    MIYAZONO Sadaharu

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4,550,000 ( Direct Cost: \3,500,000 、 Indirect Cost:\1,050,000 )

    Alzheimer's disease (AD) is a neurodegenerative disorder associated with the progressive impairment of cognition. The olfactory dysfunction occurs early in AD. However, the mechanism behind the dysfunction remains largely unknown. In this study, we tried to understand how Amyloid-β peptide (Aβ) induces the olfactory dysfunction, using transgenic mice deleting amyloid precursor protein binding protein, X11, that regulates amyloidogenesis. The young KO mice, that showed normal olfaction, have the higher level of soluble Aβ in the olfactory bulb (OB) than the wild-type mice. The KO mice accumulated the insoluble Aβ abundantly by aging. The Aβ aggregation might reduce an activity in the neural circuit of the OB and induce the olfactory dysfunction. Additionally, donepezil, an acetylcholinesterase inhibitor, prevented the Aβ aggregation in the OB, and improved the impaired olfactory function.

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  • 薬物の鼻腔内投与による脳内神経機能の制御

    2010 - 2011

    旭川医科大学  独創性のある生命科学研究 

    宮園貞治

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Teaching Experience

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Social Activities

  • 体験型サイエンスイベント「わくわくサイエンス」

    旭川ウェルビーイング・コンソーシアム  旭川市科学館「サイパル」(北海道・旭川市)  2019

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  • 体験型サイエンスイベント「わくわくサイエンス」

    旭川ウェルビーイング・コンソーシアム  旭川市科学館「サイパル」(北海道・旭川市)  2018

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  • 嗅覚と情動<天敵のにおいは恐怖を与える>

    Role(s): Lecturer

    SSH特別講座  旭川西高校(北海道・旭川市)  2016

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    Type:Visiting lecture

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  • 体験型サイエンスイベント「わくわくサイエンス」

    旭川ウェルビーイング・コンソーシアム  Feeeal 旭川(北海道・旭川市)  2016

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