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Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders

Abstract

Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.

Introduction

“Amor est vitae essentia”, as a proverb states, “love” is consistent with “pleasure” in neuroscience. Oxytocin (OXT), an ancient, conserved, “love” related neuropeptide, is an endogenous hormone consisted of 9 amino acids and is well-known for its effect on lactation and parturition in mammals. It’s now over one century since pharmacologist Sir Henrry Hallet Dale discovered that a pituitary extract can promote uterotonic activity and be named by “Oxytocin” meaning “quick birth” [1]. OXT was synthesized by magnocellular and parvocellular neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and transported by the posterior pituitary into the circulation [2,3,4]. At whole brain level, the distribution of OXT receptor (OXTR) is mainly in different brain regions, especially in the projection of magnocellular and parvocellular neurons, including hippocampus, amygdala, prefrontal cortex [5,6,7].

Stress is always a natural response of organism to environmental disturbances, which is often associated with the experience of the emotional and physiological challenge. The chronic stress environment may impair individual mental health and induce depression, anxiety, fatigue, PTSD [8]. The physiological and pathophysiological mechanism of OXT have attracted sustained research interest given its role in complex behavioral traits and in the mental health conditions [3]. In our previous work, we found that OXT may be a modulator of stress-related neuropsychiatric disorders [9].

Here, we reviewed recent advances in preclinical and clinical study regarding the potential use of OXT in stress-related neuropsychiatric disorders. For a more comprehensive understanding of the mechanism of oxytocin's anti-stress action, we summarized the signaling cascade of OXT binding to targeting stress. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. The efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. Finally, current biological strategies to augment the level of OXT in stress-related neuropsychiatric disorders were summarized, shedding a light on the treatment of stress-induced psychiatric disorders.

Oxytocin receptor coupled signaling cascade

Understanding how OXT mediated a signaling cascade under stress is a biochemical basis for attenuating the neuropsychiatric disorders. OXTR, as a G protein-coupled receptor (GPCR) consisting of 389 amino acids, plays a vital role in maternal behavior, social behavior, and parturition [10]. And OXTR is coupled to the heterotrimeric complex of G proteins, including the Gα, Gβ, Gγ subunits [11]. In general, OXTR mediates Ca2+ release and transport pathways. When Gβ and Gγ subunits bind to OXTR, activation of Gα enhance the activation of phospholipase C (PLC) and downstream inositol 3 phosphate (IP3) and 1,2-dicyaglycerol (DAG), inducing Ca2+ release from the endoplasmic reticulum [12]. Elevated intracellular Ca2+ ions concentration forms a complex with calmodulin protein and induces smooth muscle contraction, which may be involved in myometrial cells contraction during labor [13, 14].

OXT-mediated elevation of intracellular Ca2+ concentration was associated with activation of IP3-sensitive Ca2+ storages of astrocytes in vitro [15]. OXT also induces Ca2+ influx by regulating transient receptor potential vanilloid type 2 (TRPV2) channels to induces anxiolytic activity in male rats [16]. The process of OXT-induced intracellular Ca2+ changes may also be involved in the regulation of neuronal excitability or synaptic plasticity, but depends on the type of neuronal cell [16]. In the paraventricular OXT neurons, OXTR mediates increased neuropeptide S synthesis and induces anxiolysis [17]. In addition, it was found that OXTR interacts mitogen-activated protein kinase (MAPK) signaling pathway by acting with epidermal growth factor receptor (EGFR) [18]. And OXTR-EGFR signaling promotes the maintenance of LTP in the CA1 region synapses of the hippocampus of female and male rats [19].

The distribution characteristic of OXTR mediate the physiological effect in the stress response. In hypothalamic corticotrophin-releasing hormone (CRH) neurons, restraint stress induces the CRH expression and cAMP response element-binding (CREB) translocation into nuclear in rat [20]. As a co-activator of CREB phosphorylation, CREB-regulated transcriptional coactivators (CRTC) dephosphorylates and enters the nucleus to interact with the CRF promoter, activating CRF gene expression in the stress [21]. Moreover, Estrogen receptor-mediated signaling also interacts with the OXTR signaling cascade. Immunohistochemistry and in situ hybridization results revealed that estrogen receptor beta (ERβ) was highly expressed in hypothalamic OXT neurons in rats and mice [22, 23]. Interaction between hypothalamic ERβ and OXT can modulate anxiety behavior and HPA axis activity in restraint-stressed rats [24]. And treatment with ERβ ligand agonist, 5α-androstane, 3β,17β-diol (3β-diol), upregulates the expression of OXT mRNA and promotes OXT transcription via CREB and steroid receptor coactivator-1 [25]. In particular, estrogen withdrawal induces hypothalamic oxytocin neuronal plasticity and increases anxiety behaviors via enhancing OXT transmission between the PVN and dorsal raphe nucleus [26]. In addition, androgen receptors have been found to co-localize with hypothalamic OXT by immunocytochemistry in the postmortem brain of patients with mood disorders [27]. The application of techniques for the study of co-expression of OXT and other hormone receptors is still limited and remains at the level of in situ hybridization or immunohistochemistry only. The utilization of single-cell transcriptomics, spatial transcriptomics, and the development of other hormone receptor sensors may provide technical support to address this issue. Spatial transcriptomics (ST) is a technique to understand gene expression differences between tissues, organs and pathological states by describing the gene expression profiles of specific cell types through spatial dimensionality analysis, which is capable of resolving transcripts at different spatial locations in tissues [28]. This could help understand the mechanisms by which signaling pathways activated by oxytocin and other hormone receptors produce different behavioral paradigms in different brain regions. In addition, the application of single-cell transcriptomics has enabled the observation of tissues at single-cell resolution. Computational tools have been developed to estimate cell–cell communication activity from RNA-seq data using signaling databases [29, 30]. A recent study analyzed multiple error robust fluorescence in situ hybridization (MERFISH) data from the mouse hypothalamic preoptic region, featuring 161 genes and 73,655 cells [31]. Self-regulation of excitatory neurons and modulation of inhibitory neurons by excitatory neurons through OXT signaling were found in all slices, a result consistent with the known primary function of OXT signaling [31]. Further analysis identified localized regions of high activity and spatial orientation of OXT signaling, which is consistent with protein staining of OXT and its receptors [31]. A gradual change in the direction of predicted OXT signaling and in the region of high activity was observed through adjacent slices [31]. Notably, whole-brain quantitative expression of OXTR is important for understanding expression specificity in temporal and spatial patterns. Kyra et al. constructed quantitative expression changes of OXTR during postnatal development and at the whole-brain level using OXTR fluorescent reporter mice (OXTRvenus/+) [32]. They also built an open OXTR web-based visualization data (https://kimlab.io/brain-map/OTR/), which provides an anatomical basis for subsequent OXT/OXTR-mediated behavioral and neural circuits differences across age [32]. A clear pattern of OXTR gene expression in the developing brain was found in postmortem human brain samples, with OXTR expression increasing during the prenatal period, peaking in early childhood, and strong spatiotemporal coupling to psychiatric disorders [33]. Brandon et al. revealed spatial and temporal enrichment of OXTR expression in adult neurons of the mouse olfactory bulb, with OXTR expression peaking during activity-dependent integration [34]. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, they demonstrated that OXTR signaling promotes morphogenesis and synapse maturation by regulating newly integrated adult neurons [34]. Therefore, analyzing OXT and its related receptors from a temporal and spatial perspective may provide a more precise strategy for application. Furthermore, the stress response is often accompanied by overactivation of the neuroimmune system. OXT (i.c.v injection) ameliorated the negative effects of maternal separation (MS) on the hippocampal neuroimmune system and reduced inflammatory cytokine via suppressing the Toll like receptor 4 (TLR4) pathway (IL-1β, Myd88, TNF-α, NLRP3) [35]. Increased OXTR expression is regulated by NF-κB downstream of TLR4 and attenuates LPS-induced macrophage inflammatory response [36]. Collectively, these findings shed light on the role of the interaction of OXTR-mediated signaling cascades with other signals in PVN (Fig. 1).

Fig. 1
figure 1

Schematic description of the signaling cascade of Oxytocinergic neurons in PVN. OXT binding to OXTR stimulates the transcription of EGFR, which leads to subsequent MAPK pathway activation. The Ca2+, influx into the cytoplasm via activated TRPV4 and release from PLC dependent pathway, interacts the ERK1/2 and MEK1/2 to regulate the subsequent transcription factor (CREB, CTRC, CD38). Furthermore, OXT binding also suppress the TLR4 mediated signaling cascade, which causes the inhibition of immune response genes (TNF-α, IL-1β, NLRP3). When ERβ is activated, intracellular cascades promote the transcription of OXT via CREB and coactivators. These signaling cascades ultimately buffer the molecular changes induced by stress. Image created with Biorender.com

Given the molecular structure of OXT, it’s usually harder to cross the blood–brain barrier. Therefore, OXT is administered by nasal spray and diffuses in the cerebrospinal fluid through the olfactory bulb axonal projections rather than through the blood–brain barrier [37, 38]. It should be mentioned that the hypothalamus is the first region to respond to peripheral physiological changes, such as starvation and cold. Hypothalamus has permeable microvessels attached and nuclei with looser tight junction structures for transit of hormones (i.e., leptin, ghrelin etc.), such as the medial basal hypothalamus and arcuate nucleus [39, 40]. It has been shown that the median eminence (ME), located in the medial basal hypothalamus, near the arcuate nucleus, is the entry point for some neuropeptide hormones and circulating signals into the brain via the fenestrated capillaries [40, 41]. Leptin is a 16 kDa peptide hormone that maintains energy homeostasis by activating leptin receptors (LepR) in the brain [42]. Previous studies have suggested that leptin is unable to enter the brain through the blood–brain barrier, but Manon et al. found that LepR are expressed in hypothalamic ME tanycytes and respond to leptin [43]. Leptin can be transported by transcytotic route across tanycytes, and the LepR mediates the process of leptin internalized, which is necessary for transport into the cerebrospinal fluid [43]. The above results suggest that leptin can enter the brain through routes outside the blood–brain barrier to participate in the control of feeding and the maintenance of energy homeostasis [43]. It is still unclear whether OXT also enters the brain from fenestrated capillaries of the medial basal hypothalamus similarly to leptin. However, it has been found that the nose-to-blood route is more critical for the pharmacological effects of nasal OXT than the nose-to-brain route, and that nasal OXT produces its effects by increasing peripheral blood concentrations rather than directly entering the brain in the human subject [44]. In addition, Chen et al. also confirmed that oral and nasal spray OXT increased peripheral circulating concentrations [45]. OXT selectively enhances C-touch fiber-targeted pleasurable responses to social touch processing via peripheral pathways rather than directly into the brain [45]. And OXT-deficient secreting mice (Oxt−/−, Cd38−/−, Oxtr−/−) exhibit deficits in maternal bonding behavior, whereas peripheral OXT delivery results in the restoration of maternal bonding behaviour, implying that circulating OXT may cross the blood–brain barrier [46]. Further, OXT is transported to the brain via the receptor for advanced glycosylation end products (RAGE) on brain capillary endothelial cells and validated in RAGE-deficient mice (Ager−/−) [46, 47]. In addition, the nanoparticle formulation also enables sustained delivery of peripheral OXT to the brain [48]. The application of nano-delivery systems not only improves the infiltration of OT in the brain, but also prolongs the half-life of OXT by encapsulation and sustained release [49]. The above results imply that OXT's role in entering the brain is important for pharmacological intervention in stress-related neuropsychiatric disorders, but more clinical studies are needed to verify this.

The major projection of intracerebral oxytocin in stress

Hippocampus

The hippocampus is usually considered to be a vital brain region that regulates emotion, cognition and particularly vulnerable to stress exposure. And OXTR is abundantly distributed in the hippocampus, suggesting that the OXT system may mediate the hippocampal regulation of stress responses [50]. Using double-labeled confocal immunofluorescence images, Lin et al. found that OXTR is mainly expressed in pyramidal neurons in the CA2/3 and dorsal DG region in OXTR-Venus knock-in mice [51]. The expression and binding of OXTR is detectable in subregions, such as CA1, CA2, CA3 and dentate gyrus (DG) of hippocampus in rodents [12]. In stressed brain, there are three potential mechanisms mediated the regulation of OXTR signaling in hippocampus, including regulation of neuronal excitability, neurogenesis, and regulation of glucocorticoid level.

Whole-cell recordings showed that activation of OXTR led to an increase in the frequency and amplitude of spontaneous inhibitory postsynaptic currents by evoking GABAergic interneurons [52]. And Silvia et al. also suggested that OXT exposure inhibit hippocampal glutamatergic neurons and maintain the balance of physiological excitation/inhibition in vivo and vitro [53]. In hippocampal slices, OXT induced membrane depolarization and enhanced electrically triggered action potential discharges in CA3 pyramidal neurons, indicating neuronal excitability occurred in CA3 pyramidal neurons in hippocampus [54]. Taken together, these studies identified that OXT mediated pathway can maintain the homeostasis of neuronal excitability.

Adult neurogenesis refers to the generation and proliferation of new neurons, while stress often negatively regulates hippocampal neurogenesis [55]. To the best of our knowledge, there is currently no evidence for OXT on hippocampal neurogenesis in the human brain, thus we mainly focus on the mammalian brain to discuss the OXT mediated neurogenesis in hippocampus [56]. Peripheral OXT administration (1 ng/μl) significantly enhanced the BrdU-labeled cells in the ventral DG, indicating OXT injection increased adult-generated cells in neurons and glia when animal exposure to acute cold-water stress [57]. OXT treatment was also accompanied by a phenotype of hippocampal cell proliferation and dendritic maturation [58]. Further research discovered that PVN oxytocinergic signaling promotes neurogenesis in the sub-granular zone of DG by activating OXTR in pyramidal neurons in the CA3 region of the hippocampus [54].

Furthermore, previous studies pointed out that systemic administration of OXT reduces glucocorticoid receptor mRNA expression in hippocampal CA1, CA2 and DG of rat [59]. The high concentrations of stress-induced corticosteroids (CORT) level reduced hippocampal synaptic plasticity by activating glucocorticoid receptors, which may be a hindrance to NMDA receptor-dependent synaptic plasticity [60, 61]. These studies all showed that stress affects the hippocampus and behaviors through the regulation of glucocorticoid.

Prefrontal cortex

Prefrontal cortex is a key target region in stress-related neuropsychiatric disorders. In rodent, acute restraint stress triggered the reinstatement of methamphetamine conditioned place preference induced by methamphetamine, whereas microinjection of OXT can reverse it via the glutamatergic system of mPFC [62]. In the rodent model of PTSD, single prolonged stress (SPS) stimulated the expression of neuroinflammation factors (i.e., IL-1β, IFN-γ) in mPFC, hippocampus, and amygdala [63]. But intranasal OXT administration effectively ameliorated SPS-induced fear extinction recovery through anti-inflammatory effects and reduced the higher CRHR1 protein levels in mPFC and amygdala [63, 64]. Using c-fos immunofluorescence labeling and quantification, the hypo-activation of prefrontal cortex and amygdala neurons were found in vulnerable rats with a robust PTSD syndrome including increased anxiety and decreased arousal. These phenomena can be rescued by intracerebral infusion of OXT via emotional remodeling [65]. Nevertheless, there are still some studies revealing the mechanism of OXT's intervention of stress by targeting the prefrontal cortex at different levels. Blood OXTR mRNA is not only thought as a potential biological biomarker in the prefrontal cortex of hyporesponsive HPA axis subtype of PTSD, but also likely regarded translational evidence that the HPA axis response specificity is dependent on the regulation of OXTR expression [66]. Likewise, OXTR-mediated ERK and MAPK phosphorylation in mPFC relieved the neonatal maternal separation-induced social deficits behaviors [67]. Interestingly, in the early paternal deprivation (PD) experiences, optogenetic activation of OXT neurons in PVN projected to the prelimbic cortex can reverse PD-induced emotional and social preference behaviors [68].

Furthermore, OXT plays a specific regulatory role in the prelimbic subregion of mPFC and produces anxiolytic phenotype via interact with GABAergic neurons [69]. Meanwhile, OXT neuron-specific circuits in the cortex also have sex dependence in interventions for anxiety. Using optogenetic techniques and electrophysiological recordings, OXTR interneurons (OXTRINS) of mPFC was found to modulate anxiety behavior in male mice, but not in female mice [70]. This process may be associated with corticotropin releasing hormone binding protein (CRHBP), an OXTRINS-specific expressed protein, blocking CRH-induced activation of pyramidal 2/3 neurons of mPFC. Surprisingly, our previous work also demonstrated that mPFC has been activated in maternal separation (MS) [9]. Among them, unpredictable MS impaired the structural and functional glutamatergic synapses in pyramidal neurons of mPFC and increased stress susceptibility [9]. And RNA-sequencing revealed that the OXT gene played a crucial role in predictable MS-induced stress resilience [9].

The obvious studies have proved the specific mechanism of action of OXT and neurons in prefrontal cortex, but the OXT mediated biological mechanism and the change of subregion of prefrontal cortex in other stress model still need more evidences. In the clinical studies, the effect of intranasal OXT administration on different stress groups is usually related to the functional connectivity between the prefrontal cortex and other brain regions. Early life stress alters amygdala-prefrontal functional connectivity and sensitivity to the effects of OXT treatment [71]. In PTSD patients, OXT may reduce anxiety and fear expression in the amygdala in PTSD by increasing control of the ventromedial prefrontal cortex (vlPFC) over CeM (males) or by reducing salience processing of dorsal anterior cingulate cortex over BLA (females) [72]. In trauma-exposed individuals, amygdala responses to fearful faces were significantly enhanced after a single dose of OXT, and amygdala-ventromedial and vlPFC connections were weakened [73]. Therefore, repeated intranasal injections OXT is a promising early preventive intervention for individuals with increased risk of PTSD due to severe acute symptoms [73]. In addition, the results also showed that PTSD patients with the treatment of OXT have increased connectivity between the dorsolateral prefrontal cortex and anterior cingulate gyrus in working memory and control system connectivity compared to placebo [74]. And OXT use was found to affect the functional connectivity of the BLA and vlPFC hindering the functioning of emotion regulation networks in response to trauma-exposed situation [75]. This suggests that in traumatized individuals, intranasal OXT administration needs to be administered more cautiously to intervene in PTSD.

Amygdala

Previous evidence supported that OXT can attenuate stress-induced fear responses by targeting the amygdala. Excessive fear expression may be associated with the development of anxiety disorders such as PTSD, panic disorder, and phobias. It was found that amygdala neurons participate in the emotional remodeling of OXT through morphological changes, but cannot be ruled out the non-specificity in other brain regions, such as prefrontal cortex [65]. Traumatic experiences can lead to abnormal fear extinction due to the biological imbalance between HPA and amygdala fear circuit. Therefore, intranasal OXT administration restores the impaired prosocial behavior of male rats under SPS stimulation and the expression of amygdala OXTR by regulating CRHR sensitivity [64]. Interestingly, the amygdala not only played a role in trauma-related stress, but also mediated the efficacy of OXT in social stress-induced avoidance behavior in prairie female voles [76]. In autistic mice, OXT intranasal administration improved microglia activation in the amygdala and reduced neuroinflammation and oxidative stress [77].

Additionally, centralof the amygdala (CeA) has been shown to be involved in the stress regulation of OXT and OXTR or GABA receptor are enriched in this region [78]. In forced swimming stress, OXTergic neurons of CeA regulated stress-coping behavior, and the mechanism may be through the inhibition of excitatory amino acids [78]. OXT microinjection in CeA promoted social preference and reduced the anxiety levels, whereas CeA infusion with OXTR-antagonist dose-dependently reduced sociality and increased anxiety [79]. But administration of the GABAA receptor antagonist bicuculline in combination with OXT to the CeA blocked the effect of the anxiolytic property of OXT [79], suggesting that OXT interacts the GABAergic neurons of CeA in anxiolytic effect. In the long-term isolation stress, OXT ameliorated depressive and anxious behaviors via increases miniature inhibitory postsynaptic currents in CeA neurons, indicating that OXT rescues glutamatergic synaptic transmission in CeA of isolated mice [80]. In recent study, Francesconi et al. found that OXT also projects to CeA through type II bed nucleus of the stria terminalis (BNST) neurons by recording retrogradely labeled [81]. And they found that OXT increases the frequency of spontaneous inhibitory post-synaptic currents in type II BNST → CeA output neurons, suggesting that OXT inhibits BNST → CeA neurons to promote cued fear stress [81]. Hence, these studies suggested that OXT mediate the neuronal excitability of CeA in the improvement of trauma and fear related stress, but still need more research to elucidate biological mechanism.

Oxytocin in regulation of stress responsivity

Oxytocin regulates the HPA axis in response to stress

The relationship of OXT activation and HPA axis hormone interactions are critical to elucidate the regulation of OXT in stress. Among changes of stress-related hormone levels, the feedback inhibition of corticosteroids is mediated by OXT signaling pathway and related to CRH, which is called the main driver of HPA axis [82, 83]. Intracerebroventricular (i.c.v) injection of CRH may act directly or indirectly upon magnocellular neurons to facilitate OXT release in rat [84]. Then, using double labelling in situ hybridization, Arima et al. observed the localization of CRH receptors type-1(CRHR1) and type-2(CRHR2) in the SON and PVN, suggested the colocalization of CRHR2 with OXT mRNA in the SON [85]. Consistent with the above findings, CRHR1 antagonist significantly attenuated the stress-induced alteration of OXT, CORT and displays anxiolytic effects in rats [86]. Thus, antagonism of CRHR may be necessary for the release of OXT in stress. Interestingly, OXT receptor interneurons are involved in regulate anxiety-related behaviors via specifical expression of CRHBP, an antagonist of CRHR [70]. In a rat model of PTSD, it is in line with the above evidence that the CRHR regulation of anxiety was sensitive to OXT signaling via OXT antagonist atosiban [64]. Among these, the expression of CRHR1 was more sensitive than CRHR2 and the higher protein level was found in the amygdala in SPS, while the OXT signaling pathway demonstrated a therapeutic specificity to the amygdala, indicating that the amygdala OXT signaling pathway may amended SPS induced PTSD by regulating CRHR1 [64]. Therefore, the CRHR plays a critical role in regulation of OXT in the stress response and cause a cascade reaction of HPA axis.

Previously, central OXT administration has been implicated in downregulation of HPA responses to noise stress and inhibition of CRF and CORT release in rodents [87]. There is a study also showed that the i.c.v OXT injection after oophorectomy reduced plasma ACTH concentrations and the expression of CRH mRNA in the rat’s hypothalamus after stress stimulation [88]. Treating with an OXT antagonist, male marmosets expressed significantly higher HPA-axis activity across the stressor compared with saline, indicating that the OXT system reduces the stress-induced cortisol secretion [89]. Hence, the fluctuations of both endogenous and exogenous OXT level are reflected the resilience of stress response and resistance to stress related hormone.

It should be noted, OXT may act as a buffer in stress induced HPA axis response via prosocial behaviors. Previous findings supported those social behaviors act as a buffer for the imbalance between HPA axis and stress responses, and OXT is considered as mediator in the buffering of social [90, 91]. To further confirm mediation effect of OXT, Smith and colleagues first demonstrated that OXT release in PVN and OXT neurons modulate HPA axis responses and alleviate immobilization stress induced anxiety-like behavior in the prairie vole (a socially monogamous rodent for long term pair bonds) [92]. Similarly, consolation behavior, a common empathetic response and a prosocial behavior, can make prairie vole to increase grooming in stress partner, suggesting that they provide a social buffering when partner experience an unobserved stressor [93]. Exposure to the stress, the level of CORT and the ACC activity were increased in the prairie vole [93]. And i.c.v injection of OXT receptor antagonist induced the previous molecular changes and abolish the benefit of consolation behavior [93]. Therefore, OXT can improve the stress induced dysfunction of HPA axis via a social behavior dependent way. But there are growing evidences presented that OXT sometimes cannot attenuate the anxiety behavior and even led to an increase in social anxiety and aggressive behaviors [94, 95]. To explain this phenomenon, the social salience hypothesis of OXT argued that OXT regulates the salience of social cues, like competitive, cooperative or stress environment, which modulates individual’s responses though circuit-specific action [96]. This hypothesis proposes that OXT increases the salience of safety signals in positive situations (e.g., empathy, trust, cooperation etc.), thereby improving stress responses [97]. Conversely, OXT induces a bias toward negative social cues in the unpredictable threatening situations (e.g., competition, scare, aggression) and increases stress responses [95]. These results show that OXT neurons play a critical role in regulating stress responses, especially in the social buffering. The level of OXT showed resilience in regulating stress response, and the difference may be caused by the salience of social cues.

The exogenous and endogenous oxytocin efficacy in stress responses

The OXT system was greatly activated by stressful or threatening condition, and either endogenous or synthetic oxytocin produces stress resistance. In general, the discussion of oxytocin mainly focuses on the intervention effect of exogenous synthetic OXT administration on stress state, and the expression level of endogenous OXT in anxiety and stress [12, 98]. There are several preclinical and clinical studies suggested that exogenous administration of recombinant OXT exerts strongly anxiolytic, stress resistant, social-buffering effect on humans and rodents (Table 1). Various animal studies aimed to uncover the role of synthetic OXT in anxiolytic effect and stress response, even though the mechanism of action varies. However, in mice, the alterations in anxiety-behavior were described to be controversial, with elevated stress response in mild stress model, which may dependent on the instability of behavior of rat or the dose of OXT (chronic i.c.v OXT injection) [99]. Similarly, chronic high-dose i.c.v OXT administration (over 14 days) produced an anxiety-like behavioral phenotype and reduced the expression of OXTR levels, whereas chronic low-dose OXT prevented hyper anxiety and reduced ACTH sensitivity and adrenal hypertrophy [100]. These results suggest that the dose-dependent effect of OXT needs to be revisited in the application of stress-induced psychiatric disorders [100].

Table 1 The efficacy of exogenous administration of OXT in different stress

It is also worth noting that changes in endogenous OXT levels and neuronal activities during stress, which may lead to the identification of biomarkers for the diagnosis of stress-related neuropsychiatric disorders (Table 2). Generally, the oxytocin system of the hypothalamus is activated both in human and rodent, and even peripheral OXT levels are affected by stress. But the opposite results were found that the OXT system plays a buffering role in reducing the sensitivity of stress responses [101]. The above results indicate that endogenous changes in OXT expression may be safer and more efficient in stress regulation than peripheral OXT administration, but these are based on the normal endocrine system of the oxytocin system.

Table 2 The endogenous changes of OXT in stress

Oxytocin and stress-related neuropsychiatric disorders

Anxiolytic role of oxytocin

Anxiety disorder is characterized by excessive fear, anxiety and avoidance of stress, including: separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (SAD), panic disorder, agoraphobia, and generalized anxiety disorder [102]. In the previous studies, OXT has been demonstrated to have anxiolytic effects on different types of anxiety. Separation anxiety disorder is the presence of inappropriate and excessive fear or anxiety while leaving the familiar environment or being separated from the attachment object. In lactating rats, long-term MS altered maternal care, anxiety-like behavior, and paraventricular OXT and corticotropin-releasing factor immunoreactivity expression in lactating rats [103]. At postnatal day 21, rat pups were experienced MS stress, resulting in anxiety behaviors with higher levels of blood CORT and impaired social and learning and memory functions [104]. Intranasal OXT administration rescued anxious behavior by restoring impaired LTP differentiation in hippocampal CA1 region [104]. Acute injection of fibroblast growth factor 2 (FGF2) was associated with the acH3K14 of the OXTR promoter in short term MS rat pups, suggesting that FGF2 mediates the anxiolytic effects by increasing acetylation of OXTR promoters to overcome decreased OXT levels [105]. In contrast, repeated daily experiences of brief separation from pups resulted in increases the level of estrogens receptor (ER) and OXTR and a decrease in 5-HT1Ars in the brain of rat dams [106]. Neurochemical changes may be responsible for the observed increase in maternal behavior and decreased anxiety [106]. However, MS after exposure to stressful environment during pregnancy will reduce stress susceptibility and anxiety behavior of offspring, and the mechanism may be related to changes of the serum concentration of 17-beta-oestradiol, OXT and Erβ/Erα ratio [107]. Further, our previous study designed that rat pups were subjected to early stress, and then exposed to restraint stress in adulthood to observe the stress sensitivity and susceptibility of rats. We found that predictable MS increased stress resilience in adulthood, while unpredictable MS increased susceptibility in “two-hit” stress model [9].

In clinical use, salivary OXT levels were inversely correlated with separation anxiety symptoms and be positively associated with the separation anxiety scores in children [108]. Thus, OXT has a potential implication for adolescent anxiety and treatment, especially those who have experienced childhood separation from their mothers [109]. Interestingly, OXTR and G protein β3 subunit genes were specifically associated with the presence and severity of MS, but this specificity is not associated with anxiety and depression [110].

SAD is characterized by a marked and persistent fear of social situations or potentially embarrassing social behaviors and activities, and features of avoidance behavior. Given its effects on social functioning and behavior, there are several studies about OXT use in SAD. An fMRI study of fearful face processing found decreased functional connectivity between the amygdala and anterior cingulate gyrus in the SAD patient compared to healthy controls with elevated anxiety symptoms [111]. However, intranasal OXT normalized the decreased connectivity between the amygdala and anterior cingulate gyrus in the SAD patient [111]. Plasma OXT levels were higher in SAD patients with more severe social anxiety symptoms, possibly because the high levels of oxytocin secretion in SAD patients compensated for reduced social anxiety symptoms [112]. In another study of patients with SAD, intranasal administration of OXT enhanced other-oriented reward motivation in patients with lower anxiety but higher anxiety, suggesting that OXT prosocial effects are related to the severity of symptoms [113]. Oxytocin may be a predictor of social anxiety disorder. Although the above-mentioned preclinical and clinical studies have provided the evidences of OXT in the intervention and biomarkers of different anxiety, the biological mechanism and neural activity of OXT have not been fully elucidated.

Oxytocin mediated improvement of depressive behavior

Depression is a stress-related neuropsychiatric disorders characterized by lower mood, thought retardation, loss of interest, and reduction of action and language, accompanied by suicidal attempts [114]. A previous study found that serum OXT was significantly negatively correlated with Hamilton Depression Scale score [115]. Another study of postpartum depression used the Edinburgh postnatal depression scale (EPDS) to assess the risk of postpartum depression and showed that plasma OXT plasma OXT concentrations were lower in the high-risk group compared with subjects in the low-risk group for postpartum depression [116]. The relationship between OXT and depressive behavior in animals was first reported in 1980s via i.c.v injection of OXT [117]. Then, Arletti et al. found that intraperitoneal injection (i.p) of OXT (0.25–1.0 mg/kg) could significantly improve depressive behavior [117]. And OXT was shown to like the pharmacological effects of impramine (7.5–30 mg/kg i.p) in depressive mice [117]. In the desperate behavior of rats, i.c.v injection of OXT reduced the immobility time of the forced swimming test and tail suspension test of rats via a dose-dependent effect [118]. The results shown that behavioral despair promote the synthesis and secretion of OXT in the brain and periphery [118]. But brain-derived OXT played a role in behavioral hopelessness depression, rather than the periphery-derived OXT [118]. In a socially isolated model of depression, OXT mediated the development of depressive-like behaviors following neuronal injury in mice [119]. The preventative pharmacotherapy of OXT can also attenuated the depressive behavior and deterioration of mood in male and female rats after early life stress [120]. I.c.v injection of oxytocin reversed depression-like behavior in a rat model of postpartum depression by regulating the HPA axis and TrkB in PVN signaling pathway [121, 122]. In clinical studies, it was found that OXT concentrations in the plasma of depressed patients were higher than those in healthy controls [123]. Intranasal oxytocin had no effect on facial emotion recognition and was associated with a reduction in negative thoughts in mothers with postpartum depression [124]. Interestingly, serum OXT levels during pregnancy were associated with depressive symptoms in early pregnancy or postpartum and may serve as a predictive target for postpartum depression [116, 125]. A allele of rs53576 in the oxytocin gene was also found to be associated with suicidal behavior in people with a history of suicide attempts, suggesting that OXT can also be used as a potential target for predicting suicide attempts [126]. However, there was no significant difference in the level of intravenous OXT in women with postpartum depression and healthy subjects measured through the Beck Depression Inventory II scale [127]. A meta-analysis also found that plasma OXT levels in depressed patients were not different from healthy subjects, suggesting that the effect of OXT needs to consider the heterogeneity of subtypes and samples of depressed patients [128].

Despite so much preclinical and clinical evidences for the intervention effects of OXT in depression, its biological mechanisms have not been systematically elucidated. The regulation of serotonergic function and HPA axis may mediate the antidepressant mechanism of OXT. Increased the expression of 5-hydroxytryptamine receptors and serotonin transporter of hippocampus correlated with oxytocin levels in a MS induced animal model of depression [129]. But OXT exerted a synergistic function of antidepressant efficacy, such as increasing SSRI sensitivity by regulating Integrin β3 (ITGB3) and Close homolog of L1 protein (CHL1) in BDNF expression [130]. Similarly, OXT can modulate stress behaviors and autonomic nervous system responses by attenuating HPA axis activity, thereby reducing depressive behaviors [88]. Infusion of oxytocin (100 ng/h, i.c.v) in ovariectomized rats reduced plasma ACTH concentrations and CRF mRNA in the hypothalamus after 30 min stress stimulation [88]. Also, MS-induced depression-like behaviors were attenuated by OXT mediated improvement of mitochondrial function and immune-inflammatory response in the hippocampus [35]. In terms of gene polymorphisms, some studies have found that the polymorphism of oxytocin-related genes (rs2254298) has a predictive effect on anxiety and depression symptoms in adolescent girls [131]. Catherine et al. found that the reduction of OXTR gene DNA methylation is related to perinatal stress and postnatal depression, while the increase of DNA methylation is related to social cognition and emotional recognition disorders [132]. Generally, there are differences in the evidence that OXT improves depression, but this may be related to the heterogeneity of the pathogenesis of depression per se. The mechanism of oxytocin improving depressive behavior also requires further exploration at the neuronal and molecular levels. Achieving the best therapeutic effect, as well as the intervention of different depression subtypes, needs more attention in future work.

The potential of oxytocin treatment in PTSD

After experiencing traumatic events, individuals are prone to the PTSD symptoms of social avoidance, cognitive and emotional changes, and hyperarousal. And it have been shown that the potential of OXT for the treatment of PTSD. In a meta-analysis, OXT was found to be effective in PTSD interventions [133]. Plasma OXT Levels of PTSD patient was lower than healthy subjects [134]. Intranasal OXT has been shown to improve social cognitive abilities such as emotion recognition, interpersonal trust, and prosocial behaviors, which are often impaired in patients with PTSD [135]. In the brain, OXT enhances functional connectivity between the amygdala and prefrontal regions and suppresses fear responses in the amygdala, which in turn is involved in the regulation of salience processing [136]. In male patients, OXT may reduce the control of CeM via enhancing mPFC regulation [72]. And in female patients, it reduces the control of amygdala in PTSD by reducing the projection of basolateral amygdala (BLA), which can attenuate anxiety and decreased fear expression [72]. The results implied that sex differences underly PTSD-related neurobiological mechanisms[72]. The patient with PTSD always exhibited social impairment and with the symptoms of emotional and cognitive empathy deficits [137]. Although intranasal OXT (24 IU) administration does not improve emotional cognitive empathy, it can selectively enhance the perception of angry body movements in man PTSD patients [137]. In Chinese earthquake survivors, serum OXT levels were not associated with overall PTSD symptoms and were associated with PTSD anxiety arousal symptoms [138]. But in the women patient with PTSD, the results indicated that a single intranasal dose of OXT enhances empathy for women [139]. OXT appears to affect males and females with PTSD differently, implying a need for gender-specific treatment in this population. In a study of OXT and Prolonged Exposure co-intervention in PTSD, it was found that intranasal OXT (40 IU) administration reduced PTSD and depressive symptoms in PE treatment, but there was no statistical difference [140]. A recent study also found that OXT is a potential biomarker for PTSD subtypes with high HPA response [66]. In the HPA axis subgroup, blood OXTR mRNA was associated with PTSD symptoms, and can predicted the activation levels in the prefrontal cortex of mice with PTSD-like symptoms [66].

In the rodent, moderate restraint stress increased social support-seeking behavior and decreasing the aggression by the activation of hypothalamic OXT signaling [141]. Conversely, after experiencing the stress contents of predator odor, the results have shown that social affiliation was disrupted (a PTSD-like symptom) with reduced OXT signaling in rat[141]. OXT administered immediately after trauma produced a short-term increase in recall of traumatic memories, whereas chronic administration of low-dose OXT had cumulative anxiolytic effects in social co-housing in a rodent model of PTSD [142]. In SPS, an animal model that effectively mimics PTSD, intranasal OXT administration reversed SPS-induced fear extinction repair and downregulated the levels of inflammatory factors (IL-1β, TNF-α) in the hippocampus and serum [63]. Meanwhile, OXT also promoted the recovery of SPS-induced social behavior abnormalities through the OXTR binding in mPFC and amygdala [64]. Interestingly, in the SPS model, OXT signaling also attenuated fear acquisition in the social-sexual partner pairing of prairie vole, providing a buffer for partner absence [143]. As mentioned above, OXT plays a potential role in social behavior via regulating stress response of PTSD. But given the heterogeneity of PSTD, the construction of animal models provides obstacles to the exploration of the biological mechanism in therapeutic uses of OXT.

The augmentation of oxytocin expression

The secretion of endogenous OXT may serve as a predictive target for stress-related neuropsychiatric disorders and may also provide buffers for stress-induced neuropsychiatric disorders. Inducing the release of OXT in the brain may produce a safe and effective anti-stress effect via stress response, maternal behavior, sexual behavior, social behavior and physical activity (Fig. 2).

Fig. 2
figure 2

The augmentation of Oxytocin expression. a a illustration of early life stress. b and c, both oxytocin mRNA level and protein level were significantly increased in predictable maternal separation (mild early life stress), while were decreased in unpredictable maternal separation. a-c adapted from [9]. d copulation (i.e., acute effects of sexual activity) increases OXTR mRNA levels in the medial preoptic area (MPOA). e Previous sexual experience increases OXTR protein levels in the MPOA, ventromedial hypothalamus. d and e adapted from [148]. f Setup for recordings of behavior, ultrasonic vocalizations and neural activity. g Average firing rate of 15 OXT neurons from 5 rats. Free social interactions (FSI) led to the greatest change in firing rate and synchronous activity in simultaneously recorded OXT neurons. h Frames of recorded videos (top) of experimental rats that were placed either alone (Open field exploration), or with a mesh between rats (Chambered social interaction) or for FSI with a stimulus rat; representative spike raster plots of an OXT cell in each condition (bottom). experimental and stimulus rats were separated by a transparent wall with small holes (7.5 mm), allowing rats to see, sniff and hear, but not touch, each other. i Representative spike raster plots, averaged response and peristimulus time histograms of OXT cell activity during ‘crawling on top’. fi adapted from [151]

Firstly, OXT levels are regulated by stress response. The obvious part shown that both chronic stress and acute stress can increase OXT expression in humans and animals, although this result is different in human studies, indicating that changes in OXT levels may be heterogeneous with disease. And OXT may be affected at different stages of the disease pathological process. Therefore, the expression of OXT should take into account these factors, such as the type of stress, the subtype of stress related neuropsychiatric disease, and the population differences. For instance, we found elevated levels and expression of OXT in the blood and mPFC of rats in a model of predictable MS, whereas the opposite effect was exhibited in unpredictable MS [9]. Stress-induced increase in OXT secretion was involved in increased cortisol responsiveness and recovery of vagus [144].

Secondly, pregnancy, lactation, and sexual behavior can increase OXT secretion in central and peripheral. OXT neurons were involved in the process of milk secretion in rats [145]. Inhibition of OXT neurons also reduced prolactin levels, suggesting that oxytocin neuron activation promotes prolactin activation during pregnancy and lactation [145, 146]. Interestingly, virgin mice, mother mice and pups were co-housed and the maternal behavior of the mother mice would be perceived by the virgin mice through visual learning [147]. Then maternal behavior promotes the virgin mice to react with their companion pups [147]. Through recordings of PVN neural activity, it was found that OXT neuron activation in PVN modulates increased plasticity in left auditory cortex and promotes alloparenting in virgin mice [147]. During sexual behavior, sexual experience increased the expression of oxytocin gene and protein in the medial preoptic area of male rats [148]. Conversely, intracerebral OXT injection also promoted sexual behavior in male rats, regardless of previous sexual experience [148]. And sexual self-stimulation also increases salivary OXT levels in healthy adult men and women [149]. Sexual behavior of male rats OXT release mode is not only synaptic axonal release but also occurs exocrine vesicle transmission and diffusion locally acts on OXTR neurons and promotes male sexual function [150].

Thirdly, Social touch induces activation of parvocellular OXT neurons in a small population of the hypothalamus and transmission to magnocellular neurons in rats [151]. Feedback regulation of social behavior by OXT neurons has also been validated in a mice model of autism [152, 153]. Lastly, some evidence suggested that exercise also modulates changes in OXT levels and OXT expression. In rats with gastric injury, regular, moderate-intensity exercise upregulates oxytocin activity and alleviates gastric injury [154]. Similar results were obtained in a mouse model of breast cancer [155]. Interval exercise training reduced the activity of PI3K/Akt and ERK through OXT secretion, thereby reducing tumor volume and weight [155]. Serum OXT levels in well-trained male and female runners rose from 1.5 pg/ml at rest to 3.5 pg/ml after prolonged, high-intensity endurance running [156]. In conclusion, OXT expression is affected by multiple factors, and increasing OXT levels and expression in a healthy, endogenous manner may improve resistance to stress-induced neuropsychiatric diseases.

Concluding remarks

Growing evidence has shown that OXT has an important role in stress-related neuropsychiatric diseases. To understand the effects of OXT in psychiatric disorders, this article reviews the OXT system and the main brain regions where OXT neurons project in stress. Based on recent evidence, we have also shown that targets and predictive roles of OXT signaling and neuronal interventions in stress-related neuropsychiatric disorders. Finally, we propose several methods to increase the expression of OXT to provide ideas for follow-up research (Fig. 3).

Fig. 3
figure 3

The regulation of endogenous and exogenous OXT in stress-related neuropsychiatric diseases and the bidirectional influencing factors of oxytocin expression in the brain. In humans and animals, intranasal OXT administration and other stimuli, such as stress, maternal behavior, and sexual behavior et al., induce elevated OXT levels that project primarily to the prefrontal cortex, hippocampus, and amygdala. The interaction of OXT with OXTR increases stress resistance and improves stress-related neuropsychiatric diseases by regulating stress response, signaling pathways, neuronal excitability. Image created with Biorender.com

Although there are many evidences for OXT and stress-related neuropsychiatric disorders, there are still many puzzles waiting for us to solve. As a potential target of neuropsychiatric diseases, how OXT signaling plays its role in improving neuropsychiatric diseases needs to be further explored and fully grasped in future research. Given the complexity and heterogeneity of stress-induced neuropsychiatric disease processes, the following questions need to be addressed. Firstly, whether the molecular pathways mediated by peripheral OXT levels differ from those in central oxytocinergic neurons. Secondly, the dose-dependent effect of OXT needs to be further clarified in different diseases, populations, and animal models. Thirdly, how OXT neuronal activity and molecular changes are linked to stress-induced neuropsychiatric disorders. The elaboration of the above questions can make better use of OXT as a target to further improve neuropsychiatric diseases and provide stronger evidence for the mechanism.

Availability of data and materials

The authors declare the availability of data and material.

Abbreviations

BNST:

Bed nucleus of the stria terminalis

CeA:

Central amygdala

CORT:

Corticosterone

CREB:

CAMP response element-binding

CRH:

Corticotrophin-releasing hormone

CRHBP:

Corticotropin releasing hormone binding protein

CRHR:

CRH receptors

CRTC:

CREB-regulated transcriptional coactivators

DAG:

1,2-Dicyaglycerol

DG:

Dentate gyrus

EGFR:

Epidermal growth factor receptor

EPDS:

Edinburgh postnatal depression scale

ER:

Estrogens receptor

ERβ:

Estrogen receptor beta

FGF2:

Fibroblast growth factor 2

GPCR:

G protein-coupled receptor

i.c.v injection:

Intracerebroventricular injection

i.p injection:

Intraperitoneal injection

IP3:

Inositol 3 phosphate

MAPK:

Mitogen-activated protein kinase

MS:

Maternal separation

OXT:

Oxytocin

OXTR:

Oxytocin receptor

OXTRINS:

OXTR interneurons

PD:

Paternal deprivation

PLC:

Phospholipase C

PTSD:

Post-traumatic stress disorder

PVN:

Paraventricular nucleus

SAD:

Social anxiety disorder

SON:

Supraoptic nucleus

SPS:

Single prolonged stress

TLR4:

Toll like receptor 4

TRPV2:

Transient receptor potential vanilloid type 2

vlPFC:

Ventromedial prefrontal cortex

References

  1. Dale HH. On some physiological actions of ergot. J Physiol. 1906;34:163–206.

    Article  PubMed  PubMed Central  Google Scholar 

  2. du Vigneaud V, Ressler C, Trippett S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem. 1953;205:949–57.

    Article  CAS  PubMed  Google Scholar 

  3. Insel TR. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron. 2010;65:768–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ivell R, Richter D. Structure and comparison of the oxytocin and vasopressin genes from rat. P Natl Acad Sci Usa. 1984;81:2006–10.

    Article  CAS  Google Scholar 

  5. Lee HJ, Macbeth AH, Pagani JH, Young WR. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88:127–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sharma SR, Gonda X, Dome P, Tarazi FI. What’s love got to do with it: role of oxytocin in trauma, attachment and resilience. Pharmacol Therapeut. 2020;214:107602.

    Article  CAS  Google Scholar 

  7. Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, et al. Review: oxytocin: crossing the bridge between basic science and pharmacotherapy. Cns Neurosci Ther. 2010;16:e138–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Santomauro DF, Mantilla Herrera AM, Shadid J, Zheng P, Ashbaugh C, Pigott DM, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. The Lancet. 2021;398:1700–12.

    Article  Google Scholar 

  9. Shi DD, Zhang YD, Ren YY, Peng SY, Yuan TF, Wang Z. Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats. Mol Psychiatr. 2021;26:7296–307.

    Article  CAS  Google Scholar 

  10. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81:629–83.

    Article  CAS  PubMed  Google Scholar 

  11. Zingg HH, Laporte SA. The oxytocin receptor. Trends Endocrin Met. 2003;14:222–7.

    Article  CAS  Google Scholar 

  12. Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev. 2018;98:1805–908.

    Article  CAS  PubMed  Google Scholar 

  13. Monga M, Campbell DF, Sanborn BM. Oxytocin-stimulated capacitative calcium entry in human myometrial cells. Am J Obstet Gynecol. 1999;181:424–9.

    Article  CAS  PubMed  Google Scholar 

  14. Zak M, Kestler B, Cornwell T, Taylor MS. Augmented KCa2.3 channel feedback regulation of oxytocin stimulated uterine strips from nonpregnant mice. Int J Mol Sci. 2021;22:13585. https://doi.org/10.3390/ijms222413585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Di Scala-Guenot D, Mouginot D, Strosser MT. Increase of intracellular calcium induced by oxytocin in hypothalamic cultured astrocytes. Glia. 1994;11:269–76.

    Article  PubMed  Google Scholar 

  16. van den Burg EH, Stindl J, Grund T, Neumann ID, Strauss O. Oxytocin stimulates extracellular Ca2+ influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects. Neuropsychopharmacol. 2015;40:2938–47.

    Article  Google Scholar 

  17. Grund T, Goyon S, Li Y, Eliava M, Liu H, Charlet A, et al. Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci. 2017;37:12214–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rimoldi V, Reversi A, Taverna E, Rosa P, Francolini M, Cassoni P, et al. Oxytocin receptor elicits different EGFR/MAPK activation patterns depending on its localization in caveolin-1 enriched domains. Oncogene. 2003;22:6054–60.

    Article  CAS  PubMed  Google Scholar 

  19. Lin YT, Huang CC, Hsu KS. Oxytocin promotes long-term potentiation by enhancing epidermal growth factor receptor-mediated local translation of protein kinase Mzeta. J Neurosci. 2012;32:15476–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Y, Knobloch HS, Grinevich V, Aguilera G. Stress induces parallel changes in corticotrophin-releasing hormone (CRH) transcription and nuclear translocation of transducer of regulated cAMP response element-binding activity 2 in hypothalamic CRH neurones. J Neuroendocrinol. 2011;23:216–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB, et al. TORCs: transducers of regulated CREB activity. Mol Cell. 2003;12:413–23.

    Article  CAS  PubMed  Google Scholar 

  22. Hrabovszky E, Kallo I, Steinhauser A, Merchenthaler I, Coen CW, Petersen SL, et al. Estrogen receptor-beta in oxytocin and vasopressin neurons of the rat and human hypothalamus: Immunocytochemical and in situ hybridization studies. J Comp Neurol. 2004;473:315–33.

    Article  CAS  PubMed  Google Scholar 

  23. Suzuki S, Handa RJ. Estrogen receptor-beta, but not estrogen receptor-alpha, is expressed in prolactin neurons of the female rat paraventricular and supraoptic nuclei: comparison with other neuropeptides. J Comp Neurol. 2005;484:28–42.

    Article  CAS  PubMed  Google Scholar 

  24. Kudwa AE, McGivern RF, Handa RJ. Estrogen receptor beta and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats. Physiol Behav. 2014;129:287–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sharma D, Handa RJ, Uht RM. The ERbeta ligand 5alpha-androstane, 3beta,17beta-diol (3beta-diol) regulates hypothalamic oxytocin (Oxt) gene expression. Endocrinology. 2012;153:2353–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hedges VL, Heaton EC, Amaral C, Benedetto LE, Bodie CL, D’Antonio BI, et al. Estrogen withdrawal increases postpartum anxiety via oxytocin plasticity in the paraventricular hypothalamus and dorsal raphe nucleus. Biol Psychiat. 2021;89:929–38.

    Article  CAS  PubMed  Google Scholar 

  27. Dai D, Li QC, Zhu QB, Hu SH, Balesar R, Swaab D, et al. Direct involvement of androgen receptor in oxytocin gene expression: possible relevance for mood disorders. Neuropsychopharmacol. 2017;42:2064–71.

    Article  CAS  Google Scholar 

  28. Bressan D, Battistoni G, Hannon GJ. The dawn of spatial omics. Science. 2023;381:q4964.

    Article  Google Scholar 

  29. Jovic D, Liang X, Zeng H, Lin L, Xu F, Luo Y. Single-cell RNA sequencing technologies and applications: a brief overview. Clin Transl Med. 2022;12:e694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ding J, Sharon N, Bar-Joseph Z. Temporal modelling using single-cell transcriptomics. Nat Rev Genet. 2022;23:355–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cang Z, Zhao Y, Almet AA, Stabell A, Ramos R, Plikus MV, et al. Screening cell-cell communication in spatial transcriptomics via collective optimal transport. Nat Methods. 2023;20:218–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Newmaster KT, Nolan ZT, Chon U, Vanselow DJ, Weit AR, Tabbaa M, et al. Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains. Nat Commun. 2020;11:1885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rokicki J, Kaufmann T, de Lange AG, van der Meer D, Bahrami S, Sartorius AM, et al. Oxytocin receptor expression patterns in the human brain across development. Neuropsychopharmacol. 2022;47:1550–60.

    Article  CAS  Google Scholar 

  34. Pekarek BT, Kochukov M, Lozzi B, Wu T, Hunt PJ, Tepe B, et al. Oxytocin signaling is necessary for synaptic maturation of adult-born neurons. Gene Dev. 2022;36:1100–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Amini-Khoei H, Mohammadi-Asl A, Amiri S, Hosseini MJ, Momeny M, Hassanipour M, et al. Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation. Prog Neuro-Psychoph. 2017;76:169–78.

    Article  CAS  Google Scholar 

  36. Szeto A, Sun-Suslow N, Mendez AJ, Hernandez RI, Wagner KV, McCabe PM. Regulation of the macrophage oxytocin receptor in response to inflammation. Am J Physiol-Endoc M. 2017;312:E183–9.

    Google Scholar 

  37. Quintana DS, Alvares GA, Hickie IB, Guastella AJ. Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav R. 2015;49:182–92.

    Article  CAS  Google Scholar 

  38. Lee MR, Shnitko TA, Blue SW, Kaucher AV, Winchell AJ, Erikson DW, et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat Commun. 2020;11:2783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn-Meynell AA, et al. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab. 2013;17:607–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schaeffer M, Langlet F, Lafont C, Molino F, Hodson DJ, Roux T, et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. P Natl Acad Sci Usa. 2013;110:1512–7.

    Article  CAS  Google Scholar 

  41. Lafont C, Desarmenien MG, Cassou M, Molino F, Lecoq J, Hodson D, et al. Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function. P Natl Acad Sci Usa. 2010;107:4465–70.

    Article  CAS  Google Scholar 

  42. Pan WW, Myers MJ. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci. 2018;19:95–105.

    Article  CAS  PubMed  Google Scholar 

  43. Duquenne M, Folgueira C, Bourouh C, Millet M, Silva A, Clasadonte J, et al. Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function. Nat Metab. 2021;3:1071–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yao S, Chen Y, Zhuang Q, Zhang Y, Lan C, Zhu S, et al. Sniffing oxytocin: nose to brain or nose to blood? Mol Psychiatr. 2023;28(7):3083–91. https://doi.org/10.1038/s41380-023-02075-2.

    Article  CAS  Google Scholar 

  45. Chen Y, Zou H, Hou X, Lan C, Wang J, Qing Y, et al. Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations. Elife. 2023;12:e85847. https://doi.org/10.7554/eLife.8584.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yamamoto Y, Liang M, Munesue S, Deguchi K, Harashima A, Furuhara K, et al. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun Biol. 2019;2:76.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Yamamoto Y, Higashida H. RAGE regulates oxytocin transport into the brain. Commun Biol. 2020;3:70.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zaman RU, Mulla NS, Braz GK, D’Souza C, Murnane KS, D’Souza MJ. Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin. Int J Pharmaceut. 2018;548:698–706.

    Article  CAS  Google Scholar 

  49. Al-Suhaimi EA, Nawaz M, Khan FA, Aljafary MA, Baykal A, Homeida AM. Emerging trends in the delivery of nanoformulated oxytocin across Blood-Brain barrier. Int J Pharmaceut. 2021;609:121141.

    Article  CAS  Google Scholar 

  50. Raam T, McAvoy KM, Besnard A, Veenema AH, Sahay A. Hippocampal oxytocin receptors are necessary for discrimination of social stimuli. Nat Commun. 2017;8:2001.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lin YT, Hsieh TY, Tsai TC, Chen CC, Huang CC, Hsu KS. Conditional deletion of hippocampal CA2/CA3a oxytocin receptors impairs the persistence of long-term social recognition memory in Mice. J Neurosci. 2018;38:1218–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zaninetti M, Raggenbass M. Oxytocin receptor agonists enhance inhibitory synaptic transmission in the rat hippocampus by activating interneurons in stratum pyramidale. Eur J Neurosci. 2000;12:3975–84.

    Article  CAS  PubMed  Google Scholar 

  53. Ripamonti S, Ambrozkiewicz MC, Guzzi F, Gravati M, Biella G, Bormuth I, et al. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons. Elife. 2017;6:e22466. https://doi.org/10.7554/eLife.22466.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lin YT, Chen CC, Huang CC, Nishimori K, Hsu KS. Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. Nat Commun. 2017;8:537.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Czeh B, Welt T, Fischer AK, Erhardt A, Schmitt W, Muller MB, et al. Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis. Biol Psychiat. 2002;52:1057–65.

    Article  CAS  PubMed  Google Scholar 

  56. Opendak M, Offit L, Monari P, Schoenfeld TJ, Sonti AN, Cameron HA, et al. Lasting adaptations in social behavior produced by social disruption and inhibition of adult neurogenesis. J Neurosci. 2016;36:7027–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Leuner B, Caponiti JM, Gould E. Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids. Hippocampus. 2012;22:861–8.

    Article  CAS  PubMed  Google Scholar 

  58. Sanchez-Vidana DI, Chan NM, Chan AH, Hui KK, Lee S, Chan HY, et al. Repeated treatment with oxytocin promotes hippocampal cell proliferation, dendritic maturation and affects socio-emotional behavior. Neuroscience. 2016;333:65–77.

    Article  CAS  PubMed  Google Scholar 

  59. Petersson M, Uvnas-Moberg K. Systemic oxytocin treatment modulates glucocorticoid and mineralocorticoid receptor mRNA in the rat hippocampus. Neurosci Lett. 2003;343:97–100.

    Article  CAS  PubMed  Google Scholar 

  60. Park HJ, Lee S, Jung JW, Kim BC, Ryu JH, Kim DH. Glucocorticoid- and long-term stress-induced aberrant synaptic plasticity are mediated by activation of the glucocorticoid receptor. Arch Pharm Res. 2015;38:1204–12.

    Article  CAS  PubMed  Google Scholar 

  61. Sun DS, Zhong G, Cao HX, Hu Y, Hong XY, Li T, et al. Repeated restraint stress led to cognitive dysfunction by NMDA receptor-mediated hippocampal CA3 dendritic spine impairments in Juvenile Sprague-Dawley Rats. Front Mol Neurosci. 2020;13:552787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Han WY, Du P, Fu SY, Wang F, Song M, Wu CF, et al. Oxytocin via its receptor affects restraint stress-induced methamphetamine CPP reinstatement in mice: Involvement of the medial prefrontal cortex and dorsal hippocampus glutamatergic system. Pharmacol Biochem be. 2014;119:80–7.

    Article  CAS  Google Scholar 

  63. Wang SC, Lin CC, Chen CC, Tzeng NS, Liu YP. Effects of oxytocin on fear memory and neuroinflammation in a rodent model of posttraumatic stress disorder. Int J Mol Sci. 2018;19(12):3848. https://doi.org/10.3390/ijms19123848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang SC, Lin CC, Tzeng NS, Tung CS, Liu YP. Effects of oxytocin on prosocial behavior and the associated profiles of oxytocinergic and corticotropin-releasing hormone receptors in a rodent model of posttraumatic stress disorder. J Biomed Sci. 2019;26:26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Le Dorze C, Borreca A, Pignataro A, Ammassari-Teule M, Gisquet-Verrier P. Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD. Transl Psychiat. 2020;10:27.

    Article  Google Scholar 

  66. Hofmann J, Huber C, Novak B, Schreckenbach M, Schubert CF, Touma C, et al. Oxytocin receptor is a potential biomarker of the hyporesponsive HPA axis subtype of PTSD and might be modulated by HPA axis reactivity traits in humans and mice. Psychoneuroendocrino. 2021;129:105242.

    Article  CAS  Google Scholar 

  67. Wei J, Ma L, Ju P, Yang B, Wang YX, Chen J. Involvement of oxytocin receptor/Erk/MAPK signaling in the mPFC in early life stress-induced autistic-like behaviors. Front Cell Dev Biol. 2020;8:564485.

    Article  PubMed  PubMed Central  Google Scholar 

  68. He Z, Young L, Ma XM, Guo Q, Wang L, Yang Y, et al. Increased anxiety and decreased sociability induced by paternal deprivation involve the PVN-PrL OTergic pathway. Elife. 2019;8:e44026. https://doi.org/10.7554/eLife.44026.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sabihi S, Dong SM, Maurer SD, Post C, Leuner B. Oxytocin in the medial prefrontal cortex attenuates anxiety: anatomical and receptor specificity and mechanism of action. Neuropharmacology. 2017;125:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li K, Nakajima M, Ibanez-Tallon I, Heintz N. A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell. 2016;167:60–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fan Y, Herrera-Melendez AL, Pestke K, Feeser M, Aust S, Otte C, et al. Early life stress modulates amygdala-prefrontal functional connectivity: implications for oxytocin effects. Hum Brain Mapp. 2014;35:5328–39.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M. Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacol. 2016;41:2041–51.

    Article  CAS  Google Scholar 

  73. Frijling JL. Preventing PTSD with oxytocin: effects of oxytocin administration on fear neurocircuitry and PTSD symptom development in recently trauma-exposed individuals. Eur J Psychotraumato. 2017;8:1302652.

    Article  Google Scholar 

  74. Flanagan JC, Hand A, Jarnecke AM, Moran-Santa MM, Brady KT, Joseph JE. Effects of oxytocin on working memory and executive control system connectivity in posttraumatic stress disorder. Exp Clin Psychopharm. 2018;26:391–402.

    Article  Google Scholar 

  75. Frijling JL, van Zuiden M, Koch SB, Nawijn L, Veltman DJ, Olff M. Intranasal oxytocin affects amygdala functional connectivity after trauma script-driven imagery in distressed recently trauma-exposed individuals. Neuropsychopharmacol. 2016;41:1286–96.

    Article  Google Scholar 

  76. Hale LH, Tickerhoof MC, Smith AS. Chronic intranasal oxytocin reverses stress-induced social avoidance in female prairie voles. Neuropharmacology. 2021;198:108770.

    Article  CAS  PubMed  Google Scholar 

  77. Wang Y, Zhao S, Liu X, Zheng Y, Li L, Meng S. Oxytocin improves animal behaviors and ameliorates oxidative stress and inflammation in autistic mice. Biomed Pharmacother. 2018;107:262–9.

    Article  CAS  PubMed  Google Scholar 

  78. Ebner K, Bosch OJ, Kromer SA, Singewald N, Neumann ID. Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids. Neuropsychopharmacol. 2005;30:223–30.

    Article  CAS  Google Scholar 

  79. Dong N, Du P, Hao X, He Z, Hou W, Wang L, et al. Involvement of GABAA receptors in the regulation of social preference and emotional behaviors by oxytocin in the central amygdala of female mandarin voles. Neuropeptides. 2017;66:8–17.

    Article  CAS  PubMed  Google Scholar 

  80. Han RT, Kim YB, Park EH, Kim JY, Ryu C, Kim HY, et al. Long-term isolation elicits depression and anxiety-related behaviors by reducing oxytocin-induced gabaergic transmission in central amygdala. Front Mol Neurosci. 2018;11:246.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Francesconi W, Berton F, Olivera-Pasilio V, Dabrowska J. Oxytocin excites BNST interneurons and inhibits BNST output neurons to the central amygdala. Neuropharmacology. 2021;192:108601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Neumann ID, Wigger A, Torner L, Holsboer F, Landgraf R. Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J Neuroendocrinol. 2000;12:235–43.

    Article  CAS  PubMed  Google Scholar 

  83. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4:141–94.

    Article  CAS  PubMed  Google Scholar 

  84. Bruhn TO, Sutton SW, Plotsky PM, Vale WW. Central administration of corticotropin-releasing factor modulates oxytocin secretion in the rat. Endocrinology. 1986;119:1558–63.

    Article  CAS  PubMed  Google Scholar 

  85. Arima H, Aguilera G. Vasopressin and oxytocin neurones of hypothalamic supraoptic and paraventricular nuclei co-express mRNA for Type-1 and Type-2 corticotropin-releasing hormone receptors. J Neuroendocrinol. 2000;12:833–42.

    Article  CAS  PubMed  Google Scholar 

  86. Klampfl SM, Schramm MM, Gassner BM, Hubner K, Seasholtz AF, Brunton PJ, et al. Maternal stress and the mpoa: activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats. Neuropharmacology. 2018;133:440–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Windle RJ, Shanks N, Lightman SL, Ingram CD. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology. 1997;138:2829–34.

    Article  CAS  PubMed  Google Scholar 

  88. Ochedalski T, Subburaju S, Wynn PC, Aguilera G. Interaction between oestrogen and oxytocin on hypothalamic-pituitary-adrenal axis activity. J Neuroendocrinol. 2007;19:189–97.

    Article  CAS  PubMed  Google Scholar 

  89. Cavanaugh J, Carp SB, Rock CM, French JA. Oxytocin modulates behavioral and physiological responses to a stressor in marmoset monkeys. Psychoneuroendocrino. 2016;66:22–30.

    Article  CAS  Google Scholar 

  90. Beery AK, Kaufer D. Stress, social behavior, and resilience: insights from rodents. Neurobiol Stress. 2015;1:116–27.

    Article  PubMed  Google Scholar 

  91. Sterley TL, Baimoukhametova D, Fuzesi T, Zurek AA, Daviu N, Rasiah NP, et al. Social transmission and buffering of synaptic changes after stress. Nat Neurosci. 2018;21:393–403.

    Article  CAS  PubMed  Google Scholar 

  92. Smith AS, Wang Z. Hypothalamic oxytocin mediates social buffering of the stress response. Biol Psychiat. 2014;76:281–8.

    Article  CAS  PubMed  Google Scholar 

  93. Burkett JP, Andari E, Johnson ZV, Curry DC, de Waal FB, Young LJ. Oxytocin-dependent consolation behavior in rodents. Science. 2016;351:375–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Eckstein M, Scheele D, Weber K, Stoffel-Wagner B, Maier W, Hurlemann R. Oxytocin facilitates the sensation of social stress. Hum Brain Mapp. 2014;35:4741–50.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Grillon C, Krimsky M, Charney DR, Vytal K, Ernst M, Cornwell B. Oxytocin increases anxiety to unpredictable threat. Mol Psychiatr. 2013;18:958–60.

    Article  CAS  Google Scholar 

  96. Shamay-Tsoory SG, Abu-Akel A. The social salience hypothesis of oxytocin. Biol Psychiat. 2016;79:194–202.

    Article  CAS  PubMed  Google Scholar 

  97. Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiat. 2007;62:1187–90.

    Article  CAS  PubMed  Google Scholar 

  98. Takayanagi Y, Onaka T. Roles of oxytocin in stress responses, allostasis and resilience. Int J Mol Sci. 2021;23(1):150.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Winter J, Meyer M, Berger I, Royer M, Bianchi M, Kuffner K, et al. Chronic oxytocin-driven alternative splicing of Crfr2alpha induces anxiety. Mol Psychiatr. 2021. https://doi.org/10.1038/s41380-021-01141-x.

    Article  Google Scholar 

  100. Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann ID. Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrino. 2014;42:225–36.

    Article  CAS  Google Scholar 

  101. Belem-Filho I, Brasil T, Fortaleza E, Antunes-Rodrigues J, Correa F. A functional selective effect of oxytocin secreted under restraint stress in rats. Eur J Pharmacol. 2021;904:174182.

    Article  CAS  PubMed  Google Scholar 

  102. Craske MG, Stein MB. Anxiety. Lancet. 2016;388:3048–59.

    Article  PubMed  Google Scholar 

  103. Baracz SJ, Everett NA, Robinson KJ, Campbell GR, Cornish JL. Maternal separation changes maternal care, anxiety-like behaviour and expression of paraventricular oxytocin and corticotrophin-releasing factor immunoreactivity in lactating rats. J Neuroendocrinol. 2020;32:e12861.

    Article  CAS  PubMed  Google Scholar 

  104. Joushi S, Esmaeilpour K, Masoumi-Ardakani Y, Esmaeili-Mahani S, Sheibani V. Intranasal oxytocin administration facilitates the induction of long-term potentiation and promotes cognitive performance of maternally separated rats. Psychoneuroendocrino. 2021;123:105044.

    Article  CAS  Google Scholar 

  105. Litvin Y, Turner CA, Rios MB, Maras PM, Chaudhury S, Baker MR, et al. Fibroblast growth factor 2 alters the oxytocin receptor in a developmental model of anxiety-like behavior in male rat pups. Horm Behav. 2016;86:64–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stamatakis A, Kalpachidou T, Raftogianni A, Zografou E, Tzanou A, Pondiki S, et al. Rat dams exposed repeatedly to a daily brief separation from the pups exhibit increased maternal behavior, decreased anxiety and altered levels of receptors for estrogens (ERalpha, ERbeta), oxytocin and serotonin (5-HT1A) in their brain. Psychoneuroendocrino. 2015;52:212–28.

    Article  CAS  Google Scholar 

  107. He F, Wang Z, Guo G. Postnatal separation prevents the development of prenatal stress-induced anxiety in association with changes in oestrogen receptor and oxytocin immunoreactivity in female mandarin vole (Microtus mandarinus) offspring. Eur J Neurosci. 2018;47:95–108.

    Article  PubMed  Google Scholar 

  108. Lebowitz ER, Leckman JF, Feldman R, Zagoory-Sharon O, McDonald N, Silverman WK. Salivary oxytocin in clinically anxious youth: associations with separation anxiety and family accommodation. Psychoneuroendocrino. 2016;65:35–43.

    Article  CAS  Google Scholar 

  109. Lebowitz ER, Silverman WK, Martino AM, Zagoory-Sharon O, Feldman R, Leckman JF. Oxytocin response to youth-mother interactions in clinically anxious youth is associated with separation anxiety and dyadic behavior. Depress Anxiety. 2017;34:127–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Costa B, Pini S, Baldwin DS, Silove D, Manicavasagar V, Abelli M, et al. Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety. J Affect Disorders. 2017;218:365–73.

    Article  CAS  PubMed  Google Scholar 

  111. Gorka SM, Fitzgerald DA, Labuschagne I, Hosanagar A, Wood AG, Nathan PJ, et al. Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder. Neuropsychopharmacol. 2015;40:278–86.

    Article  CAS  Google Scholar 

  112. Oh KS, Kim EJ, Ha JW, Woo HY, Kwon MJ, Shin DW, et al. The relationship between plasma oxytocin levels and social anxiety symptoms. Psychiat Invest. 2018;15:1079–86.

    Article  CAS  Google Scholar 

  113. Fang A, Treadway MT, Hofmann SG. Working hard for oneself or others: effects of oxytocin on reward motivation in social anxiety disorder. Biol Psychol. 2017;127:157–62.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Smith K. Mental health: a world of depression. Nature. 2014;515:181.

    Article  PubMed  Google Scholar 

  115. Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Marechal P, Pequeux C, et al. Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrino. 2007;32:407–10.

    Article  CAS  Google Scholar 

  116. Skrundz M, Bolten M, Nast I, Hellhammer DH, Meinlschmidt G. Plasma oxytocin concentration during pregnancy is associated with development of postpartum depression. Neuropsychopharmacol. 2011;36:1886–93.

    Article  CAS  Google Scholar 

  117. Arletti R, Bertolini A. Oxytocin acts as an antidepressant in two animal models of depression. Life Sci. 1987;41:1725–30.

    Article  CAS  PubMed  Google Scholar 

  118. Yan Y, Wang YL, Su Z, Zhang Y, Guo SX, Liu AJ, et al. Effect of oxytocin on the behavioral activity in the behavioral despair depression rat model. Neuropeptides. 2014;48:83–9.

    Article  CAS  PubMed  Google Scholar 

  119. Norman GJ, Karelina K, Morris JS, Zhang N, Cochran M, Courtney DA. Social interaction prevents the development of depressive-like behavior post nerve injury in mice: a potential role for oxytocin. Psychosom Med. 2010;72:519–26.

    Article  CAS  PubMed  Google Scholar 

  120. Thornton JL, Everett NA, Webb P, Turner AJ, Cornish JL, Baracz SJ. Adolescent oxytocin administration reduces depression-like behaviour induced by early life stress in adult male and female rats. Prog Neuro-Psychoph. 2021;110:110279.

    Article  CAS  Google Scholar 

  121. Phan J, Alhassen L, Argelagos A, Alhassen W, Vachirakorntong B, Lin Z, et al. Mating and parenting experiences sculpture mood-modulating effects of oxytocin-MCH signaling. Sci Rep-Uk. 2020;10:13611.

    Article  CAS  Google Scholar 

  122. Wang T, Shi C, Li X, Zhang P, Liu B, Wang H, et al. Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model. Behav Brain Res. 2018;336:236–43.

    Article  CAS  PubMed  Google Scholar 

  123. Holt-Lunstad J, Birmingham W, Light KC. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrino. 2011;36:1249–56.

    Article  CAS  Google Scholar 

  124. Donadon MF, Martin-Santos R, Osório FL. Oxytocin effects on the cognition of women with postpartum depression: a randomized, placebo-controlled clinical trial. Prog Neuro-Psychoph. 2021;111:110098.

    Article  CAS  Google Scholar 

  125. Ma X, Wei Q, Jiang Z, Shi Y, Zhang Y, Shi H. The role of serum oxytocin levels in the second trimester in regulating prenatal anxiety and depression: a sample from Shanghai Maternal-Child Pairs Cohort study. J Affect Disorders. 2020;264:150–6.

    Article  CAS  PubMed  Google Scholar 

  126. Parris MS, Grunebaum MF, Galfalvy HC, Andronikashvili A, Burke AK, Yin H, et al. Attempted suicide and oxytocin-related gene polymorphisms. J Affect Disorders. 2018;238:62–8.

    Article  CAS  PubMed  Google Scholar 

  127. Whitley J, Wouk K, Bauer AE, Grewen K, Gottfredson NC, Meltzer-Brody S, et al. Oxytocin during breastfeeding and maternal mood symptoms. Psychoneuroendocrino. 2020;113:104581.

    Article  CAS  Google Scholar 

  128. Engel S, Laufer S, Knaevelsrud C, Schumacher S. The endogenous oxytocin system in depressive disorders: a systematic review and meta-analysis. Psychoneuroendocrino. 2019;101:138–49.

    Article  CAS  Google Scholar 

  129. Abdelwahab LA, Galal OO, Abd ES, El-Brairy AI, Khattab MM, El-Khatib AS. Targeting the oxytocin system to ameliorate early life depressive-like behaviors in maternally-separated rats. Biol Pharm Bull. 2021;44:1445–57.

    Article  CAS  PubMed  Google Scholar 

  130. Stanic D, Oved K, Israel-Elgali I, Jukic M, Batinic B, Puskas N, et al. Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: relevance to sensitivity to SSRI therapy. Psychoneuroendocrino. 2021;129:105234.

    Article  CAS  Google Scholar 

  131. Thompson RJ, Parker KJ, Hallmayer JF, Waugh CE, Gotlib IH. Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. Psychoneuroendocrino. 2011;36:144–7.

    Article  CAS  Google Scholar 

  132. Maud C, Ryan J, McIntosh JE, Olsson CA. The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review. BMC Psychiatry. 2018;18:154.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Astill WL, Sijbrandij M, Sinnerton R, Lewis C, Roberts NP, Bisson JI. Pharmacological prevention and early treatment of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis. Transl Psychiat. 2019;9:334.

    Article  Google Scholar 

  134. Carmassi C, Marazziti D, Mucci F, Della VA, Barberi FM, Baroni S, et al. Decreased plasma oxytocin levels in patients with PTSD. Front Psychol. 2021;12:612338.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Donadon MF, Martin-Santos R, Osorio FL. The Associations between oxytocin and trauma in humans: a systematic review. Front Pharmacol. 2018;9:154.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M. Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes. Psychoneuroendocrino. 2014;40:242–56.

    Article  CAS  Google Scholar 

  137. Palgi S, Klein E, Shamay-Tsoory S. The role of oxytocin in empathy in PTSD. Psychol Trauma-Us. 2017;9:70–5.

    Article  Google Scholar 

  138. Cao C, Wang L, Wang R, Qing Y, Zhang J. Oxytocin is associated with PTSD’s anxious arousal symptoms in Chinese male earthquake survivors. Eur J Psychotraumato. 2014;5:26530.

    Article  Google Scholar 

  139. Palgi S, Klein E, Shamay-Tsoory SG. Oxytocin improves compassion toward women among patients with PTSD. Psychoneuroendocrino. 2016;64:143–9.

    Article  CAS  Google Scholar 

  140. Flanagan JC, Sippel LM, Wahlquist A, Moran-Santa MM, Back SE. Augmenting prolonged exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial. J Psychiatr Res. 2018;98:64–9.

    Article  PubMed  Google Scholar 

  141. Muroy SE, Long KL, Kaufer D, Kirby ED. Moderate stress-induced social bonding and oxytocin signaling are disrupted by predator Odor in male rats. Neuropsychopharmacol. 2016;41:2160–70.

    Article  CAS  Google Scholar 

  142. Janezic EM, Uppalapati S, Nagl S, Contreras M, French ED, Fellous JM. Beneficial effects of chronic oxytocin administration and social co-housing in a rodent model of post-traumatic stress disorder. Behav Pharmacol. 2016;27:704–17.

    Article  CAS  PubMed  Google Scholar 

  143. Hirota Y, Arai A, Young LJ, Osako Y, Yuri K, Mitsui S. Oxytocin receptor antagonist reverses the blunting effect of pair bonding on fear learning in monogamous prairie voles. Horm Behav. 2020;120:104685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Engert V, Koester AM, Riepenhausen A, Singer T. Boosting recovery rather than buffering reactivity: Higher stress-induced oxytocin secretion is associated with increased cortisol reactivity and faster vagal recovery after acute psychosocial stress. Psychoneuroendocrino. 2016;74:111–20.

    Article  CAS  Google Scholar 

  145. Augustine RA, Ladyman SR, Bouwer GT, Alyousif Y, Sapsford TJ, Scott V, et al. Prolactin regulation of oxytocin neurone activity in pregnancy and lactation. J Physiol. 2017;595:3591–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Villegas-Gabutti CM, Pennacchio GE, Vivas L, Jahn GA, Soaje M. Role of oxytocin in prolactin secretion during late pregnancy. Neuroendocrinology. 2018;106:324–34.

    Article  CAS  PubMed  Google Scholar 

  147. Carcea I, Caraballo NL, Marlin BJ, Ooyama R, Riceberg JS, Mendoza NJ, et al. Oxytocin neurons enable social transmission of maternal behaviour. Nature. 2021;596:553–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gil M, Bhatt R, Picotte KB, Hull EM. Sexual experience increases oxytocin receptor gene expression and protein in the medial preoptic area of the male rat. Psychoneuroendocrino. 2013;38:1688–97.

    Article  CAS  Google Scholar 

  149. Jong TR, Menon R, Bludau A, Grund T, Biermeier V, Klampfl SM, et al. Salivary oxytocin concentrations in response to running, sexual self-stimulation, breastfeeding and the TSST: the regensburg oxytocin challenge (ROC) study. Psychoneuroendocrino. 2015;62:381–8.

    Article  CAS  Google Scholar 

  150. Oti T, Satoh K, Uta D, Nagafuchi J, Tateishi S, Ueda R, et al. Oxytocin influences male sexual activity via non-synaptic axonal release in the spinal cord. Curr Biol. 2021;31:103–14.

    Article  CAS  PubMed  Google Scholar 

  151. Tang Y, Benusiglio D, Lefevre A, Hilfiger L, Althammer F, Bludau A, et al. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat Neurosci. 2020;23:1125–37.

    Article  CAS  PubMed  Google Scholar 

  152. Nunes AR, Gliksberg M, Varela S, Teles M, Wircer E, Blechman J, et al. Developmental effects of oxytocin neurons on social affiliation and processing of social information. J Neurosci. 2021;41:8742–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Penagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, et al. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med. 2015;7:271r–8r.

    Article  Google Scholar 

  154. Arabaci TS, Ucem S, Buke B, Guner M, Karakucuk AG, Yigit N, et al. Regular moderate exercise alleviates gastric oxidative damage in rats via the contribution of oxytocin receptors. J Physiol-London. 2020;598:2355–70.

    Article  Google Scholar 

  155. Alizadeh AM, Heydari Z, Rahimi M, Bazgir B, Shirvani H, Alipour S, et al. Oxytocin mediates the beneficial effects of the exercise training on breast cancer. Exp Physiol. 2018;103:222–35.

    Article  CAS  PubMed  Google Scholar 

  156. Hew-Butler T, Noakes TD, Soldin SJ, Verbalis JG. Acute changes in endocrine and fluid balance markers during high-intensity, steady-state, and prolonged endurance running: unexpected increases in oxytocin and brain natriuretic peptide during exercise. Eur J Endocrinol. 2008;159:729–37.

    Article  CAS  PubMed  Google Scholar 

  157. Stanic D, Plecas-Solarovic B, Mirkovic D, Jovanovic P, Dronjak S, Markovic B, et al. Oxytocin in corticosterone-induced chronic stress model: focus on adrenal gland function. Psychoneuroendocrino. 2017;80:137–46.

    Article  CAS  Google Scholar 

  158. Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, et al. Oxytocin regulates stress-induced Crf gene transcription through creb-regulated transcription coactivator 3. J Neurosci. 2015;35:12248–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Park SH, Kim YJ, Park JC, Han JS, Choi SY. Intranasal oxytocin following uncontrollable stress blocks impairments in hippocampal plasticity and recognition memory in stressed rats. Int J Neuropsychoph. 2017;20:861–6.

    Article  CAS  Google Scholar 

  160. Laviola G, Busdraghi LM, Meschino N, Petrella C, Fiore M. Aberrant early in life stimulation of the stress-response system affects emotional contagion and oxytocin regulation in adult male mice. Int J Mol Sci. 2021;22(9):5039. https://doi.org/10.3390/ijms22095039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cai J, Che X, Xu T, Luo Y, Yin M, Lu X, et al. Repeated oxytocin treatment during abstinence inhibited context- or restraint stress-induced reinstatement of methamphetamine-conditioned place preference and promoted adult hippocampal neurogenesis in mice. Exp Neurol. 2022;347:113907.

    Article  CAS  PubMed  Google Scholar 

  162. Steinman MQ, Duque-Wilckens N, Greenberg GD, Hao R, Campi KL, Laredo SA, et al. Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin. Biol Psychiat. 2016;80:406–14.

    Article  CAS  PubMed  Google Scholar 

  163. Li XH, Matsuura T, Xue M, Chen QY, Liu RH, Lu JS, et al. Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation. Cell Rep. 2021;36:109411.

    Article  CAS  PubMed  Google Scholar 

  164. Grippo AJ, Trahanas DM, Zimmerman RN, Porges SW, Carter CS. Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrino. 2009;34:1542–53.

    Article  CAS  Google Scholar 

  165. Stevenson JR, McMahon EK, Boner W, Haussmann MF. Oxytocin administration prevents cellular aging caused by social isolation. Psychoneuroendocrino. 2019;103:52–60.

    Article  CAS  Google Scholar 

  166. Smith AS, Tabbaa M, Lei K, Eastham P, Butler MJ, Linton L, et al. Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrino. 2016;63:50–8.

    Article  CAS  Google Scholar 

  167. Fan Y, Pestke K, Feeser M, Aust S, Pruessner JC, Boker H, et al. Amygdala-hippocampal connectivity changes during acute psychosocial stress: joint effect of early life stress and oxytocin. Neuropsychopharmacol. 2015;40:2736–44.

    Article  CAS  Google Scholar 

  168. Grimm S, Pestke K, Feeser M, Aust S, Weigand A, Wang J, et al. Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress. Soc Cogn Affect Neur. 2014;9:1828–35.

    Article  Google Scholar 

  169. Riem M, Kunst LE, Kop WJ. Intranasal oxytocin and the stress-buffering effects of social support during experimentally induced pain: the role of attachment security. J Affect Disorders. 2021;278:149–56.

    Article  CAS  PubMed  Google Scholar 

  170. Borrow AP, Heck AL, Miller AM, Sheng JA, Stover SA, Daniels RM, et al. Chronic variable stress alters hypothalamic-pituitary-adrenal axis function in the female mouse. Physiol Behav. 2019;209:112613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Bosch OJ, Kromer SA, Brunton PJ, Neumann ID. Release of oxytocin in the hypothalamic paraventricular nucleus, but not central amygdala or lateral septum in lactating residents and virgin intruders during maternal defence. Neuroscience. 2004;124:439–48.

    Article  CAS  PubMed  Google Scholar 

  172. Young KS, Pressman SD, Celniker J, Grewen KM, Sumida KD, Jonathan N, et al. Oxytocin, cortisol, and cognitive control during acute and naturalistic stress. Stress. 2021;24:370–83.

    Article  Google Scholar 

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Acknowledgements

All the figures were drawn with BioRender.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82230045, 32271066, 31900730), Shanghai Science and Technology Committee (20XD1423100), Shanghai Municipal Education Commission (2021-01-07-00-02-E0086, 20161321) and Lingang Laboratory (LG202106-03-02).

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SZ, DDS and ZW conceptualized, wrote the manuscript and made the figures. YDZ and ZW were involved in reviewing and editing the manuscript. All authors have given their final approval for the submission.

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Correspondence to Dong-Dong Shi or Zhen Wang.

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Zhang, S., Zhang, YD., Shi, DD. et al. Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders. Cell Biosci 13, 216 (2023). https://doi.org/10.1186/s13578-023-01173-6

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