34 K Nagai et al.Autonomic Neuroscience:Basic and Clinical 185 (2014)29-35 Table 1 Effects of olfactory stimulation with the scent of grapefruit oil on autonomic neurotransmission and physiological function in rats. Nerve Changes innerve activity Changes in physiological phenomena Reference White adipose tissue sympathetic nerve Facilitation Increase in lipolysis Niijima and Nagai,2003 Shen et aL,2005a Brown adipose tissue Facilitation Increase in thermogenesis Shen et aL,2005a Sympathetic nerve Increase in BT Tanida et al,2008a Adrenal sympathetic nerve Facilitation Increase in adrenaline Shen et al,2005a Secretion,increase in BP Tanida et al,2005b Renal sympathetic nerve Facilitation Increase in BP Tanida et aL,2005b Gastric vagal nerve Suppression Decrease in appetite Shen et aL,2005a BT.body temperature:BP.blood pressure findings,the authors examined the changes in autonomic neurotrans- 6.Concluding remarks mission and a physiological phenomenon(i.e.,BP)elicited by GFO and LVO in Cryl and Cry2 double KO mice and Clock-mutant mice. This review described that olfactory stimulation with GFO and LVO In this study.it was found that GFO-induced increases in RSNA and scents affect physiological functions in association with changes in auto- BP and the LVO-induced increase in GVNA were not observed in Cryl nomic neurotransmission in rats (Tables 1 and 2).That is,olfactory and Cry2 double KO mice,which lack circadian rhythm of locomotive stimulation with the GFO scent increases lipolysis,thermogenesis activity under constant dark condition (Tanida et al.,2007a).However. (BT),and BP,and suppresses appetite in association with increases in GFO-induced increases in RSNA and BP were not observed in Clock- WAT-SNA,BAT-SNA,ASNA and RSNA and a decrease in GVNA in rats. mutant mice,but LVO-induced suppressions of RSNA and BP were ob- However,olfactory stimulation with the LVO scent represses lipolysis, served (Tanida et al.,2008a).These findings suggest that the molecular thermogenesis(BT)and BP,and facilitates appetite in association with clock mechanisms in the SCN,which involve the Cry1,Cry2 and Clock decreases in WAT-SNA,BAT-SNA,ASNA and RSNA and an increase in genes,are partially involved in mediating these autonomic and cardio- GVNA in rats.Because olfactory stimulation with the scent of R-(+)- vascular actions of GFO and LVO. limonene causes similar changes in physiological phenomena and auto- Using the pseudorabies virus,which is retrogradely and nomic functions after olfactory stimulation as does the GFO scent(Shen multisynaptically transported in nerves,we(Buijs et al.,2001,2003) et al..2005a:Tanida et al,2005b),limonene may be at least one of the and others (Bamshad et al.,1999.;Sly et al.,1999;Bartness et al. effective substances in GFO.In contrast,()-linalool resulted in similar 2001)have found evidence that the SCN sends sympathetic and para- changes in physiological phenomena and autonomic functions after ol- sympathetic neuronal projections to peripheral organs and tissues in- factory stimulation as does the LVO scent (Shen et al.,2005b;Tanida cluding the pancreas,liver,kidney,adrenal glands,and white and et al.,2006).Thus,linalool may be at least one of the effective substances brown adipose tissues.This represents the neural transmission route in LVO.Furthermore,evidence suggesting the involvement of the mas- from the SCN to peripheral organs.In this respect,we presented evi- ter circadian clock,the SCN,circadian clock mechanisms,and histamine dence that sympathetic preautonomic neurons and parasympathetic mechanisms in the changes in autonomic neurotransmission and phys- preautonomic neurons are different at the level of the SCN(Buijs et al. iological phenomena induced by stimulations with GFO and LVO were 2003).With regard to the relationship between histamine neurons in described in this review. the hypothalamic tuberomammillary nucleus(TMN)and the SCN,it With respect to the effects of olfactory stimulation with the scents of has been suggested that histaminergic neurons in the TMN project to essential oils in human beings,it has been described that psychosensory the SCN neurons (Michelsen et al.,2005).Therefore,the signals of the effects that are derived from individual experience and events are im- GFO and LVO scents that are responsible for the changes in neurotrans- portant in the effects of essential oils(Bureau,2012).Therefore,how mission and thus in the physiological phenomena described above much innate functional changes due to essential oils observed in animal might be transmitted from olfactory receptors in the nose to the SCN experiments are detected in human beings must be examined in the fu- through histamine neurons in the TMN.Then,this signal might be trans- ture.It was reported that an increase in the parasympathetic tone, mitted from the SCN down to the peripheral organs/tissues,and in this which was determined by the power spectral analysis of human heart way,the effects of olfactory stimulation with GFO,LVO and other essen- rate variability,were observed after the lavender fragrance (Duan tial oils on physiological functions might be realized (Fig.2). et al.,2007),and that blood norepinephrine levels following the cold Table 2 Effects of olfactory simulation with the scent of lavender oil on autonomic neurotransmission and physiological functions in rats Nerve Changes in nerve activity Changes in physiological phenomena Reference White adipose tissue Suppression Decrease in lipolysis Shen et al..2005b Sympathetic nerve Brown adipose tissue Suppression Decrease in thermogenesis Shen et al 2005b Sympathetic nerve Decrease in BT Tanida et al.2008a Adrenal sympathetic Suppression Decrease in adrenaline Shen et al.,2005b nerve Secretion,decrease in BP Tanida et al 2006 Renal sympathetic Suppression Decrease in BP Tanida et al.2006 nerve Gastric vagal Facilitation Increase in appetite Shen et al.,2005b nerve BT.body temperature:BP.blood pressure.findings, the authors examined the changes in autonomic neurotrans￾mission and a physiological phenomenon (i.e., BP) elicited by GFO and LVO in Cry1 and Cry2 double KO mice and Clock-mutant mice. In this study, it was found that GFO-induced increases in RSNA and BP and the LVO-induced increase in GVNA were not observed in Cry1 and Cry2 double KO mice, which lack circadian rhythm of locomotive activity under constant dark condition (Tanida et al., 2007a). However, GFO-induced increases in RSNA and BP were not observed in Clock￾mutant mice, but LVO-induced suppressions of RSNA and BP were ob￾served (Tanida et al., 2008a). These findings suggest that the molecular clock mechanisms in the SCN, which involve the Cry1, Cry2 and Clock genes, are partially involved in mediating these autonomic and cardio￾vascular actions of GFO and LVO. Using the pseudorabies virus, which is retrogradely and multisynaptically transported in nerves, we (Buijs et al., 2001, 2003) and others (Bamshad et al., 1999,; Sly et al., 1999; Bartness et al., 2001) have found evidence that the SCN sends sympathetic and para￾sympathetic neuronal projections to peripheral organs and tissues in￾cluding the pancreas, liver, kidney, adrenal glands, and white and brown adipose tissues. This represents the neural transmission route from the SCN to peripheral organs. In this respect, we presented evi￾dence that sympathetic preautonomic neurons and parasympathetic preautonomic neurons are different at the level of the SCN (Buijs et al., 2003). With regard to the relationship between histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) and the SCN, it has been suggested that histaminergic neurons in the TMN project to the SCN neurons (Michelsen et al., 2005). Therefore, the signals of the GFO and LVO scents that are responsible for the changes in neurotrans￾mission and thus in the physiological phenomena described above might be transmitted from olfactory receptors in the nose to the SCN through histamine neurons in the TMN. Then, this signal might be trans￾mitted from the SCN down to the peripheral organs/tissues, and in this way, the effects of olfactory stimulation with GFO, LVO and other essen￾tial oils on physiological functions might be realized (Fig. 2). 6. Concluding remarks This review described that olfactory stimulation with GFO and LVO scents affect physiological functions in association with changes in auto￾nomic neurotransmission in rats (Tables 1 and 2). That is, olfactory stimulation with the GFO scent increases lipolysis, thermogenesis (BT), and BP, and suppresses appetite in association with increases in WAT-SNA, BAT-SNA, ASNA and RSNA and a decrease in GVNA in rats. However, olfactory stimulation with the LVO scent represses lipolysis, thermogenesis (BT) and BP, and facilitates appetite in association with decreases in WAT-SNA, BAT-SNA, ASNA and RSNA and an increase in GVNA in rats. Because olfactory stimulation with the scent of R-(+)- limonene causes similar changes in physiological phenomena and auto￾nomic functions after olfactory stimulation as does the GFO scent (Shen et al., 2005a; Tanida et al., 2005b), limonene may be at least one of the effective substances in GFO. In contrast, (±)-linalool resulted in similar changes in physiological phenomena and autonomic functions after ol￾factory stimulation as does the LVO scent (Shen et al., 2005b; Tanida et al., 2006). Thus, linalool may be at least one of the effective substances in LVO. Furthermore, evidence suggesting the involvement of the mas￾ter circadian clock, the SCN, circadian clock mechanisms, and histamine mechanisms in the changes in autonomic neurotransmission and phys￾iological phenomena induced by stimulations with GFO and LVO were described in this review. With respect to the effects of olfactory stimulation with the scents of essential oils in human beings, it has been described that psychosensory effects that are derived from individual experience and events are im￾portant in the effects of essential oils (Bureau, 2012). Therefore, how much innate functional changes due to essential oils observed in animal experiments are detected in human beings must be examined in the fu￾ture. It was reported that an increase in the parasympathetic tone, which was determined by the power spectral analysis of human heart rate variability, were observed after the lavender fragrance (Duan et al., 2007), and that blood norepinephrine levels following the cold Table 2 Effects of olfactory simulation with the scent of lavender oil on autonomic neurotransmission and physiological functions in rats. Nerve Changes in nerve activity Changes in physiological phenomena Reference White adipose tissue Suppression Decrease in lipolysis Shen et al., 2005b Sympathetic nerve Brown adipose tissue Suppression Decrease in thermogenesis Shen et al., 2005b Sympathetic nerve Decrease in BT Tanida et al., 2008a Adrenal sympathetic nerve Suppression Decrease in adrenaline Shen et al., 2005b Secretion, decrease in BP Tanida et al., 2006 Renal sympathetic nerve Suppression Decrease in BP Tanida et al., 2006 Gastric vagal nerve Facilitation Increase in appetite Shen et al., 2005b BT, body temperature; BP, blood pressure. Table 1 Effects of olfactory stimulation with the scent of grapefruit oil on autonomic neurotransmission and physiological function in rats. Nerve Changes innerve activity Changes in physiological phenomena Reference White adipose tissue sympathetic nerve Facilitation Increase in lipolysis Niijima and Nagai, 2003 Shen et al., 2005a Brown adipose tissue Facilitation Increase in thermogenesis Shen et al., 2005a Sympathetic nerve Increase in BT Tanida et al., 2008a Adrenal sympathetic nerve Facilitation Increase in adrenaline Shen et al., 2005a Secretion, increase in BP Tanida et al., 2005b Renal sympathetic nerve Facilitation Increase in BP Tanida et al., 2005b Gastric vagal nerve Suppression Decrease in appetite Shen et al., 2005a BT, body temperature; BP, blood pressure. 34 K. Nagai et al. / Autonomic Neuroscience: Basic and Clinical 185 (2014) 29–35