Gastrointestinal motility is regulated primarily by the enteric and the central nervous systems. Our previous studies revealed that central circuits regulating colorectal motility partially overlap with those involved in pain modulation, suggesting functional interactions between the nociceptive modulatory pathway and the autonomic regulatory pathway of colorectal motility. Here, we examined whether peripheral inflammatory pain alters the neural components of the descending pathway regulating colorectal motility. Complete Freund's adjuvant (CFA) was administered unilaterally into the hind paw of rats to induce inflammation. Colorectal motility was assessed in vivo under anesthesia with α-chloralose and ketamine. In sham-treated rats, intraluminal administration of capsaicin, a noxious stimulus to the colorectal lumen, enhanced colorectal motility. In contrast, the capsaicin-induced colorectal motility response was suppressed in rats 3 days after CFA treatment. This suppression was rescued by the intrathecal administration of a GABAA receptor antagonist or an oxytocin (OXT) receptor antagonist. Furthermore, spinal OXT administration and chemogenetic activation of OXT neurons in naïve rats elicited a marked inhibition of capsaicin-induced motility responses of the colorectum. Notably, the inhibitory effect of activated OXT neurons was abolished by the intrathecal administration of a GABAA receptor antagonist. These results indicate that the descending OXT pathway becomes operative in response to persistent pain caused by peripheral inflammation and that the inhibitory effect on colorectal motility may involve local GABAergic transmission within the spinal cord. These changes may reduce parasympathetic outflow to the colorectum and contribute to defecation disorders involving central neural mechanisms.

BackgroundAnxiety disorders—including generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder—are highly prevalent psychiatric conditions that impose substantial clinical and social burdens. Preclinical and clinical studies have shown that electroacupuncture (EA) can effectively alleviate anxiety-like behaviors; however, the specific neural circuits and molecular mechanisms underlying EA’s therapeutic effects remain incompletely elucidated.MethodsWe first assessed the impacts of EA at four classical acupoints—Zusanli (ST36), Neiguan (PC6), Tianshu (ST25), and Baihui (GV20)—delivered with distinct stimulation waveforms on anxiety-like behaviors in conventionally housed mice, using the elevated plus maze and open field test paradigms. To identify the neural circuit underlying the behavioral effects of Baihui (GV20) EA, we employed pseudorabies virus expressing enhanced green fluorescent protein (PRV-EGFP) for retrograde tracing from Baihui (GV20) and quantified c-Fos expression across the whole brain as a marker of neuronal activation. ELISA was utilized to measure plasma oxytocin (OXT) levels following EA at Baihui (GV20). Furthermore, a selective pharmacological antagonist of the oxytocin receptor (OXT-R) was administered to verify the critical role of OXT signaling in mediating the anxiolytic benefits of Baihui (GV20) EA.ResultsEA at GV20 using intermittent electrical wave stimulation exhibited the most robust anxiolytic effects compared to EA at other acupoints or alternative stimulation parameters. Retrograde virus tracing from GV20 revealed a direct neuronal connection between the PVN and the GV20 acupoint region. Further experiments showed that GV20 EA significantly increased the activation of OXT-synthesizing neurons in the PVN and elevated peripheral OXT concentrations in mouse plasma. Critically, intraperitoneal injection of an OXTR antagonist completely abrogated the anxiolytic effects of GV20 EA, confirming that OXT signaling is indispensable for this therapeutic action.ConclusionsIntermittent 1.5 mA EA at Baihui (GV20) mitigates anxiety-like behavior in mice via a PVN-derived, OXT-dependent pathway. This work clarifies the anatomical and molecular mechanisms underlying EA-mediated anxiety relief and provides a basis for further exploring functional connections between specific acupoints and brain regions.

Nasal epithelial cells expressing oxytocin receptor are involved in volatilized oxytocin effects on biased and social motivations and stress-declined neural stem cell proliferation.

Screening for anti-dysmenorrhea components of Wenjing decoction: spectrum-effect relationship analysis, and efficacy equivalence validation.

Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes.

BackgroundWomen with depression are less likely to breastfeed and experience more breastfeeding challenges. Potential biological mechanisms that link maternal depression with poor breastfeeding outcomes have not been investigated. This study examined associations between lifetime history of depression (LHD), prenatal oxytocin receptor gene (OXTR) DNA methylation, and breastfeeding outcomes.ResultsLongitudinal observational data from the Norwegian Mother, Father and Child Cohort Study (MoBa) were analysed (N = 3607). LHD was self-reported during pregnancy (week 15). Blood samples were collected at 16–18 weeks of pregnancy, and DNA methylation was measured using the Illumina Methylation EPIC BeadChip 850 K array. This array includes 22 CpG sites on the OXTR gene, which were used in analyses. Mothers self-reported breastfeeding initiation (breastmilk given to child in first month), breastfeeding maintenance (breastmilk given to child for 6 months or more) and breastfeeding problems. Maternal LHD was not associated with OXTR DNA methylation. There was some evidence that prenatal OXTR DNA methylation was associated with breastfeeding outcomes. There was an association between CpG cg26455676 and breastfeeding maintenance to 6 months (odds ratio = 1.59, 95% confidence intervals = 1.11–2.27, raw p = 0.01, adjusted p = 0.04). Higher levels of DNA methylation at CpG cg26455676 was associated with a greater likelihood of maintaining breastfeeding to 6 months.ConclusionsThis highly novel study highlights the intriguing possibility that maternal prenatal DNA methylation at genes important for breastfeeding may be associated with breastfeeding experiences. Further understanding of vastly differing breastfeeding experiences would assist with the targeting efforts to support breastfeeding women, particularly those who are vulnerable, such as mothers who have depression.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13148-025-02030-8.

Early life adversities (ELA) can significantly impact brain development and adult behavior, potentially increasing vulnerability to psychopathologies. Evidence shows that ELA exposure is significantly associated with dysfunctional Oxytocin (OXT), a neuropeptide strongly engaged in social behavior and linked to the processing of rewarding stimuli, such as drugs of abuse. Moreover, it has been recently demonstrated that peripheral OXT may be transported to the brain through several mechanisms, including Receptors for Advanced Glycation End-Products (RAGE), and the RAGE-mediated OXT transport has been shown to play a key critical role in mediating some aspects of social behavior, such as social bonding. However, how OXT system alterations induced by ELA could increase vulnerability to psychopathologies is still under investigation. To investigate this link, we exploit our model of early adversity (Repeated Cross-Fostering, RCF), known to increase the sensitivity to cocaine effects in adult C57BL/6 J (C57) female mice acting on the dopaminergic mesocorticolimbic system. Here, we show that in C57 females, RCF manipulation also impairs social recognition and impacts the OXT system by altering i) OXT levels in the brain and plasma; ii) the expression of RAGE; and iii) the expression of OXT receptor (OxtR). Notably, early restoring brain and plasmatic OXT levels via subcutaneous OXT injection during RCF manipulation counteracts the RCF-induced neurobiological alterations of the OXT system and prevents short and long-lasting behavioral alterations. These findings shed light on the mechanisms by which the oxytocinergic system mediates the long-term effects of early-life adversities on drug addiction vulnerability and social behavior.

Oxytocin is involved in the regulation of maternal behavior by binding to the oxytocin receptor (OXTR) in various parts of the brain. Our previous studies demonstrated that OXTRs are specifically expressed in the anteroventral periventricular nucleus (AVPV) of female mice, but not in male mice. Furthermore, the activity of the OXTR neurons is essential for proper expression of maternal behavior. The present study aimed to characterize two different populations of OXTR neurons found in the AVPV in the previous study: tyrosine hydroxylase immunoreactive (TH+) and non-TH immunoreactive (TH-) neurons. Whole-cell patch clamp recordings were used to observe the intrinsic electrophysiological properties of the OXTR neurons. TH+ neurons displayed a pacemaker-like intrinsic rhythmic short bursting activity, whereas TH- neurons displayed either no firing at all, irregular firing, or phasic firing. Some TH- OXTR neurons could switch back and forth among these firing patterns. The differences in the firing patterns between these two populations were likely derived from the difference in their expression of afterpotentials. TH+ OXTR neurons showed more depolarizing afterpotential (DAP) than after-hyperpolarization (AHP), while TH- OXTR neurons exhibited more AHP than DAP. Activation of OXTR by a specific agonist caused a steady state depolarization and increase in Ca2+ transient resulting in changes in the firing activity in both TH+ and TH- neurons. Lastly, biocytin was injected into the OXTR neurons during the whole-cell recordings to visualize the recorded neurons for immuno-identification of neuron type and morphological analysis. TH- neurons displayed significantly more dendritic arborization than TH+ neurons. Therefore, TH+ and TH- neurons are electrophysiologically and morphologically distinct. Moreover, because activation of OXTR caused a change in the firing activity of these neurons, oxytocin likely modulates the firing activity of both TH+ and TH- OXTR neurons to influence maternal behavior.

The neuropeptide arginine-vasopressin (AVP) regulates sexually-differentiated social behaviors, including sexual behavior, aggression, and social communication. Much of AVP’s effect on social behavior is mediated by the most widely-expressed AVP receptor in the central nervous system: the vasopressin 1a receptor (V1aR). Dense expression of V1aR is found in males and females in the lateral septum (LS), which also receives heavy input from sexually-differentiated populations of AVP cells in the extended amygdala. In order to access and interrogate the structure and function of V1aR cells, we developed and validated a V1aR-Cre knockin mouse line (Avpr1a-P2A-iCre). V1aR-Cre mice did not differ from their Cre-negative littermates in their health, sensorimotor function, anxiety/motivational behavioral responses, or in their V1aR binding levels in the LS. The distribution of Cre in the brain, as assessed by crosses with Cre-reporter mouse lines and in situ hybridization (ISH), was highly similar to patterns of V1aR binding and demonstrated strong colocalization between Cre and V1aR expression within LS cells. We used this V1aR-Cre mouse to identify the inputs and outputs of V1aR+ cells in the LS, via a monosynaptic retrograde rabies virus as well as anterograde synaptophysin-mRuby AAV tracing approaches. Monosynaptic inputs to V1aR LS cells were observed from the medial preoptic area (MPA), lateral hypothalamus (LH), hippocampus (mostly ventral), medial septum, diagonal band of Broca (DBB), and the supramammillary nucleus (SuM). Synaptophysin labeling revealed outputs to some of these same structures (MS, LH, DBB, SuM) as well as parts of the lateral preoptic area (LPO), anterior hypothalamic area (AHA), and ventral pallidum. Notably, most structures (except for hippocampus) bidirectionally connected to V1aR LS cells also contain populations of V1aR+ cells and are targets for BNST/MeA AVP cells, suggesting an integrated AVP/V1aR circuit. Finally, using ISH, we measured levels of V1aR mRNA expression in subregions of the LS and colocalization of V1aR with oxytocin receptor (OTR) mRNA, which also has a high affinity for AVP, within the LS. We found similar high percentages of cells containing V1aR+ puncta across dorsal and intermediate LS in both males and females. In contrast, the ventral LS contained fewer V1aR+ cells in both males and females. The highest level of co-expression of V1aR and OTR was found in the intermediate LS in both sexes, suggesting the possible location of functional interactions between AVP and oxytocin within the LS. We also sought to identify other phenotypic aspects of V1aR cells using ISH and confirmed that all LS V1aR cells are GABAergic and that most also express corticotropin-releasing hormone receptor 2, suggesting a substrate by which AVP could interact with stress-related systems in the LS. Our characterized V1aR-Cre mouse will be a valuable resource for understanding the role of AVP/V1aR in behavioral and physiological systems. Using this mouse, we have characterized the connectional architecture of V1aR cells in the LS and revealed an interlocking set of structures that may be the substrate through which AVP regulates social and emotional behavior.

The transition to parenthood brings significant changes in behavior toward offspring. For instance, in anticipation of their offspring, male mice shift from infanticidal to caregiving behaviors. While the release of oxytocin from the paraventricular hypothalamus (PVH) plays a critical role in paternal caregiving, it does not fully account for the entire behavioral shift. The specific downstream neurons and signaling mechanisms involved in this process remain obscure. Here, we demonstrate that PVH vasopressin neurons also essentially contribute to a paternal behavioral shift. This vasopressin signal is partially transmitted through oxytocin receptors (OTRs) expressed in the anterior commissure and medial nuclei of the preoptic area. These OTR-expressing neurons receive inputs from both PVH oxytocin and vasopressin neurons and are responsible for expressing paternal caregiving behaviors. Collectively, this non-canonical vasopressin-to-OTR crosstalk within specific limbic circuits acts as a pivotal regulator of paternal behavioral changes in mice.

OXTR overexpression induces polycystic ovary syndrome-like phenotype via prolactin/p-STAT3 signaling in mice.

Effects of oxytocin receptor ligands on anxiogenic-like effect, social avoidance and changes on medial prefrontal cortex oxytocin receptor expression evoked by chronic social defeat stress in rats.

ABSTRACTThe oxytocinergic system is highly responsive to early‐life experiences, playing a crucial role in regulating social behaviors. In this study, we examined the effects of a neonatal experience modeling maternal neglect on the oxytocinergic system in the adult rat brain. To investigate this, rat pups were exposed to a T‐maze during Postnatal Days 10–13, where prohibition of contact with the mother—which served as the expected reward—constituted a mildly aversive experience (Denial of Expected Reward, DER). Our findings revealed that adult males subjected to the DER experience exhibited reduced levels of close social interaction, which could be ameliorated by acute intranasal oxytocin administration. Moreover, adult DER males had decreased expression of oxytocin receptors (OTR) in the medial nucleus of the amygdala (MeA) accompanied by alterations in the methylation profile of the OTR gene proximal promoter in MeA, specifically increased methylation levels of cytosines at positions −65, −19 and −11. No such effects were detected in the hippocampus or the medial‐orbital prefrontal cortex (MO PFC). Notably, in adult females the DER experience did not affect OTR expression in the brain areas examined (MeA, hippocampus and MO PFC) or their social interaction. These results suggest that the aversive early‐life experience of DER has affected the epigenetic regulation of OTR expression in a sexually dimorphic, brain region‐specific manner, leading to a reduction in oxytocinergic activity within the adult male amygdala, accompanied by impaired social interactions.

Impaired Gq signaling underlies oxytocin hyporesponsiveness in LPS and poly I:C-induced preterm labor in mice.

BackgroundScientists spend vast amounts of resources and time to produce safe and effective treatments across a large range of diseases and symptoms. Often, 3 or more years are spent in drug discovery for compound screening and lead optimization. We show an AI model that accelerates the discovery process, thereby allowing researchers to reach clinical phases faster, eliminating years of lab work.MethodsWe used the protein–ligand with adversarial augmentations network (PLA‐Net) to predict target–ligand interactions as a first step in a hybrid in‐silico and in‐vitro pipeline. We extended the target proteins of this model with AD related targets such as dopamine and serotonin receptors and transporters, and muscarinic, oxytocin, cannabinoids, beta‐adrenergic, and GLP1 receptors. We then predicted the interaction of the targets on our patented molecules. The next steps in this process include: testing foundational models of bioactivity and contrastive learning, to identify possible activities of molecules, including some of ours; dynamic molecular docking for some targets of interest in AD; and finally, assays of activity to validate our in‐silico findings on an in‐vitro environment.ResultsWe successfully validated the new targets with commercial molecules that have previously known interactions. For example, we tested Semaglutide, which is an effective GLP1 agonist, and the model predicted a 0.9316 probability of the molecule to be an agonist with GLP1. We repeated this process for each target. From there, we tested 4 of our families of drugs (1’s, M’s, TGR’s, and LMP’s) on the trained targets. We identified some families with significant interactions such as the LMP’s with Serotonin‐1B, the TGR’s with beta‐adrenergic‐2, and the 1’s with GLP1. Table 1 has a subset of the results from this first phase.ConclusionsThe results show the promise of an appropriate AI framework to accelerate the discovery of activity between molecules and targets, particularly in receptors with importance to therapeutic treatments for AD. For example, targeting beta‐adrenergic‐2 receptors because of its relation to neurogenesis and synaptic disfunction. Moving to later stages of the proposed pipeline will highlight and validate the potential of our molecules in the field of medicine and AD.

Exposure to EP-1 during lactation on maternal behavior, offspring early development, quinestrol transfer and relative receptors in maternal and offspring of Kunming mice.

Regulation of oxytocin receptor by zinc coumarin derivatives: a mechanistic approach to alleviate anxiety and enhance folliculogenesis in letrozole-induced PCOS in zebrafish model.

Estrogen and oxytocin receptors interplay in the medial amygdala to rapidly facilitate social recognition.

Social familiarity-dependent modulation of emotional responses to stressed conspecifics and the role of oxytocin receptors in rats.

In the shadowed aftermath of trauma, where social bonds fracture and anhedonia calcifies into isolation, oxytocin emerges not merely as a neuropeptide but as a molecular key to reclaiming human connection, yet its therapeutic promise in Post-traumatic stress disorder (PTSD) has long been shackled by profound response heterogeneity. This review unveils the oxytocin receptor gene (OXTR) as the master regulator of this variability, with rs53576 and rs2254298 polymorphisms orchestrating receptor density, synaptic plasticity, and vmPFC-NAcc synchrony in ways that stratify clinical destiny: G-allele carriers, endowed with heightened oxytocin sensitivity, exhibit robust fear extinction and social trust restoration under genotype-guided intranasal oxytocin (IN-OT) augmentation of prolonged exposure therapy, achieving effect sizes rivaling first-line pharmacotherapies; A-allele bearers, by contrast, confront epigenetic silencing and receptor desensitization, demanding escalation to 3,4-Methylenedioxymethamphetamine (MDMA), epigenetic editing, or exosomal delivery. Synthesizing stratified Randomized Controlled Trials (RCTs), functional neuroimaging, and a novel three-tier pharmacogenetic algorithm validated at 78% accuracy across 312 veterans, we chart a precision pathway that transforms oxytocin from probabilistic intervention to predictable recovery heralding routine OXTR genotyping in trauma clinics by 2027 and, ultimately, a future where social reward is no longer a casualty of survival.