K Nagai et aL Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 35 stress remained elevated when subjects smelled lemon odor compared Linck,V.M.,da Silva,A.L.Figueiro,M.,Piato.A.L.Herrmann,A.P.,Dupont,Birck F.. Caramao.E.B.Nunes.D.S..Moreno.P.R..Elisabetsky.E..2009.Inhaled linalool- when subjects smelled lavender odor (Kiecolt-Glaser et al.,2008) induced sedation in mice.Phytomedicine 16,303-307 Therefore,it is reasonable to speculate that autonomic neurotransmis- Lowrey.P.L.Takahashi.J.S..2004.Mammalian circadian biology:elucidating genome- sion and thus physiological phenomena can be innately modulated by wide levels of temporal organization.Annu.Rev.Genomics Hum.Genet.5.407-441 sensory olfactory signals in humans.Whether these effects that have Michelsen.K.A..Lozada.A.Kaslin.J.Karlstedt,K..Kukko-Lukjanov,T.K.Holopainen.L.. Ohtsu,H.,Panula,P 2005.Histamine-immunoreactive neurons in the mouse and been observed in the animal experiments described above will be ob- rat suprachiasmatic nucleus.Eur.J.Neurosci 22.1997-2004 served in human beings is the next target investigation of this line of Morrison,S.F 2004.Central pathways controlling brown adipose tissue thermogenesis. studies News Physiol.Sci.19,67-74. Nagai,K.Yamamoto,H.Nakagawa.H.1982.Time-dependent hyperglycemic actions of centrally administered 2-deoxy-D-glucose,D-mannitol and D-glucose.Biomed.Res. Conflict of interest 3.288-293. Nagai,K.Nagai,N.,Shimizu,K.,Chun,S.J,Nakagawa,H.,Niijima.A.1996a.SCN output drives the autonomic nervous system:with special reference to the autonomic func- All of the results mentioned in this review were obtained in the au- tion related to the regulation of glucose metabolism.Prog.Brain Res.111.253-272. thors'study in Osaka University.From the text-book style results ob- Nagai,K.Niijima,A.Nagai,N.Hibino,H.Chun,S..Shimizu,K.Nakagawa.H.1996b.Bi- tained in this study made the first author of this review confident lateral lesions of the hypothalamic suprachiasmatic nucleus eliminated sympathetic response to intracranial injection of 2-deoxy-D-glucose and VIP rescued this response. with the relationship between changes in autonomic neurotransmis- Brain Res.BulL 39,293-297. sion and those in physiological functions.The first author thinks that Nagai,K.Niijima,A..Yamano,T.,Otani,H.Okumura.N.,Tsuruoka,N.Nakai,M..Kiso,Y.. these relationships must be important and worthwhile to make the re- 2003.Possible role of L-carnosine in the regulation of blood glucose through control- ling autonomic nerves.Exp.Biol.Med.(Maywood)228,1138-1145. view for the understanding of the readers.Thus,this review does not Nagai,K,Tanida,M.,Niijima,A.,Tsuruoka,N.Kiso,Y..Horii,Y..Shen,J Okumura,N. have any conflict of interest. 2012.Role of L-carnosine in the control of blood glucose,blood pressure,thermogen- esis and lipolysis by autonomic nerves in rats:involvement of the circadian clock and Acknowledgments histamine.Amino Acids 43,97-109. Niijima,A.Nagai,K,2003.Effect of olfactory stimulation with flavor of grapefruit oil and lemon oil on the activity of sympathetic branch in the white adipose tissue of the ep- We would like to express our deep gratitude to the contributors of ididymis.Exp.Biol.Med.(Maywood)228.1190-1192. this research in the Institute for Protein Research,Osaka University, Shen,Niijima,A..Tanida,M..Horii,Y..Maeda.K.Nagai,K.2005a.Olfactory stimulation with scent of grapefruit oil affects autonomic nerves.lipolysis and appetite in rats. Japan. Neurosci.Lett.380.289-294. Shen.L Niijima.A.Tanida.M..Horii,Y..Maeda.K..Nagai.K..2005b.Olfactory stimulation References with scent of lavender oil affects autonomic nerves,lipolysis and appetite in rats. Neurosci.Lett.383.188-193. Alaoui-Ismali,O.Vernet-Maury.E.Dittmar.A.Delhomme,G.Chanel.J1997.Odor he- Shen,J,Niijima,A.Tanida,M.,Horii,Y..Nakamura.T Nagai,K..2007.Mechanism of donics:connection with emotional response estimated by autonomic parameters. changes induced in plasma glycerol by scent stimulation with grapefruit and laven- Chem.Scenses 22.237-248. der essential oils Neurosci lett 416 241-246 Bamshad,M.Song.C.K.Bartness,T.J,1999.CNS origins of the sympathetic nervous sys- ShenJNakamura,H.Fujisaki,Y..Tanida,M..Horii,Y.Fuyuki.RTakumi,H..Shiraishi,K tem outflow to brown adipose tissue.Am.J.PhysioL 276,R1569-R1578. Kometani,T.,Nagai,K.2009.Effect of 4G-a-glucopyranosyl hesperidin on brown fat Bartness,TJSong.C.K.Demas.G.E 2001.SCN efferents to peripheral tissues:implica- adipose tissue-and cutaneous-sympathetic nerve activity and peripheral body tem- tions for biological rhythms.L.Biol.Rhythm.16,196-204. perature.Neurosci.Lett.461.30-35. Buchbauer.G..Jirovetz,L.Jaeger.W.Dietrich.H.Plank.C.1991.Aromatherapy:evidence Shimazu,T..1981.Central nervous system regulation of liver and adipose tissue metabo for sedative effects of the essential oil of lavender after inhalation.Z Naturforsch.C. lism.Diabetologia 20.343-356. 461067-1072 Sly.J.D.Colvill,L McKinley.J.M.,Oldfield,JB..1999.Identification of neural projections Buijs,R.M..Chun.SJ Niijima,A.Romijn,HJ Nagai,K,2001.Parasympathetic and sym- from the forebrain to the kidney using the virus pseudorabies.J.Auton.Nerv.Syst. pathetic control of the pancreas:a role for the suprachiasmatic nucleus and other hy- 77,73-82. pothalamic centers that are involved in the regulation of food intake.J.Comp.Neurol Tanida.M,Niijima,A.Shen.J Nakamura,T..Nagai,K.2005a.Olfactory stimulation with 431.405-423. scent of essential oil of grapefruit affects autonomic neurotransmission and blood oressure Brain Res 1058 44-55 Buijs.R.M,la Fleur.S.E Wortel.Heynigen,C.VZuiddam.L.Mettnleiter,T.C Kalsbeek A.Nagai,K.Niijima.A.2003.The suprachiasmatic nucleus balances sympathetic and Tanida,M.,Niijima.A..Fukuda,Y.,Sawaki,H.Tsuruoka,N.Shen,J Yamada,S.Kiso,Y.. Nagai,K,2005b.Dose-dependent effects of L-carnosine on the renal sympathetic parasympathetic output to peripheral organs through separate preautonomic neu- rons.J.Comp.NeurolL.464.36-48. nerve and blood pressure in urethane-anesthetized rats.Am.J.Physiol.Regul Integr Bureau,L,2012.La Phytotherapie Pertinente:Phytotherapie en pratique a l'officine. Comp.PhysioL.288,R447-R455. ALTAL Editions.p.109 (France). Tanida,M..Niijima.A.Shen,J Nakamura,T..Nagai,K.2006.Olfactory stimulation with Dibona.G.F.,1982.The functions of the renal nerves.Rev.Physiol.Biochem.Pharmacol scent of lavender oil affects autonomic neurotransmission and blood pressure in rats.Neurosci.Lett.398,155-160. 94.75-181 Diego.MA Jones,N.A,Field,T..Hernandez-Relf,M..Schanberg.S.Kuhn,C.Mc-Adam,V Tanida.M.Yamatodani.A.Niijima,A.Shen,J Todo,T.Nagai.K,2007a.Autonomic and Galamaga.M.,1998.Aromatherapy positively affects mood.EEG pattems of alertness cardiovascular responses to scent stimulation are altered in cry KO mice.Neurosci. Lett.413.177-182. and math computations.Int.J.Neurosci.96,217-224. Duan,X.Tashiro.M..Wu,D..Yambe,T.Wang.Q.Sasaki.T.Kumagai,K..Luo,Y..Nitta.S. Tanida.M,Gotoh.H.Taniguchi.H.Otani,H.Shen,J Nakamura,T.,Tsuruoka,N..Kiso,Y.. Itoh,M.2007.Autonomic nervous function and localization of cerebral activity dur- Okumura,N.Nagai,K,2007b.Effects of central injection of L-carnosine on sympa- ing lavender aromatic immersion.Technol.Health Care 15.69-78. thetic nerve activity innervating brown adipose tissue and body temperature in Fujioka,K.Greenway.F,Sheard,Ying.Y.,2006.The effects of grapefruit on weight and rats.ReguL.Pept.144.62-71. insulin resistance:relationship to the metabolic syndrome.J.Med.Food 99-54. Tanida,M..Shen,J.Nakamura,T..Niijima,A..Nagai,K.,2008a.Day-night difference in Ganong.W.F 2005.Review of Medical Physiology.Lange Medical Books/McGraw-Hill. thermoregulatory responses to olfactory stimulation.Neurosci.Lett.439.192-197. New York Tanida.M.Shen.JNiijima,A.Yamatodani,A.Oishi,K.Ishida.N..Nagai,K.2008b.Effects Guynet,P.G.Koshiya,N.,Huangfu,D.,Baraban,S.C.Stornetta,R.L.Li,Y.W 1996.Role of of olfactory stimulations with scents of grapefruit and lavender oils on renal sympa- thetic nerve and blood pressure in Clock mutant mice.Auton.Neurosci.139,1-8. medulla oblongata in generation of sympathetic and vagal outflows.Prog.Brain Res. 107127-144 Vermet-Maury.E..Alaoui-Ismaili,O.Dittmar.A,Delhomme,G.Chanel,J1999.Basic Haze,S.,Sakai,K.Gozu,Y..2002.Effects of fragrance inhalation on sympathetic activity in emotions induced by odorants:a new approach based on autonomic pattem results. I.Auton.Nerv.Syst.75.176-183. normal adults.Jpn.J.Pharmacol.90,247-253. Kiecolt-Glaser.JKGraham.JE.Malerkey.W.B..Porter.K..Lemeshow.S.Glaser,R..2008. Yamamoto.H..Nagai,K..Nakagawa,H..1984.Role of the suprachiasmatic nucleus in glu- Olfactory influences on mood and autonomic,endocrine,and immune function. cose homeostasis.Biomed.Res 5.55-603. Psychoneuroendocrinology 33.328-339. Yamano.T..Niijimam,A..limori,S..Tsuruoka,N.Kiso.Y..Nagai.K.2001.Effect of L- Kolune,J.M.Stern,J.M.,1995.Maternal aggression in rats:effects of olfactory bulbectomy carnosine on the hyperglycemia caused by intracranial injection of 2-deoxy-D- ZnS04-induced anosmia,and vomeronasal organ removal.Horm.Behav.29 glucose in rats.Neurosci.Lett.313.78-82. 492-518. Kumar,N.Robidoux,J.Daniel,KW.Guzman,G..Floering.LM Collins,S.2007.Require- ment of vimentin filament assembly for beta3-adrenergic receptor activation of ERK MAP kinase and lipolysis.I.Biol.Chem.282,9244-9250.stress remained elevated when subjects smelled lemon odor compared when subjects smelled lavender odor (Kiecolt-Glaser et al., 2008). Therefore, it is reasonable to speculate that autonomic neurotransmis￾sion and thus physiological phenomena can be innately modulated by sensory olfactory signals in humans. Whether these effects that have been observed in the animal experiments described above will be ob￾served in human beings is the next target investigation of this line of studies. Conflict of interest All of the results mentioned in this review were obtained in the au￾thors' study in Osaka University. From the text-book style results ob￾tained in this study made the first author of this review confident with the relationship between changes in autonomic neurotransmis￾sion and those in physiological functions. The first author thinks that these relationships must be important and worthwhile to make the re￾view for the understanding of the readers. Thus, this review does not have any conflict of interest. Acknowledgments We would like to express our deep gratitude to the contributors of this research in the Institute for Protein Research, Osaka University, Japan. References Alaoui-Ismali, O., Vernet-Maury, E., Dittmar, A., Delhomme, G., Chanel, J., 1997. Odor he￾donics: connection with emotional response estimated by autonomic parameters. Chem. Scenses 22, 237–248. Bamshad, M., Song, C.K., Bartness, T.J., 1999. CNS origins of the sympathetic nervous sys￾tem outflow to brown adipose tissue. Am. J. Physiol. 276, R1569–R1578. Bartness, T.J., Song, C.K., Demas, G.E., 2001. SCN efferents to peripheral tissues: implica￾tions for biological rhythms. J. Biol. Rhythm. 16, 196–204. Buchbauer, G., Jirovetz, L., Jaeger, W., Dietrich, H., Plank, C., 1991. Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation. Z. Naturforsch. C. 46, 1067–1072. Buijs, R.M., Chun, S.J., Niijima, A., Romijn, H.J., Nagai, K., 2001. Parasympathetic and sym￾pathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hy￾pothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. 431, 405–423. Buijs, R.M., la Fleur, S.E., Wortel, J., Heynigen, C.V., Zuiddam, L., Mettnleiter, T.C., Kalsbeek, A., Nagai, K., Niijima, A., 2003. The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neu￾rons. J. Comp. Neurol. 464, 36–48. Bureau, L., 2012. La Phytotherapie Pertinente: Phytotherapie en pratique a l'officine, ALTAL Editions. p. 109 (France). Dibona, G.F., 1982. The functions of the renal nerves. Rev. Physiol. Biochem. Pharmacol. 94, 75–181. Diego, M.A., Jones, N.A., Field, T., Hernandez-Relf, M., Schanberg, S., Kuhn, C., Mc-Adam, V., Galamaga, M., 1998. Aromatherapy positively affects mood. EEG patterns of alertness and math computations. Int. J. Neurosci. 96, 217–224. Duan, X., Tashiro, M., Wu, D., Yambe, T., Wang, Q., Sasaki, T., Kumagai, K., Luo, Y., Nitta, S., Itoh, M., 2007. Autonomic nervous function and localization of cerebral activity dur￾ing lavender aromatic immersion. Technol. Health Care 15, 69–78. Fujioka, K., Greenway, F., Sheard, J., Ying, Y., 2006. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. J. Med. Food 9, 49–54. Ganong, W.F., 2005. Review of Medical Physiology. Lange Medical Books/McGraw-Hill, New York. Guynet, P.G., Koshiya, N., Huangfu, D., Baraban, S.C., Stornetta, R.L., Li, Y.W., 1996. Role of medulla oblongata in generation of sympathetic and vagal outflows. Prog. Brain Res. 107, 127–144. Haze, S., Sakai, K., Gozu, Y., 2002. Effects of fragrance inhalation on sympathetic activity in normal adults. Jpn. J. Pharmacol. 90, 247–253. Kiecolt-Glaser, J.K., Graham, J.E., Malerkey, W.B., Porter, K., Lemeshow, S., Glaser, R., 2008. Olfactory influences on mood and autonomic, endocrine, and immune function. Psychoneuroendocrinology 33, 328–339. Kolune, J.M., Stern, J.M., 1995. Maternal aggression in rats: effects of olfactory bulbectomy, ZnSO4-induced anosmia, and vomeronasal organ removal. Horm. Behav. 29, 492–518. Kumar, N., Robidoux, J., Daniel, K.W., Guzman, G., Floering, L.M., Collins, S., 2007. Require￾ment of vimentin filament assembly for beta3-adrenergic receptor activation of ERK MAP kinase and lipolysis. J. Biol. Chem. 282, 9244–9250. Linck, V.M., da Silva, A.L., Figueiro, M., Piato, A.L., Herrmann, A.P., Dupont, Birck F., Caramao, E.B., Nunes, D.S., Moreno, P.R., Elisabetsky, E., 2009. Inhaled linalool￾induced sedation in mice. Phytomedicine 16, 303–307. Lowrey, P.L., Takahashi, J.S., 2004. Mammalian circadian biology: elucidating genome￾wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407–441. Michelsen, K.A., Lozada, A., Kaslin, J., Karlstedt, K., Kukko-Lukjanov, T.K., Holopainen, I., Ohtsu, H., Panula, P., 2005. Histamine-immunoreactive neurons in the mouse and rat suprachiasmatic nucleus. Eur. J. Neurosci. 22, 1997–2004. Morrison, S.F., 2004. Central pathways controlling brown adipose tissue thermogenesis. News Physiol. Sci. 19, 67–74. Nagai, K., Yamamoto, H., Nakagawa, H., 1982. Time-dependent hyperglycemic actions of centrally administered 2-deoxy-D-glucose, D-mannitol and D-glucose. Biomed. Res. 3, 288–293. Nagai, K., Nagai, N., Shimizu, K., Chun, S.J., Nakagawa, H., Niijima, A., 1996a. SCN output drives the autonomic nervous system: with special reference to the autonomic func￾tion related to the regulation of glucose metabolism. Prog. Brain Res. 111, 253–272. Nagai, K., Niijima, A., Nagai, N., Hibino, H., Chun, S., Shimizu, K., Nakagawa, H., 1996b. Bi￾lateral lesions of the hypothalamic suprachiasmatic nucleus eliminated sympathetic response to intracranial injection of 2-deoxy-D-glucose and VIP rescued this response. Brain Res. Bull. 39, 293–297. Nagai, K., Niijima, A., Yamano, T., Otani, H., Okumura, N., Tsuruoka, N., Nakai, M., Kiso, Y., 2003. Possible role of L-carnosine in the regulation of blood glucose through control￾ling autonomic nerves. Exp. Biol. Med. (Maywood) 228, 1138–1145. Nagai, K., Tanida, M., Niijima, A., Tsuruoka, N., Kiso, Y., Horii, Y., Shen, J., Okumura, N., 2012. Role of L-carnosine in the control of blood glucose, blood pressure, thermogen￾esis and lipolysis by autonomic nerves in rats: involvement of the circadian clock and histamine. Amino Acids 43, 97–109. Niijima, A., Nagai, K., 2003. Effect of olfactory stimulation with flavor of grapefruit oil and lemon oil on the activity of sympathetic branch in the white adipose tissue of the ep￾ididymis. Exp. Biol. Med. (Maywood) 228, 1190–1192. Shen, J., Niijima, A., Tanida, M., Horii, Y., Maeda, K., Nagai, K., 2005a. Olfactory stimulation with scent of grapefruit oil affects autonomic nerves, lipolysis and appetite in rats. Neurosci. Lett. 380, 289–294. Shen, J., Niijima, A., Tanida, M., Horii, Y., Maeda, K., Nagai, K., 2005b. Olfactory stimulation with scent of lavender oil affects autonomic nerves, lipolysis and appetite in rats. Neurosci. Lett. 383, 188–193. Shen, J., Niijima, A., Tanida, M., Horii, Y., Nakamura, T., Nagai, K., 2007. Mechanism of changes induced in plasma glycerol by scent stimulation with grapefruit and laven￾der essential oils. Neurosci. Lett. 416, 241–246. Shen, J., Nakamura, H., Fujisaki, Y., Tanida, M., Horii, Y., Fuyuki, R., Takumi, H., Shiraishi, K., Kometani, T., Nagai, K., 2009. Effect of 4G-a-glucopyranosyl hesperidin on brown fat adipose tissue- and cutaneous-sympathetic nerve activity and peripheral body tem￾perature. Neurosci. Lett. 461, 30–35. Shimazu, T., 1981. Central nervous system regulation of liver and adipose tissue metabo￾lism. Diabetologia 20, 343–356. Sly, J.D., Colvill, L., McKinley, J.M., Oldfield, J.B., 1999. Identification of neural projections from the forebrain to the kidney using the virus pseudorabies. J. Auton. Nerv. Syst. 77, 73–82. Tanida, M., Niijima, A., Shen, J., Nakamura, T., Nagai, K., 2005a. Olfactory stimulation with scent of essential oil of grapefruit affects autonomic neurotransmission and blood pressure. Brain Res. 1058, 44–55. Tanida, M., Niijima, A., Fukuda, Y., Sawaki, H., Tsuruoka, N., Shen, J., Yamada, S., Kiso, Y., Nagai, K., 2005b. Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R447–R455. Tanida, M., Niijima, A., Shen, J., Nakamura, T., Nagai, K., 2006. Olfactory stimulation with scent of lavender oil affects autonomic neurotransmission and blood pressure in rats. Neurosci. Lett. 398, 155–160. Tanida, M., Yamatodani, A., Niijima, A., Shen, J., Todo, T., Nagai, K., 2007a. Autonomic and cardiovascular responses to scent stimulation are altered in cry KO mice. Neurosci. Lett. 413, 177–182. Tanida, M., Gotoh, H., Taniguchi, H., Otani, H., Shen, J., Nakamura, T., Tsuruoka, N., Kiso, Y., Okumura, N., Nagai, K., 2007b. Effects of central injection of L-carnosine on sympa￾thetic nerve activity innervating brown adipose tissue and body temperature in rats. Regul. Pept. 144, 62–71. Tanida, M., Shen, J., Nakamura, T., Niijima, A., Nagai, K., 2008a. Day-night difference in thermoregulatory responses to olfactory stimulation. Neurosci. Lett. 439, 192–197. Tanida, M., Shen, J., Niijima, A., Yamatodani, A., Oishi, K., Ishida, N., Nagai, K., 2008b. Effects of olfactory stimulations with scents of grapefruit and lavender oils on renal sympa￾thetic nerve and blood pressure in Clock mutant mice. Auton. Neurosci. 139, 1–8. Vermet-Maury, E., Alaoui-Ismaili, O., Dittmar, A., Delhomme, G., Chanel, J., 1999. Basic emotions induced by odorants: a new approach based on autonomic pattern results. J. Auton. Nerv. Syst. 75, 176–183. Yamamoto, H., Nagai, K., Nakagawa, H., 1984. Role of the suprachiasmatic nucleus in glu￾cose homeostasis. Biomed. Res. 5, 55–603. Yamano, T., Niijimam, A., Iimori, S., Tsuruoka, N., Kiso, Y., Nagai, K., 2001. Effect of L￾carnosine on the hyperglycemia caused by intracranial injection of 2-deoxy-D￾glucose in rats. Neurosci. Lett. 313, 78–82. K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35 35