mystery of yawning
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Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
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Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
21 septembre 2012
Horm Behav
2012;62(4):505-514
Oxytocin-induced yawning: Sites of action in the brain and interaction with mesolimbic/mesocortical and incertohypothalamic dopaminergic neurons in male rats
 
Sanna F, Argiolas A, Melis MR.
 
Department of Biomedical Sciences, Neuroscience Section, and Centre of Excellence for the Neurobiology of Addictions, University of Cagliari, and Institute of Neuroscience, National Research Council, Cagliari, Italy.  

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Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren
 
 
Abstract
 
Oxytocin (80ng) induces yawning when injected into the caudal part of the ventral tegmental area, the hippocampal ventral subiculum and the posteromedial nucleus of the amygdala of male rats.
 
The behavioural response occurred concomitantly with an increase in the concentration of extracellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the shell of the nucleus accumbens and of the prelimbic medial prefrontal cortex by means of intracerebral microdialysis. Both oxytocin responses were significantly reduced by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin, a selective oxytocin receptor antagonist, injected in the above brain areas 15min before oxytocin. Similar results were obtained by activating central oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to the ventral tegmental area, the hippocampus and the amygdala, with the dopamine agonist apomorphine given at a dose that induces yawning when injected into the paraventricular nucleus.
 
Since oxytocin is considered a key regulator of emotional and social reward that enhances amygdala-dependent, socially reinforced learning and emotional empathy, mesolimbic and mesocortical dopamine neurons play a key role in motivation and reward, and yawning in mammals is considered a primitive, unconscious form of empathy, the present results support the hypothesis that oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to the above brain areas and mesolimbic and mesocortical dopaminergic neurons participate in the complex neural circuits that play a role in the above mentioned functions.
 
 yawning
 
Introduction
 
Yawning is a phylogenetically old, stereotyped event that occurs alone or associated with stretching and/or penile erection with a low frequency in humans, in animals from reptiles to birds and mammals, under different conditions (see Argiolas and Melis, 1998). Yawning occurs at bed and waking times and in boring situations more frequently than at other times of the day and situations. In rats and non human primates yawning is androgen-dependent and sexually dimorphic, with males yawning more than females (see Argiolas and Melis, 1998; Graves and Wallen, 2006).
 
The internal physiological stimuli that evoke spontaneous yawning and its physiological functions are unknown, although a role has been suggested in stretching and arousal (Baenninger, 1997; Provine et al., 1987a), in normalizing internal ear pressure (Laskiewicz, 1953), in increasing oxygen-CO2 exchange in the lung (Provine et al., 1987b), or even in cooling of the brain (Gallup and Gallup, 2008) (but see also Elo, 2010, 2011).
 
As yawning occurs concomitantly with an increased cortical electroencephalographic activity, it has been also suggested that yawning is an ancestral vestige survived through evolution that occurs when attention is low and arousal needs to be increased (see Bertolini and Gessa, 1981; Huston, 1971, but see also Guggisberg et al., 2007). Yawning is also contagious, as it can be also evoked in humans or non-human primates by a yawn produced by another subject of the same specie. This led to suggest that yawning may be linked to empathy (Anderson et al., 2004; Campbell and de Waal, 2011; Palagi et al., 2009; Paukner and Anderson, 2006).
 
Neuropharmacological studies revealed that occurrence of yawning alone or associated with stretching and penile erection, is under the control of several neurotransmitters and neuropeptides at central level. Of these, the best known are adrenocorticotropin, alpha-melanocyte stimulating hormone and related peptides, acetylcholine, dopamine, serotonin, excitatory amino acids, oxytocin, gamma-amminobutyrric acid (GABA) and opioid peptides. Some of these interact at the level of the paraventricular nucleus of the hypothalamus (PVN) in the control of this behavioural response.
 
Briefly, dopamine receptor agonists, N-methyl-D-aspartic acid (NMDA) and oxytocin itself induce yawning by activating oxytocinergic neurons projecting from the PVN to extra-hypothalamic brain areas, such as the hippocampus, the amygdala, the ventral tegmental area (VTA), the frontal cortex, the nucleus accumbens and/or the medulla oblongata, while GABA and opioids prevent this behavioural response induced by the above compounds by inhibiting these neurons (see Argiolas and Melis, 1998; Melis et al., 2007, 2009, 2010; Succu et al., 2007).
 
Recent studies show that oxytocinergic neurons reaching the VTA, the hippocampus and the amygdala activate mesolimbic/mesocortical dopaminergic neurons, and that the stimulation of these dopaminergic neurons in turn activates oxytocinergic neurons in the PVN, i.e., those controlling erectile function and sexual behaviour (see Melis et al., 2007, 2009; Succu et al., 2007, 2011). This neural circuit including oxytocin and mesolimbic/mesocortical dopamine neurons, is thought to play a role in the main aspects of both the anticipatory phase (sexual motivation and reward) and the consummatory phase (erection and copulation) of sexual activity (see Melis and Argiolas, 2011).
 
As oxytocin is also considered a key regulator of emotional and social behaviour in both females and males (Lee et al., 2009; Neumann, 2008 and references therein) or a neuropeptide that determines the sexually dimorphic aspect of social reciprocity and enhances amygdala dependent, socially reinforced learning and emotional empathy (Hurlemann et al., 2010), and yawning may be an unconscious signal that communicates one's own physiological/ psychological state to other members of a social group, e.g., a primitive, unconscious form of empathy (Campbell and de Waal, 2011; Guggisberg et al., 2010; Lehmann, 1979; Preston and de Waal, 2002), the above neural circuit might also play a role in these functions.
 
In order to test this possibility, we studied: 1) the effect of oxytocin injected into the VTA, the hippocampal ventral subiculum and the posteromedial nucleus of the amygdala (PMCo), on yawning and on the concentration of extracellular dopamine in the shell of the nucleus accumbens (NAs) and in the prelimbic medial prefrontal cortex (mPFC) by means of intracerebral microdialysis; and 2) if yawning induced by the activation of PVN oxytocinergic neurons projecting to the above brain areas by the dopamine agonist apomorphine, occurs concomitantly to an increase in extracellular dopamine in the NAs and in the mPFC.
 
Discussion
 
The present results show that oxytocin (80 ng) induces yawning when injected into the caudal VTA, the ventral subiculum of the hippocampus or into the PMCo, three brain areas containing oxytocin nerve endings (Adan et al., 1995; Buijs, 1978) and rich in oxytocin receptors (Boccia et al., 2007; Freund-Mercier et al., 1987; Vaccari et al., 1998). This dose of oxytocin is similar to those that induce yawning and penile erection when the peptide is injected into the CA1 field of the hippocampus (Melis et al., 1986) or penile erection when the peptide is injected into the caudal VTA (Melis et al., 2007; Succu et al., 2008), the ventral subiculum or the PMCo (Melis et al., 2009).
 
The pro-yawning effect of oxytocin did not occur when the peptide was injected in surrounding areas outside the VTA, the ventral subiculum and/or the PMCo, strengthening the anatomical specificity of the oxytocin effect (see also Melis et al., 2007, 2009). As the pro-yawning effect of oxytocin injected into the VTA, the ventral subiculum or the PMCo was markedly reduced by the prior injection of d(CH2)5Tyr(Me)2-Orn8-vasotocin, a potent and selective oxytocin receptor antagonist (Bankowski et al., 1980), this effect is apparently mediated by the stimulation of oxytocin receptors present in these brain areas, as found for oxytocin-induced yawning when injected into the PVN (see Argiolas and Melis, 1998).
 
This study also shows that VTA, ventral subiculum and PMCo oxytocin-induced yawning occurs concomitantly to an increase in the concentrations of extracellular dopamine and DOPAC in the dialysates obtained from the NAs and the mPFC. As expected, extracellular dopamine and DOPAC increases were also markedly reduced by the prior injection of a dose of d(CH2)5Tyr(Me)2-Orn8-vasotocin that reduced yawning, in line with the hypothesis that this effect is also mediated by the stimulation of oxytocin receptors present in these brain areas (see above).
 
Dopamine and DOPAC increases in the NAs and the mPFC dialysates and yawning were already measurable within the first 15 min period after oxytocin injection into the caudal VTA, but not into the ventral subiculum or the PMCo, when yawning occurred mainly in the second 15 min period after oxytocin injection and the dopamine increase.
 
This resembles the appearance of penile erection, which was observed only 30 min after injection of oxytocin into the ventral subiculum or the PMCo (see Melis et al., 2007, 2009) and is at variance from the effect of the peptide on yawning and penile erection that appear in 5&endash;10 min after injection of the peptide into the PVN (Melis et al., 1986). However, since accurate assessment and comparison of the temporal patterns of dopamine release and yawning appearance is not feasible due the fact that dialysate aliquots collection and yawning episodes counting are made only at 15 min intervals, it remains to be ascertained whether this indicates that more steps than those required for the dopamine increase need to be activated after oxytocin injection in these areas when compared to the VTA before yawning may occur.
 
Despite this uncertainty, the increase of extracellular dopamine and DOPAC in the dialysate from the NAs and from the mPFC induced by oxytocin injected into the VTA, the ventral subiculum or into the PMCo and its reduction by d(CH2)5Tyr(Me)2-Orn8-vasotocin, which blocks oxytocin receptors, confirms that oxytocin injected into these brain areas activates mesolimbic and mesocortical dopaminergic neurons.
 
This in turn leads to the appearance of yawning by yet unknown mechanisms. The activation of these dopaminergic neurons by oxytocin injected into the VTA may occur directly through oxytocinergic receptors located in the cell bodies of dopaminergic neurons, as already suggested for penile erection induced by oxytocin injected into the VTA.
 
Accordingly, oxytocinergic fibres impinging on VTA dopaminergic cell bodies retrogradely labelled by Fluorogold previously injected into the nucleus accumbens have been identified by double labelling immunohistochemistry (Melis et al., 2007). As to the mechanism by which oxytocin injected into the ventral subiculum or into the PMCo activates mesolimbic and mesocortical dopaminergic neurons, this may occur through the activation by the stimulation of oxytocinergic receptors of direct or indirect neuronal (mainly glutamatergic) pathways projecting from the ventral subiculum or the PMCo to the VTA, as already discussed in detail (see Melis and Argiolas, 2011).
 
Indeed, oxytocin injected into the ventral subiculum or the PMCo at a dose similar to that used in this study induces not only yawning, but also penile erection. This response was shown to be secondary to an increase in NO production, at least in the VTA and in the ventral subiculum (Melis et al., 2010; Succu et al., 2008). While NO in the VTA seems to activate directly mesolimbic/ mesocortical dopaminergic neurons by increasing cGMP production (Succu et al., 2008), in the ventral subiculum NO stimulates glutamic acid neurotransmission, leading to the activation of neural efferent (possibly glutamatergic) projections to yet unknown brain areas, which increase glutamic acid neurotransmission in the VTA, thereby modulating the activity of mesolimbic and mesocortical dopaminergic neurons (Melis et al., 2009, 2010; Succu et al., 2011).
 
Irrespective of the exact mechanism through which oxytocin injected into the VTA, the ventral subiculum or the PMCo, causes the activation of mesolimbic and mesocortical dopaminergic neurons, this also leads to the occurrence of yawning. One possibility is that the activation of mesolimbic and/or mesocortical dopaminergic neurons causes the activation of incerto-hypothalamic dopaminergic neurons, which impinge on PVN oxytocinergic neurons mediating yawning, as already suggested for penile erection induced by oxytocin injected into the VTA, the hippocampal ventral subiculum or the PMCo. Indeed oxytocin injected into the VTA increases extracellular dopamine in the dialysate obtained not only from the NAs, but also from the PVN (Melis et al., 2007).
 
In line with this interpretation, this study shows that a dose of apomorphine well known for its ability to induce yawning when injected into the PVN by stimulating dopamine D2-like receptors located in the cell bodies of PVN oxytocinergic neurons (see Sanna et al., 2011, 2012 and references therein), increases also extracellular dopamine in the dialysate not only from the NAs but also from the mPFC, and that these responses are markedly reduced by d(CH2)5Tyr(Me)2-Orn8-vasotocin given ICV (see also Melis et al., 2007).
 
Although further experiments are necessary to show that yawning occurs concomitantly to an increase in extracellular dopamine not only in the dialysate obtained from the NAs and the mPFC, but also from the PVN, after the injection of oxytocin into the ventral subiculum or into the PMCo, together the above findings suggest that oxytocinergic neurons originating in the PVN and projecting to the VTA, the hippocampal ventral subiculum and the PMCo, and mesolimbic and mesocortical dopaminergic neurons (originating in the VTA and projecting to the NA and the mPFC) participate to a complex neural circuit involved in the occurrence of yawning.
 
The involvement of the above oxytocinergic and dopaminergic neurons in the occurrence of yawning deserves some comment. Although the internal physiological stimuli that evoke spontaneous yawning and its physiological functions are unknown (see Introduction), its occurrence has been linked to the environment (increased vigilance level, danger, hunting prey) or even to communicative actions (sign of aggressiveness, hierarchical dominance, frustration, sexual excitement, boredom), or a mean of synchronizing activities within the group (see Giganti and Salzarulo, 2009; Guggisberg et al., 2007, 2010; Senju, 2010). Interestingly, brain oxytocin has been shown to be important in coordinating well-defined activities related to sociosexual behaviours and to have anxiolytic and anti-stress properties (see Baskerville and Douglas, 2010). Indeed oxytocin receptor-null mice exhibit deficits in social recognition and social memory, suggesting a role of the neuropeptide in facilitating interaction between individuals (Ferguson et al., 2000, 2001). Similarly, disruption of dopamine signalling in transgenic mice also causes social abnormalities (Baskerville and Douglas, 2010).
 
Common central brain regions involved in mediating socio-sexual behaviours include the nucleus accumbens, the prefrontal cortex, the hippocampus, the amygdala, the VTA the medial preoptic area (MPOA), the PVN and the supraoptic nucleus (SON). All these limbic and hypothalamic brain areas appear to be crucial components for the execution of socio-affiliative behaviours in rodents and for modulating neural reward pathways as a consequence of social interaction (Aragona et al., 2006; Edwards and Self, 2006; Keverne and Curley, 2004; Young and Wang, 2004).
 
In particular, mesolimbic and mesocortical dopaminergic neurons are thought to play a key role in motivation and reward, and an increase in extracellular dopamine concentration in the dialysate from the NAs and from the mPFC has been usually related to motivation and reward processes (Everitt and Robbins, 2005; Wise and Rompre, 1989) as well as to the execution of goal-directed behaviours (Goto and Grace, 2005).
 
Therefore yawning might be considered as a symptom that reflects the activation and/or inhibition of brain areas important in the control of social behaviour.
 
In this regard, it is noteworthy that a lower number of yawning episodes (Lehmann, 1979) and diminished plasma oxytocin levels have been reported in schizophrenic patients with neuroendocrine dysfunction and emotional deficits (e.g., with predominant negative symptoms) (Goldman et al., 2008) when compared to healthy volunteers, even after apomorphine administration (Legros et al., 1992). Likewise, in male rats chronic treatment with phencyclidine, an animal model of schizophrenia (Javitt and Zukin, 1991), causes a decrease of OT mRNA expression in the PVN and induces social deficits which are reduced by oxytocin infused into the amygdala (Lee et al., 2005), and adjunctive intranasal oxytocin reduces symptoms in schizophrenic patients (Feifel et al., 2010).
 
Yawning is also altered in autism, where contagious yawning is markedly reduced or absent (Helt et al., 2010; Senju et al., 2007) as found in schizophrenia (Haker and Rossler, 2009; see Walusinski, 2009 for a review on yawning and disease). The lack of contagious yawning seems to occur with lower concentrations of plasma oxytocin in autistic children when compared to healthy controls (Modahl et al., 1998). Dopamine dysfunctions have been also found in autism (Gadow et al., 2008; but see also Anderson et al., 2008), making it plausible a joint role for oxytocin and dopamine in brain regions relevant for this pathological condition, such as the VTA, the nucleus accumbens, the hippocampus and the prefrontal cortex (Baskerville and Douglas, 2010; Skuse and Gallagher, 2009).
 
In this regard, it is noteworthy that functional magnetic resonance imaging (fMRI) studies have shown that contagious yawning activates the parahippocampal gyrus (Schürmann et al., 2005), a part of the limbic system including the amygdala and the hippocampus, which are strictly connected to the VTA, the nucleus accumbens and the mPFC, and the ventromedial prefrontal cortex as well (Nahab et al., 2009).
 
Finally, impaired social and emotional capabilities are often observed in drug addicts (Brady et al., 2007; van den Bosch and Verheul, 2007), and a huge body of experimental evidence suggest that central dopamine and oxytocin neural pathways may be two potential neural correlates mediating drug addiction (Carson et al., 2010; Everitt and Robbins, 2005; McGregor et al., 2008).
 
In conclusion, oxytocin induces yawning not only when injected into the PVN or the CA1 field of the hippocampus, but also when injected into the VTA, the hippocampal ventral subiculum and the PMCo. This occurred with a concomitant increase of extracellular dopamine and its main metabolite DOPAC in the dialysate from the NAs and the mPFC. Oxytocin-induced yawning and extracellular dopamine increase in the NAs and the mPFC are markedly reduced by d(CH2)5Tyr(Me)2-Orn8-vasotocin, which blocks central oxytocin receptors.
 
Similar results are obtained with apomorphine injected into the PVN, a treatment that activates oxytocinergic neurons projecting to the VTA, the hippocampus and the amygdala (Melis and Argiolas, 2011; Melis et al., 2007, 2009, 2010; Succu et al., 2007, 2008, 2011).
 
Also in this case yawning occurred concomitantly with an increase of extracellular dopamine and DOPAC in the NAS and mPFC dialysate. These results confirm that PVN oxytocinergic neurons projecting to the VTA, the hippocampus and the amygdala activate directly or indirectly mesolimbic and mesocortical dopamine neurons, which in turn activate yet unknown neural pathways leading to the activation of incerto-hypothalamic dopamine neurons impinging on the cell bodies of PVN oxytocinergic neurons controlling yawning other than erectile function and sexual behaviour (Melis and Argiolas, 2011). This neural circuit and the mechanisms described above may be also involved in other functions in which dopamine and oxytocin are thought to play a role, from the regulation of emotional and social behaviours (Baskerville and Douglas, 2010; Everitt and Robbins, 2005; Lee et al., 2009,2009; Neumann, 2008), to the control of motivation and rewarding processes linked not only to natural stimuli (feeding, sexual behaviour) (Everitt and Robbins, 2005; Fulton, 2010) or to drugs of abuse (Carson et al., 2010; Kovacs et al., 1998), but also to mental pathologies, such as schizophrenia and autism (see Baskerville and Douglas, 2010; Gadow et al., 2008; Lee et al., 2009; McGregor et al., 2008; Modahl et al., 1998).
 
Sanna F, Succu S, Melis MR, Argiolas A. Dopamine agonist-induced penile erection and yawning: Differential role of D(2)-like receptor subtypes and correlation with nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats. Behav Brain Res. 2012;230:355-364