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mystery of yawning 

 

 

mise à jour du
23 août 2023
Neurosci Bull
. 2026 Aug 17
doi: 10.1007/s12264-026-01695-2.
Species Divergence in Oxytocin-Dependent Yawning
on a Conserved Glutamatergic Erection Circuit

 

Zhang YC, Zheng QW, Lu Y, Wang HY, Cang J,
Wu XR, Fan LY, Li L, Zhang NN, Zhang XY,
Zhu JN, Jing J, Zhang QP.

Chat-logomini
 
Oxytocin and Glutamate during Yawning and Erection
 
Yawning coupled with penile erection is a conserved neurobehavioral syndrome mediated by the paraventricular hypothalamus (PVH). However, the distinct roles of oxytocin and its co-transmitters remain unresolved. Using chemogenetics, the authors showed that activation of PVH oxytocin neurons was sufficient to elicit both responses, whereas silencing these neurons abolished them.
 
Viral tracing revealed that these neurons project collaterally to the brainstem reticular nucleus and spinal cord to spatially coordinate autonomic and somatic motor outputs. By dissecting the molecular mechanisms using CRISPR-Cas9, the authors found that vesicular glutamate transporter 2 (VGLUT2)-dependent glutamatergic transmission provides the primary drive for both behaviors, whereas the oxytocin peptide is selectively required for yawning but dispensable for erection.
 
Comparative analyses across rats, hamsters, and mice demonstrated that while the glutamatergic erectile circuit was conserved, mice lacked spontaneous yawning and were resistant to apomorphine-induced yawning. These findings suggest a hierarchical co-transmission framework in which fast glutamatergic signaling provides the core drive, while oxytocin confers behavioral specificity.
 
Ocytocine et glutamate durant le bâillement et l'érection
 
Le bâillement associé à une érection pénienne est un syndrome neurocomportemental conservé, dont le mécanisme est médié par l'hypothalamus paraventriculaire (PVH). Cependant, les rôles distincts de l'ocytocine et de ses co-transmetteurs restent à élucider.
 
À l'aide de la chimio-génétique, les auteurs ont montré que l'activation des neurones à ocytocine du PVH suffisait à déclencher ces deux réponses, tandis que l'inhibition de ces neurones les supprimait.
Le traçage viral a révélé que ces neurones projettent des collatérales vers le noyau réticulaire du tronc cérébral et la moelle épinière afin de coordonner spatialement les sorties motrices autonomes et somatiques.
 
En analysant les mécanismes moléculaires à l'aide de CRISPR-Cas9, ils ont découvert que la transmission glutamatergique dépendante du transporteur vésiculaire du glutamate 2 (VGLUT2) constitue le principal moteur de ces deux comportements, tandis que le peptide de l'ocytocine est nécessaire de manière sélective pour le bâillement, mais non indispensable pour l'érection.
 
Des analyses comparatives menées chez des rats, des hamsters et des souris ont démontré que, si le circuit érectile glutamatergique était conservé, les souris ne présentaient pas de bâillements spontanés et étaient résistantes aux bâillements induits par l'apomorphine.
 
Ces résultats suggèrent un cadre de co-transmission hiérarchique dans lequel la signalisation glutamatergique rapide constitue le moteur principal, tandis que l'ocytocine confère la spécificité comportementale.
 
Introduction
Yawning is a phylogenetically ancient and stereotypically fixed action pattern [1] that emerges prenatally in humans and persists throughout life [2]. In addition to its links to arousal transitions and brain thermoregulation [3], yawning plays a communicative role in social species and is highly sensitive to neuromodulatory states. Clinically, excessive yawning marks the prodromal phase of neurological disorders, such as Parkinson's disease and migraine [4,5,6,7,8,9,10]. Pharmacologically, yawning is robustly induced by dopamine agonists and serotonergic agents [11, 12], and propofol anesthesia frequently triggers yawning accompanied by penile erection in humans [13, 14]. This "yawning-penile erection syndrome" has therefore become a widely used behavioral readout for central dopaminergic and oxytocinergic activation [15]. Conceptually, both yawning and penile erection function as consummatory reflexes and are regulated by the hypothalamus [16], driven by shared systemic arousal states. However, despite decades of study, the precise neural mechanisms that couple these distinct responses into a synchronized syndrome remain unclear.
 
Early studies relied on intracerebral administration of candidate transmitters [17], implicating dopamine, serotonin, glutamate, nitric oxide, adrenocorticotropic hormone, and oxytocin (OXT) [18, 19]. However, these approaches lack cellular specificity and fail to recapitulate endogenous release dynamics. Subsequent work identified the paraventricular nucleus of the hypothalamus (PVH) as a critical integration hub, where dopaminergic inputs recruit oxytocinergic neurons to drive yawning and penile erection [20, 21]. Importantly, PVH OXT neurons release fast-acting neurotransmitters, particularly glutamate, alongside neuropeptides [22]. Thus, whether the oxytocin peptide itself is required [23] or whether co-released transmitters provide the principal excitatory drive remains a central unresolved question.
 
To address this question, we combined designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetics and CRISPR-Cas9-mediated gene editing with cross-species behavioral analysis [24] in rodent models, including rats (primary model), mice, and hamsters. We established the necessity and sufficiency of PVH OXT neurons for yawning and penile erection, dissociated the roles of glutamate and OXT, and revealed evolutionary divergence in yawning behavior. Our results revealed a conserved glutamatergic core that drives penile erection across species, with oxytocin selectively acting as a species-dependent gate for yawning. This hierarchical co-transmission logic redefines the PVH OXT neuron function and provides a mechanistic framework for how neuropeptides and classical transmitters jointly specify complex behavioral outputs.
 
Discussion
Our multilevel dissection of the yawning-penile erection syndrome addresses a longstanding question in neural circuitry: What are the precise roles of co-released transmitters in PVH OXT neurons? Through a comprehensive approach combining in vivo fiber photometry, circuit-specific chemogenetics, and CRISPR-Cas9 gene disruption, our data reveal a functional molecular dissociation in which VGLUT2-dependent glutamatergic transmission from PVH OXT neurons is essential for both penile erection and yawning, whereas OXT peptide signaling is selectively required for yawning and dispensable for penile erection. Furthermore, our cross-species analysis revealed a striking behavioral divergence: mice exhibited exceptionally low rates of spontaneous yawning and remained profoundly insensitive to dopamine agonists. This hierarchical organization refines the traditional peptide-centric model of PVH function, suggesting that a fast glutamatergic drive provides the core excitatory backbone, while the neuropeptide confers specific behavioral modulation.
 
Pharmacological studies have long implicated OXT as the primary mediator of both behaviors, based on observations that intracerebral administration of OXT peptide elicits yawning and erection. In this study, our results indicate that PVH OXT neurons likely serve as key integrative nodes that regulate distinct downstream outputs through separate signaling modalities. This dissociation aligns with and mechanistically provides a conceptual framework for understanding prior observations in OXT-knockout mice, where males exhibit normal mating and females show preserved parturition, despite milk ejection deficits [28]. The conserved glutamatergic pathway likely supports survival-critical autonomic reflexes (e.g., erection and uterine contraction), whereas OXT selectively enables various modulatory outputs, such as milk ejection [29] and attenuating fear responses [30]. Importantly, co-transmission of OXT and glutamate is not a rigid division of labor but exhibits a highly dynamic and plastic nature. OXT can act entirely independently of fast glutamatergic transmission, even when glutamate receptors are blocked, to modulate specific downstream targets, such as attenuating fear responses [30]. Furthermore, these neurons exhibit profound functional plasticity, indicating that the system can undergo a functional switch from OXT-dominant to Glu-dependent signaling to mediate the same behavioral response under varying physiological demands [31].
 
Therefore, we propose that descending OXT projections employ a projection-target-specific decoding strategy. In the context of the yawning-erection syndrome, rapid glutamatergic excitation reliably engages the erection reflex, whereas OXT peptide signaling acts as a permissive gate for activating high-threshold central pattern generators specific to yawning. This dynamic interplay allows a single neuronal population to seamlessly orchestrate a complex, multicomponent physiological syndrome (Fig. 6A&endash;C).
 
Extensive evidence has highlighted dopamine as a master regulator of both penile erection and yawning, primarily by activating D2-like receptors (D2&endash;D4) in oxytocinergic neurons within the PVH [32]. Previous studies have shown that stimulation of these D2-like receptors increases calcium influx within PVH OXT neurons, leading to production and release of nitric oxide (NO), which is crucial for inducing these behaviors. Interestingly, our selective knockout experiments showed that the ablation of VGLUT2 in OXT neurons abolished both behaviors, whereas OXT knockout specifically impaired yawning while sparing penile erection. This functional dissociation suggests that dopamine-triggered activation of PVH OXT neurons utilizes distinct target-specific co-transmission strategies. Furthermore, while dominant integration of dopaminergic signaling occurs at the somatic level within the PVH, it remains an open question whether local dopaminergic terminals in the brainstem and spinal cord might also presynaptically fine-tune these descending PVH OXT/glutamate projections, a possibility that warrants further investigation.
 
Dopaminergic coupling to yawning is robust in rats and hamsters but is largely absent in mice, despite intact dopaminergic signaling, conserved PVH OXT neuron density, and preserved erectile responses. Rats are the most widely used experimental animal in yawning studies, and the effects of various dopamine agonists and antagonists have been extensively characterized. In contrast, spontaneous yawning is exceptionally rare in mice; consistently, in our own 40-hour video observations across 10 mice, only a single putative yawn was recorded. Accordingly, pharmacological studies on yawning in mice are limited. Notably, Li et al. demonstrated that the efficacy of dopamine receptor agonists in inducing yawning was significantly attenuated in mice compared with rats [33]. This divergence positions the mouse as a valuable comparative tool for dissecting circuit modularity but also underscores a key limitation: as the dominant genetic model, mice inadequately recapitulate certain OXT-mediated reflexes, such as yawning. Thus, rats may be a more suitable model for studying this conserved reflex. The species-specific attenuation of yawning in mice, despite the continued involvement of PVH oxytocin neurons in social memory, social recognition, affiliation, lactation, and parenting [34], highlights how evolution can selectively modify behavioral outputs within the same neural population, likely through differential projection targeting or release dynamics.
 
These findings provide further evidence for differential neurotransmitter coding in hypothalamic command centers. They suggest that a single type of neuron can orchestrate distinct autonomic and behavioral responses via different chemical messengers (glutamate for core drive; OXT for specificity) and potentially distinct downstream targets (e.g., spinal cord for erection vs. brainstem for yawning). The evolutionary variation revealed here, preserving one output while attenuating another, illustrates a general principle for generating species-typical repertoires from conserved neuropeptide systems. Future studies should extend this comparative framework to additional mammals and identify the molecular or synaptic mechanisms that enable single OXT neurons to differentially gate co-transmitter release across targets. Such insights will deepen our understanding of how neural circuits adapt to evolutionary pressures and inform models of species-specific behavioral diversity.
 
In summary, by integrating precise circuit manipulations with cross-species analysis, this study reframes the function of PVH OXT neurons as a modular hierarchical co-transmission system. This provides a mechanistic blueprint for how classical transmitters and neuropeptides jointly specify complex behaviors, with implications for neural circuit evolution and the interpretation of genetic models in behavioral neuroscience.