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mise à jour du
6 février 2012
Neurosci Res.
2012;72(4):316-323
Corticotropin-releasing factor antagonist reduces activation of noradrenalin and serotonin neurons in the locus coeruleus and dorsal raphe in the arousal response accompanied by yawning behavior in rats
Kubota N, Amemiya S, Motoki C, Otsuka T, Nishijima T, Kita I.
 

Department of Human Health Science, Tokyo Metropolitan University Japan.

Chat-logomini

 -Kita I, Kubota N, Yanagita S, Motoki C Intracerebroventricular administration of corticotropin-releasing factor antagonist attenuates arousal response accompanied by yawning behavior in rats. Neurosci.Letter 2008;433(3):205-208 
-Kita I, Yoshida Y, Nishino S. An activation of parvocellular oxytocinergic neurons in the paraventricular nucleus in oxytocin-induced yawning and penile erection. Neurosci Res. 2006;54(4):269-275
-Kita I, Seki Y, Nakatani Y, Fumoto M, Oguri M, Sato-Suzuki I, Arita H. Corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus are involved in arousal/yawning response of rats. Behav Brain Res. 2006;169(1)48-56.
-Kita I, Sato-Suzuki et al.Yawning responses induced by local hypoxia in the paraventricular nucleus of the rat.Behavioural Brain Research 2000;117(1-2):119-126
-Kubota N, Amemiya S, Motoki C, Otsuka T, Nishijima T, Kita I. Corticotropin-releasing factor antagonist reduces activation of noradrenalin and serotonin neurons in the locus coeruleus and dorsal raphe in the arousal response accompanied by yawning behavior in rats. Neurosci Res. 2012;72(4):316-323
-Kubota N, Amemiya S, Yanagita S, Nishijima T, Kita I. Emotional stress evoked by classical fear conditioning induces yawning behavior in rats. Neurosci Lett. 2014 Mar 11.
-Seki Y, Y Nakatani, et al Light induces cortical activation and yawning in rat Behav Brain Res 2003;140(1-2):65-73
-Seki Y, Sato-Suzuki I, et al Yawning/cortical activation induced by microinjection of histamine into the paraventricular nucleus of the rat. Behav Brain Res. 2002;134(1-2):75-82.
-Sato-Suzuki I, Kita I, Oguri M, Arita H Stereotyped yawning responses induced by electrical and chemical stimulation of paraventricular nucleus of the rat Journal of Neurophysiology, 1998;80(5)2765-2775
-Sato-Suzuki I, I Kita, Seki Y, M Oguri, H Arita Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat Behavioural Brain Research 2002;128:169-177

Abstract
 
We previously reported that intracerebroventricular (icv) administration of corticotropin-releasing factor (CRF) antagonist attenuates the arousal response during yawning behavior in rats. However, the CRF-related pathway involved in the arousal response during yawning is still unclear. In the present study, we assessed the involvement of the CRF-containing pathway from the hypothalamic paraventricular nucleus (PVN) to the locus coeruleus (LC) and the dorsal raphe nucleus (DRN) in the arousal response during frequent spontaneous yawning, which was induced by several microinjections of l-glutamate into the PVN in anesthetized rats, using c-Fos immunohistochemistry. The PVN stimulation showed significant increases in activation of PVN CRF neurons, LC noradrenalin (NA) neurons and DRN serotonin (5-HT) neurons as well as arousal response during yawning. But icv administration of a CRF receptor antagonist, ?-helical CRF (9-41), significantly inhibited the activation of both LC NA neurons and DRN 5-HT neurons except the activation of CRF neurons in the PVN, and significantly suppressed the arousal response during yawning. These results suggest that the CRF-containing pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons can be involved in the arousal response during yawning behavior.
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1. Introduction
 
Yawning behavior is typically associated with the induction of an arousal response (Concu et al., 1974; Sato-Suzuki et al., 1998). We have reported that the arousal response during yawning can be evoked by several forms of chemical stimulation of paraventricular nucleus (PVN) in the hypothalamus in anesthetized, spontaneously breathing rats, which was characterized an arousal shift in the electrocorticogram (EC0G), represented by lower voltage and faster rhythms occurring prior to yawning behavior (Kita et al., 2008; Sato-Suzuki et al., 1998, 2002). Previous studies have suggested that activation of oxytocin neurons and corticotropin-releasing factor (CRF) neurons in the PVN mediate the induction of the yawning accompanied by arousal response (Argiolas et al., 1987; Argiolas and Melis, 1998; Kita et al., 2006a,b), and the CRF neurons in the PVN could be primarily responsible for the arousal response during yawning behavior (Dunn and Berridge, 1990; Heinrichs and Koob, 2004; Kita et al., 2008; Menzaghi et al., 1993). We previously showed that intracerebroventricular (icy) administration of a CRF antagonist significantly attenuates the arousal response during yawning induced by PVN stimulation (Kita et al., 2008). However, the CRF-related pathway responsible for the arousal response during yawning behavior is still unknown. A series of animal studies has suggested that CRF has excitatory effects on the locus coeruleus (LC) noradrenalin (NA) neurons and the dorsal raphe nucleus (DRN) serotonin (5-HT) neurons, which are the regions within the brainstem reticular formation responsible for arousal response (Curtis et al., 2002; jedema and Grace, 2004; Kirby et al., 2000; Lowry et al., 2000; Schulz and Lehnert, 1996; Smagin et al., 1995; Staub et al., 2005, 2006). Taken together, the neural projection from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons may be one of candidates for the CRF-containing pathway responsible for the arousal response during yawning. In the present study, to investigate the involvement of the CRFcontaining pathway in the arousal response during yawning, we evaluated the effect of CRF antagonist, ct-helical CRF (9-41) on activation of LC NA neurons, DRN 5-HT neurons and PVN CRF neurons as well as the arousal response during yawning in anesthetized, spontaneously breathing rats, using c-Fos immunohistochemistry. Our
findings suggest that the CRF-containing pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons can be involved in the arousal response during yawning behavior.
 
4. Discussion
 
Administration of CRF receptor antagonist (ct-helical CRF (941)) into the ventricle significantly suppressed the arousal response during yawning, and significantly inhibited both increases in activity of LC NA neurons and DRN 5-HT neurons during yawning induced by PVN stimulation, but not activity of PVN CRF neurons. These results suggest that CRF neurons in the PVN may mediate the arousal response during yawning behavior through activation of LC NA neurons and DRN 5-HT neurons. This is the first study suggesting the involvement of the CRF-containing pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons in the arousal response during yawning behavior.
 
It is widely believed that activation of the descending oxytocinergic system in the PVN is one of the most important mechanisms for mediating the induction of yawning (Argiolas et al., 1987; Sato-Suzuki et al., 1987). However, the PVN contains various neuropeptides besides oxytocin, such as CRF, vasopressin, and dynorphine (Swanson and Sawchenko, 1983). We previously found, using c-Fos immunohistochemistry in rats, that activation of not only oxytocin neurons but also CRF neurons in the PVN is involved in the yawning accompanied by arousal response induced by PVN stimulation (Kita et al., 2006a). The mechanism by which CRF neurons produces yawning is unclear, but nitric oxide (NO) produced within CRF neurons may cause the yawning. NO is a diffusible neurotransmitter/neuromodulator and acts as a paracrine agent. Several studies have demonstrated that co-localization of NO synthesis with CRF-producing parvocellular in the PVN (Harada et al., 1999; Siaud et al., 1994; Torres et al., 1993). It is, thus, possible that diffusible NO produced within CRF neurons activates descending oxytocinergic system in the PVN and its actions on oxytocinergic neurons elicit yawning. This possibility could be supported by previous studies showing that NO could be involved in induction of yawning via an activation of oxytocinergic neurons projecting to the pons and medulla oblongata (Argiolas et al., 1987; Argiolas and Meus, 1998; Kita et al., 2006b; Melis and Argiolas, 1997; SatoSuzuki et al., 1998).
 
CRF neurons in the PVN generally play an important role as the initiators of activation of the hypothalamic-pituitary-adrenal axis (HPA axis) during stress (Rivier and Plotsky, 1986; Vale et al., 1981). In addition, CRF can serve in extrahypophyseal brain regions as one of the neurotransmitters most likely to be involved in mediating the arousal response as well as autonomic and behavioral responses to various stressors (Dunn and Berridge, 1990; Heinrichs and Koob, 2004; Menzaghi et al., 1993). Our previous studies have shown that stress-like stimulation could induce arousal response during yawning (Kita et al., 2000; Seki et al., 2003). In the present study, we showed that the CRF antagonist despite its ability to reduce arousal response measured by EC0G was unable to reduce yawning, being consistent with our previous study (Kita et al., 2008). It, thus, is possible that CRF neurons in the PVN, which can be activated by various stressors, primarily mediate the arousal response during yawning behavior, and that the oxytocinergic system in the PVN might be responsible for behavioral responses rather than the arousal response during yawning behavior.
 
Although the CRF-containing pathway involved in an arousal response during yawning evoked by PVN stimulation is still
unknown, a series of animal studies has suggested that CRF serves as an excitatory neurotransmitter in the LC and the DRN (Curtis et al., 2002; Jedema and Grace, 2004; Kirby et al., 2000; Lowry et al., 2000; Schulz and Lehnert, 1996; Smagin et al., 1995; Staub et al., 2005), which are the regions within the brainstem reticular formation responsible for cortical activation. Several anatomical studies have identified that the LC and DRN, which are the major sources of NA and 5-HT in the central nervous system respectively, receive CRF afferents from the PVN (Curtis et al., 1997; Dunn et al., 2004; Swanson et al., 1983; Valentino et al., 1992), and project to various areas of the cortex (Foote et al., 1983; Meloni et al., 2008; Swanson and Hartman, 1975; Vertes, 1991). In addition, it is reported that CRF terminal synaptically contact the catecholaminergic dendrites of LC neurons and serotonergic dendrites of DRN neurons, and that the CRF receptor is expressed in the LC NA neurons and DRN 5-HT neurons (Commons et al., 2003; Roche et al., 2003; Van Bockstaele et al., 1996, 1998; Waselus et al., 2009). Functional studies have Q4 shown that local administration of CRF into the LC or DRN affects neuronal activity in the LC or DRN respectively (Curtis et al., 2002; Jedema and Grace, 2004; Kirby et al., 2000; Staub et al., 2005, 2006; Valentino et al., 1983), whereas microinjection of the CRF receptor antagonist greatly inhibits the magnitude of the LC or DRN activation by stress (Kirby et al., 2000; Roche et al., 2003; Schulz and Lehnert, 1996; Smagin et al., 1995; Staub et al., 2005). The present study showed that microinjection of L-glutamate into the PVN significantly increases c-Fos expression in both LC NA neurons and DRN 5-HT neurons as well as PVN CRF neurons, and induced the arousal response during yawning. Furthermore, we also found that icy administration of CRF antagonist significantly suppressed increases in the activity of LC NA neurons and DRN 5-HT neurons, but not PVN CRF neurons, during yawning induced by the PVN stimulation, and suppressed the arousal response during yawning. It is, thus, suggested that a neural pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons is involved in the arousal response during yawning. However we cannot rule out the possibility that the CRF antagonist (icy) may combine with CRF receptor in several areas of the brain besides LC and DRN, because we used icy administration of the CRF antagonist in order to examine the involvement of CRF in the arousal response during yawning in the present study. It has been reported that CRF receptor is widely distributes in the several brain areas, such as cerebral cortex, lateral septum nucleus, hippocampus, amygdale, and hypothalamus as well as LC and DRN (Aguilera et al., 2004; Chalmers et al., 1995; Reul and Holsboer, 2002). However, our data showed that icy administration of CRF antagonist significantly suppressed increases in the activity of LC and DRN neurons during yawning induced by the PVN stimulation, as well as significant attenuation of arousal response during yawning. In addition, LC and DRN are located in the periventricular area, in which CRF antagonist delivered intacerebroventricularly can be to exert its dominant effects on (Bittencourt and Sawchenko, 2000; Pardridge, 1997). Therefore, it is possible that icy administration of CRF receptor antagonist could act on at least LC and DRN neurons in the present study.
 
Several anatomical studies have indicated multiple sources of CRF innervations to the LC and DRN, including the nucleus paragigantocellularis, Barrington's nucleus, central nucleus of the amygdale, bed nucleus of the stria terminals as well as the PVN (Curtis et al., 2002; Dunn et al., 2004; Valentino et al., 1992, 1996, 2010; Van Bockstaele et al., 1998,1999). Although the PVN CRF neurons is one of the most possible sources of CRF innervations to the LC and DRN, which can mediate the arousal response, we cannot rule out the possibility that the other sources of CRF neurons projecting to the LC and DRN may contribute to the arousal response during yawning.
 
Furthermore, we cannot exclude the involvement of oxytocincontaining pathway in the arousal response during yawning behavior. It has been shown that parvocellular oxytocin neurons in the PVN are known to send descending axons to the lower brain stem, including the LC (Schulz and Lehnert, 1996; Sawchenko and Swanson, 1982). In this study, pretreatment with CRF antagonist could not completely suppress the arousal shift in EC0G and the activation of LC NA neurons during yawning induced by PVN stimulation. Therefore, the oxytocin-containing pathway projecting to the LC may also be involved in the arousal response during yawning. This possibility should be investigated further through the use of oxytocin antagonists or higher doses of CRF antagonists.
 
The present study showed that the c-Fos active 5-HT neurons in the DRN were almost completely suppressed by the CRF receptor antagonist but NA neurons in the LC were not, suggesting the functional difference of these two neurotransmitter systems in controlling arousal response during yawning. It has been suggested that NA particularly is involved in alarm and anxiety state (Elam et al., 1986; Morilak et al., 2005; Prokopova, 2010; Ressler and Nemeroff, 2000), and that 5-HT is involved in anxiolitic and antidepressant behavior (Graeff et al., 1996; Meloni et al., 2008; Ressler and Nemeroff, 2000), though both NA and 5-HT are known to be stress-related neurotransmitter as well as CRF neurons. Thus, it is considered that the difference of neuronal activity between NA and 5-HT neurons during yawning can control the quality of arousal response during yawning, for example, different levels of emotional arousal, attention, or cognition.
 
In summary, we observed that several microinjections of L-glutamate into the PVN produced frequent spontaneous yawning accompanied by an arousal response, and the arousal response is associated with significant increases in the number ofc-Fos positive PVN CRF neurons, LC NA neurons, and DRN 5-HT neurons. However, pretreatment with CRF antagonist (icv) significantly inhibited the activation of both LC NA neurons and DRN 5-HT neurons, but not the activation of PVN CRF neurons. It also significantly suppressed the arousal response during yawning. These results suggest that CRF neurons in the PVN may mediate the arousal response during yawning behavior through activation of LC NA neurons and DRN 5HT neurons. Further studies are needed to clarify the direct pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons responsible for arousal response during yawning behavior.
 
 
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-Kita I, Kubota N, Yanagita S, Motoki C Intracerebroventricular administration of corticotropin-releasing factor antagonist attenuates arousal response accompanied by yawning behavior in rats. Neurosci.Letter 2008;433(3):205-208 
-Kita I, Yoshida Y, Nishino S. An activation of parvocellular oxytocinergic neurons in the paraventricular nucleus in oxytocin-induced yawning and penile erection. Neurosci Res. 2006;54(4):269-275
-Kita I, Seki Y, Nakatani Y, Fumoto M, Oguri M, Sato-Suzuki I, Arita H. Corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus are involved in arousal/yawning response of rats. Behav Brain Res. 2006; 169; 1; 48-56.
-Kita I, Sato-Suzuki et al.Yawning responses induced by local hypoxia in the paraventricular nucleus of the rat.Beh Brain Res 2000;117(1-2):119-126
-Kubota N, Amemiya S, Motoki C, Otsuka T, Nishijima T, Kita I. Corticotropin-releasing factor antagonist reduces activation of noradrenalin and serotonin neurons in the locus coeruleus and dorsal raphe in the arousal response accompanied by yawning behavior in rats. Neurosci Res. 2012
-Moyaho A, Valencia J Grooming and yawning trace adjustment to unfamiliar environments in laboratory Sprague-Dawley rats J Comp Psychol 2002;116(3):263-269
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-Sato-Suzuki I, Kita I; Oguri M, Arita H Stereotyped yawning responses induced by electrical and chemical stimulation of paraventricular nucleus of the rat Journal of Neurophysiology, 1998;80(5):2765-2775
-Sato-Suzuki I, I Kita, YSeki, M Oguri, H Arita Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat Behav Brain Res 2002;128:169-177
-Seki Y, Y Nakatani, et al Light induces cortical activation and yawning in rat Behav Brain Res 2003;140(1-2):65-73
-Seki Y, Sato-Suzuki I, et al Yawning/cortical activation induced by microinjection of histamine into the paraventricular nucleus of the rat. Behav Brain Res. 2002;134(1-2):75-82.
-Tufik S et al Effects of stress on drug induced yawning Physiol Behav 1995;58(1):1881-1884
 
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren
 
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