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• Prenatal multispecies probiotics shape offspring emotional development. • Enduring effects on adult offspring gut microbiota by prenatal probiotic exposure. • Prenatal probiotics upregulate genes critical for gut and blood–brain barrier function. • IL-10 and the peptidoglycan transporter PepT1 showed sustained upregulation. • Males are more sensitive to prenatal multispecies probiotic exposure than females. Recent research highlights the pivotal role of the maternal gut microbiome during pregnancy in shaping offspring neurodevelopment. In this study, we investigated the impact of maternal intake of a multispecies probiotic formulation during a critical prenatal window (from gestational day 6 until birth) on neurodevelopmental trajectories in mice. Our findings demonstrate significant and persistent benefits in emotional behavior, gut microbiota composition, and expression of tight junction-related genes, particularly in male offspring, who exhibited heightened sensitivity to the probiotic intervention compared to females. Additionally, we observed elevated gene expression levels of the anti-inflammatory cytokine IL-10 and the oxytocin receptor (Oxtr) in the prefrontal cortex (PFC) of exposed juvenile offspring; however, these changes persisted only in the adult male offspring. Furthermore, the sustained increase in the expression of the proton-coupled oligopeptide transporter 1 (PepT1), which is involved in the transport of bacterial peptidoglycan motifs, in the PFC of exposed male offspring suggests a potential mechanistic pathway underlying the observed sex-dependent effects on behavior and gene expression. These results underscore the potential of prenatal multispecies probiotic interventions to promote long-term neurodevelopmental outcomes, with implications for precision microbial reconstitution aimed at promoting healthy neurodevelopment and behavior. [ABSTRACT FROM AUTHOR]

Aging is often associated with changes in social, sexual, emotional and pain functioning, as well as with the increased prevalence of certain psychopathologies. However, the neurodevelopmental basis underpinning these age‐related changes remains to be determined. Considering the key roles of oxytocin (OTR) and μ‐opioid (MOPr) receptor systems in regulating social, sexual, pain, reward and emotional processing, it seems plausible that they are also implicated in age‐related behavioural alterations. Although the ontogeny of both receptors has been well characterized in rodent brains from early development till adulthood, little is known concerning the neuroadaptations occurring from middle age to old age. Therefore, we mapped the neuroadaptations in OTR and MOPr in the brains of mice at those developmental endpoints. Quantitative OTR and MOPr autoradiographic binding was carried out in the brains of male mice at 2, 6, 9, 12 and 18 months of age. A significant whole brain decline in OTR density was detected between 2 and 6 months of age, with no additional decline thereafter. Interestingly, for MOPrs, the decline in density was not detected until 9 months of age. Region‐specific age‐related decline in OTR density was concentrated in the lateral anterior olfactory nuclei (AOL) and, for MOPr, in the AOL and the nucleus accumbens for MOPr. Identifying the tipping point of these age‐related variations in both receptors may assist with our understanding of the neurobiology underlining age‐related changes in social, pain and emotional functioning/processing. It may also help us target interventions to specific developmental windows to abrogate certain age‐related psychopathologies. [ABSTRACT FROM AUTHOR]

Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction. [Display omitted] • "CRISPRoscopy" integrates calcium imaging and gene editing in the same neuronal cell type • Co-editing of Oxtr and AVPr1a genes in VMHEsr1 neurons reduces aggression but not mounting • A line attractor encoding a scalable, persistent aggressive internal state is eliminated • Line attractor implementation in the hypothalamus requires neuropeptide signaling Oxytocin and vasopressin receptors are required in the ventromedial hypothalamus for persistent neural activity and line attractor dynamics that encode an aggressive internal state. [ABSTRACT FROM AUTHOR]

Background: Adolescent social isolation (ASI) has profound long-term effects on behavioral and neural development. Despite this, the specific long-term impact of ASI during different adolescent stages and across sexes remain underexplored. Methods: Our study addresses this gap by examining the effects of early- and late- adolescent social isolation on both male and female rats. Rats were either isolated (or group-housed) starting from PD 21 (early) or PD 42 (late) for three weeks and then rehoused into groups. In adulthood (PD 90), rats underwent a battery of tests: elevated plus-maze, open field, novel object recognition, social interaction and social recognition memory and hotplate tests. Finally, we analyzed oxytocin receptor binding in several regions in the brains of a second cohort of rats. Results: Both, male and female rats from the late adolescent social isolation (LASI) groups spent significantly less time interacting in the social interaction test. Additionally, we observed a general decrease in social recognition memory regardless of sex. Both male ASI groups demonstrated heightened thermal pain sensitivity, while the opposite was observed in early adolescent social isolation (EASI) female rats. In the brain, we observed changes in oxytocin receptor (OTR) binding in the paraventricular nucleus of the hypothalamus (PVN) and paraventricular nucleus of the thalamus (PVT) and central amygdala (CeA) with the largest changes in EASI and LASI female rats. Conclusion: Our model demonstrates long-lasting alterations on behavior and oxytocin receptor binding levels following ASI providing insights into the long-term effects of ASI in a time- and sex-specific manner. Highlights: Social Interaction Reduced: Regardless of the timing of social isolation, male rats displayed heightened sensitivity to thermal pain, while only the early social isolation altered pain sensitivity in females. Impaired Social Recognition Memory: Isolation caused a general impairment in recognizing previously encountered rats, which was specific to social encounters but not objects. Suggesting the deficit is domain specific. Alterations in Pain Sensitivity: Rats isolated during late adolescence showed significantly less social interaction compared to those raised in groups. Significant Brain Changes in Females: Female rats isolated during adolescence exhibited a substantial increase in oxytocin receptor binding in key brain regions (PVT, PVN) which are important for social behavior and anxiety. [ABSTRACT FROM AUTHOR]

Oxytocin has various effects ranging from promoting labor in pregnant women to alleviating stress. Recently, we reported the hair growth-promoting effects of oxytocin in hair follicle organoids. However, its clinical application faces challenges such as rapid degradation in vivo and poor permeability due to its large molecular weight. Therefore, in this study, we investigated the effects of the oxytocin receptor (OXTR) agonists WAY267464 and LIT001 as alternatives to oxytocin on hair growth. Human dermal papilla (DP) cells were cultured in WAY267464 or LIT001-supplemented medium. The addition of WAY267464 and LIT001 increased the expression of hair growth-related genes in DP cells. We tested the hair growth-promoting effects of WAY267464 and LIT001 using hair follicle organoids in vitro and found that they significantly promoted hair follicle sprouting. Thus, our findings indicate that WAY267464 and LIT001 are potential hair growth agents and may encourage further research on the development of novel hair growth agents targeting OXTR in patients with alopecia. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the structural and functional changes in the cervix of doe goats during different reproductive stages using advanced imaging techniques and biochemical markers. By analyzing the cervix at various stages of the estrous cycle and early pregnancy, the study aims to provide insights into reproductive management strategies. The results highlight the dynamic changes in cervical morphology and oxytocin receptor expression, which are crucial for reproductive success in goats. This research may contribute to improve artificial insemination techniques and overall reproductive health in veterinary practice. This study aimed to elucidate the morphophysiology and oxytocin receptor (OXTR) expression in the cervix of doe goats during various reproductive stages to enhance reproductive management strategies. A total of 40 cervical samples were categorized into follicular (n = 15), luteal (n = 10), and early pregnancy (n = 15) stages. Utilizing advanced imaging based on functional and morphological markers, the study employed computed tomography (CT) scans, histochemical staining (Masson trichrome and alcian blue), immunohistochemistry, Western blotting, and quantitative PCR (qPCR) to assess structural changes in the cervix and in OXTR expression during the estrous cycle and early pregnancy. CT scans revealed consistent cervical folds and a significant reduction in cervical width during pregnancy, suggesting structural adaptations for gestational integrity. Histochemical analyses indicated a well-organized collagen network and presence of mucins, essential for cervical function and integrity. Immunohistochemistry and Western blotting demonstrated elevated OXTR protein levels during the follicular stage, which were markedly reduced during pregnancy, indicating a role in facilitating cervical relaxation and sperm transport during estrus and maintaining cervical closure during gestation. qPCR analysis showed stable OXTR mRNA levels during follicular and luteal stages with a slight, non-significant increase during pregnancy, pointing towards posttranscriptional regulatory mechanisms. In conclusion, this study demonstrates that cervical morphology and OXTR expression in doe goats undergo significant changes across reproductive stages, with elevated OXTR protein levels during the follicular phase and notable reductions in cervical width and OXTR protein levels during pregnancy, indicating structural and functional adaptations for both reproductive processes and gestational integrity. [ABSTRACT FROM AUTHOR]

Background: Developmental hip dysplasia is a common condition with preventable causes, and its etiology is still not fully elucidated. In our study, we aimed to examine the use of synthetic oxytocin during childbirth as a potential risk factor for developmental hip dysplasia. Methods: This study involved comprehensive hip examinations on postnatal days 0, 14, 30, and 60, as well as hip ultrasonography results at 6-8 weeks. We specifically focused on healthy girls born with vaginal deliveries, comparing those who were applied with a low-dose oxytocin induction protocol (Group 2) and those who had vaginal deliveries without induction (Group 1). Results: When the examination findings were compared with the hip ultrasonography findings (Type 2a was detected in the left hip of one patient (6.3%) in Group 1 and in the right hip of two patients (11.8%) in Group 2), it was seen that oxytocin induction did not cause a risk for developmental hip dysplasia. The oxytocin induction rate was higher in newborns weighing more than 3400 g (p = 0.04). Conclusions: A low-dose oxytocin protocol applied at birth has not been shown to harm the hip joint in the neonatal period and on ultrasonographic α and β angle measurements applied at 6-8 weeks. However, our study also highlights the need for new studies investigating oxytocin peripheral receptors and their effects, underscoring the importance of our findings in guiding future research in this area. [ABSTRACT FROM AUTHOR]

Accumulative evidence suggested that the oxytocin system plays a role in socio-emotional disorders, although its role in neuroinflammation-induced anxiety remains unclear. In the present study, anxiety-like behavior was induced in cohorts of animals through repeated lipopolysaccharide (LPS, 0.5 mg/kg, daily, Escherichia coli O55:B5) i.p. injections for seven consecutive days. These different cohorts were subsequently used for anxiety-like behavior assessment with open field test, elevated plus maze, and novelty-suppressed feeding test or for electrophysiology (EEG) recordings of miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs), or local field potential (LFP) in vivo or ex vivo settings. Samples of the anterior cingulate cortex (ACC) from some cohorts were harvested to conduct immunostaining or western blotting analysis of oxytocin, oxytocin receptor, CamkII, GABA, vGAT, vGLUT2, and c-fos. The dendritic spine density was assessed by Golgi-Cox staining. Repeated LPS injections induced anxiety-like behavior with concurrent decreases of oxytocin, vGLUT2, mEPSC, dendritic spine, c-fos, membrane excitability, and EEG beta and gamma oscillations, but increased oxytocin receptor and vGAT expressions in the ACC; all these changes were ameliorated by oxytocin intranasal or local brain (via cannula) administration. Taken together, our data suggested that oxytocin system may be a therapeutic target for developing treatment to tackle neuroinflammation-induced anxiety. • Repeated LPS injections induced anxiety-like behavior. • Repeated LPS injections induced down-regulation of oxytocin in ACC. • Oxytocin system could regulate excitation and inhibition balance in ACC. • Oxytocin system may be a therapeutic target for neuroinflammation-induced anxiety. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid‐contacting neurons (CSF‐cNS) are considered mechanoreceptors and chemoreceptors involved in detecting changes in CSF circulation. However, considering that recent data suggest that this type of cell could exert an active response when an external stimulus is sensed, identification of CSF‐cNS may be relevant. In this regard, some data suggest that a neuronal connection exists between the ventral region of the hypothalamic paraventricular nucleus (PVN) and rostral agranular insular cortex (RAIC); indeed, a potential CSF‐cNS is hypothesized. However, a detailed analysis of this connection has not been conducted. Thus, using neuronal tracers (Fluoro‐Gold® (FG) and cholera toxin (ChT)) coupled with transmission electron microscopy and immunofluorescence assays against Fluoro‐Gold®, oxytocin (OXT), vasopressin (AVP) and oxytocin receptors (OTR), we describe an oxytocinergic or vasopressinergic CSF‐cNS between the PVN and RAIC. Our results showed that CSF‐cNS along the PVN labelled with oxytocin and/or AVP were present in dendritic projections near the third ventricle. This CSF‐cNS in the PVN seems to project to the RAIC. Inside the RAIC, ultrastructural analysis showed that axons immunopositive for oxytocin from the PVN sustained synaptic connections with neurons that expressed OTR. These findings show that the CSF‐cNS from the PVN sends projections to the RAIC. To the best of our knowledge, the relevance of CSF‐cNS has not been elucidated; however, we hypothesized that the activation of cells could concomitantly release neuropeptides (i.e., oxytocin and AVP) in the CSF and RAIC. Thus, further analysis of the impact of neuropeptides released into the third ventricle and RAIC is warranted. [ABSTRACT FROM AUTHOR]

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time‐dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor‐expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron‐projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well‐known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system. [ABSTRACT FROM AUTHOR]

Trust is an essential human trait. Although research suggests that the interplay between oxytocinergic and dopaminergic systems affects trust formation, little research has focused on epistatic (i.e., gene by gene) interaction effects of oxytocin- and dopamine-related genes on trust. Using a sample of 348 adults (114 men), we aimed to investigate the associations between genetic variants in oxytocin- and dopamine-related genes and the general, neighborhood, and institutional trust with consideration of sex differences. Three-way interaction between oxytocin-related gene genotypes, dopamine-related genotypes, and sex was found for the oxytocin receptor gene (OXTR)rs1042778 and the Catechol-O-Methyltransferase gene (COMT) rs4680 genotypes (p = 0.02) and for OXTR rs2254298 and the dopamine D2 receptor gene (DRD2) rs1800497 genotypes (p = 0.01). Further sex-stratified analyses revealed that the interaction between OXTR rs1042778 and COMT rs4680 genotypes was associated with neighborhood trust among men (p = 0.0007). Also, the interaction between OXTR rs2254298 and DRD2 rs1800497 genotypes was associated with institutional trust among men (p = 0.005). Post-hoc analyses found that men with OXTR rs1042778 TG/TT and COMT rs4680 GG genotypes reported higher neighborhood trust than those with GG + AG/AA (B = 13.49, SE = 4.68, p = 0.02), TG/TT + AG/AA (B = 23.00, SE = 5.99, p = 0.001), and GG + GG (B = 18.53, SE = 5.25, p = 0.003). Similarly, men with OXTR rs2254298 AG/AA and DRD2 rs1800497 CC genotypes showed higher institutional trust than those with AG/AA + TT/TC (B = 15.67, SE = 5.30, p = 0.02). We could not find any interacting associations among women. While we note that our sample size and candidate gene approach have a potential risk of chance findings, our study provides an important foundation toward further exploration of sex-specific epistatic interaction effects of oxytocin- and dopamine-related genes on trust, indicating the importance of both systems in trust formation. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a posterior pituitary hormone that, in addition to its role in regulating childbirth and lactation, also exerts direct regulatory effects on the skeleton through peripheral OT and oxytocin receptor (OTR). Bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), chondrocytes, and adipocytes all express OT and OTR. OT upregulates RUNX2, BMP2, ALP, and OCN, thereby enhancing the activity of BMSCs and promoting their differentiation towards OB rather than adipocytes. OT also directly regulates OPG/RANKL to inhibit adipocyte generation, increase the expression of SOX9 and COMP, and enhance chondrocyte differentiation. OB can secrete OT, exerting influence on the surrounding environment through autocrine and paracrine mechanisms. OT directly increases OC formation through the NκB/MAP kinase signaling pathway, inhibits osteoclast proliferation by triggering cytoplasmic Ca2+ release and nitric oxide synthesis, and has a dual regulatory effect on OCs. Under the stimulation of estrogen, OB synthesizes OT, amplifying the biological effects of estrogen and OT. Mediated by estrogen, the OT/OTR forms a feedforward loop with OB. Apart from estrogen, OT also interacts with arginine vasopressin (AVP), prostaglandins (PGE2), leptin, and adiponectin to regulate bone metabolism. This review summarizes recent research on the regulation of bone metabolism by OT and OTR, aiming to provide insights into their clinical applications and further research. [ABSTRACT FROM AUTHOR]

Oxytocin (OXT) is a peptide hormone and a neuropeptide that regulates various peripheral physiological processes and modulates behavioral responses in the central nervous system. While the humoral release occurs from the axons arriving at the median eminence, the neuropeptide is also released from oxytocinergic cell axons in various brain structures that contain its receptor, and from their dendrites in hypothalamic nuclei and potentially into the cerebrospinal fluid (CSF). Understanding oxytocin's complex functions requires the knowledge on patterns of oxytocinergic projections in relationship to its receptor (OXTR). This study provides the first comprehensive examination of the oxytocinergic system in the prairie vole (Microtus ochrogaster), an animal exhibiting social behaviors that mirror human social behaviors linked to oxytocinergic functioning. Using light and electron microscopy, we characterized the neuroanatomy of the oxytocinergic system in this species. OXT+ cell bodies were found primarily in the hypothalamus, and axons were densest in subcortical regions. Examination of the OXT+ fibers and their relationship to oxytocin receptor transcripts (Oxtr) revealed that except for some subcortical structures, the presence of axons was not correlated with the amount of Oxtr across the brain. Of particular interest, the cerebral cortex that had high expression of Oxtr transcripts contained little to no fibers. Electron microscopy is used to quantify dense cored vesicles (DCV) in OXT+ axons and to identify potential axonal release sites. The ependymal cells that line the ventricles were frequently permissive of DCV-containing OXT+ dendrites reaching the third ventricle. Our results highlight a mechanism in which oxytocin is released directly into the ventricles and circulates throughout the ventricular system, may serve as the primary source for oxytocin that binds to OXTR in the cerebral cortex. [ABSTRACT FROM AUTHOR]

Aim. To determine the pathogenetic role of the oxytocinergic system in the development of myocardium structural and functional changes in women with heart failure with preserved ejection fraction (HFpEF) associated with type 2 diabetes mellitus (DM2T) (diabetic phenotype of HFpEF).Material and methods. The study included 60 women aged 67.0±4.9 years with HFpEF stage I-IIA, FC I-III, 30 of them had DM2T who were admitted for elective coronary artery bypass grafting. The development of HFpEF is caused by coronary artery disease (CAD) and arterial hypertension (AH). Prior to surgery, all patients underwent a standard examination, blood levels of NT-proBNP, oxytocin (Ox), echocardiography were determined to find the types of left ventricular (LV) myocardial remodeling and diastolic dysfunction (DD). Myocardium biopsies of the right atrium auricle obtained during coronary bypass surgery were studied by microscopy, morphometry and immunohistochemistry (the expression of oxytocin receptors (OxR), a marker of proliferation ki-67).Results. According to echocardiography, eccentric LV hypertrophy (46.7/36.7%) and DD type 2 (47/17%, p=0.003) prevailed in the group of women with the diabetic phenotype of HFpEF. A higher content of NT-proBNP (480.72±241.87/434.46±282.78 ng/ml, p=0.06) and a lower concentration of Ox (102.11±35.89/320.37±294.71 pg/ml, p=0.0016) in blood serum were established, as well as an increase in the number of cardiomyocytes (CMC) with a high expression level OxR (63.69±19.47/12.16±23.09%, p=0.000) in patients with the diabetic phenotype of HFpEF. Negative associations were determined between the blood level of Ox and the CMC diameter (r=-0.10, p=0.020), the area of their cytoplasm (r=-0.16, p=0.000) and the area of the nuclei (r=-0.11, p=0.015) in patients of both groups. A decrease in Ox concentration in the blood of patients with diabetic phenotype of HFpEF was accompanied by an increase in the number of CMCs with a high level of OxR expression (r=-0.63, p=0.000).Conclusion. The study has shown the important involvement of oxytocinergic signaling pathways in the HFpEF pathogenesis. HFpEF associated with DM2T in women was characterized by more unfavorable structural and functional changes in the myocardium, a significant increase in the number of hypertrophied CMCs with a high level of OxR expression and Ox decrease in blood serum. The mechanisms of the first-established significant increase in the content of Ox in the blood of patients with HFpEF without diabetes and its significant decrease in patients with diabetic phenotype of HFpEF leading to more pronounced structural and functional changes in the myocardium, require further study.

Despite growing evidence that parent-adolescent conflict positively correlates with Internet gaming disorder (IGD) among adolescents, its underlying mediating and moderating mechanisms have yet to be thoroughly examined. Based on the social development model and gene-environment interaction perspective, this study investigates whether the indirect association of parent-adolescent conflict, which impacts adolescent IGD through peer victimization, was moderated by the oxytocin receptor (OXTR) gene rs53576 polymorphism. Overall, 673 Chinese adolescents (Meanage = 12.81 years; SD = 0.48 years; 54% boys) were included in this study. The participants completed questionnaires concerning parent-adolescent conflict, peer victimization, and IGD, and genomic DNA was extracted from each participant's saliva and buccal cells. The findings indicated that peer victimization mediated the link between parent-adolescent conflict and IGD among adolescents. The OXTR gene rs53576 polymorphism also moderated this indirect link. Specifically, the indirect effect of parent-adolescent conflict on adolescent IGD through peer victimization was significant for adolescents with AA homozygotes. However, it was non-significant for adolescents with GA and GG genotypes. This research simultaneously considers the roles of family, peers, and genetics in adolescent IGD. Furthermore, it provides beneficial information to customize interventions for adolescent IGD prevention. [ABSTRACT FROM AUTHOR]

The receptor–receptor interaction (RRI) of G protein-coupled receptors (GPCRs) leads to new functional entities that are conceptually distinct from the simple addition of signals mediated by the activation of the receptors that form the heteromers. Focusing on astrocytes, there is evidence for the existence of inhibitory and facilitatory RRIs, including the heteromers formed by the adenosine A2A and the dopamine D2 receptors, by A2A and the oxytocin receptor (OTR), and the D2-OTR heteromers. The possible involvement of these receptors in mosaicism has never been investigated in striatal astrocytes. By biophysical and functional approaches, we focused our attention on the existence of an A2A-D2-OTR high-order receptor complex and its role in modulating cytosolic calcium levels and endogenous glutamate release, when striatal astrocyte processes were stimulated with 4-aminopyridine. Functional data indicate a permissive role of OTR on dopamine signaling in the regulation of the glutamatergic transmission, and an inhibitory control mediated by A2A on both the D2-mediated signaling and on the OTR-facilitating effect on D2. Imaging biochemical and bioinformatic evidence confirmed the existence of the A2A-D2-OTR complex and its ternary structure in the membrane. In conclusion, the D2 receptor appears to be a hotspot in the control of the glutamate release from the astrocytic processes and may contribute to the regulation and integration of different neurotransmitter-mediated signaling in the striatum by the A2A-D2-OTR heterotrimers. Considering the possible selectivity of allosteric interventions on GPCRs organized as receptor mosaics, A2A-D2-OTR heterotrimers may offer selective pharmacological targets in neuropsychiatric disorders and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Oxytocin receptor gene polymorphism (OXTR rs53576) is associated with human social cognition and behavior. However, results on the contribution of OXTR rs53576 to individual differences in depressive symptoms have been inconsistent. This meta-analysis examined the association between OXTR rs53576 and depressive symptoms and under what conditions this association might hold true. A systematic search of PubMed, PsycInfo, and Web of Science was performed for English articles describing human-based studies from the inception of the databases to February 2023, as well as a manual search of the reference lists of the included articles. The search terms included OXTR rs53576, depressive symptoms, and their synonyms. Standardized mean differences in depressive symptoms between individuals classified by OXTR rs53576 genotypes were evaluated, and random-effects meta-analyses were performed. A total of 10 studies including 2972 subjects from six countries were pooled. Results provided no evidence of an association between OXTR rs53576 and depressive symptoms. The between-study differences in I2 statistics by ethnicity, disease history, and age group suggested the presence of moderating variables. However, the number of eligible studies was small with considerable heterogeneity. Findings underscore the importance of homogeneous sampling for research on depression genetics to affirm the association between OXTR rs35376 and depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Borderline personality disorder (BPD) is a complex mental health condition marked by instability in mood, relationships, self-image, and behavior. Individuals with BPD often struggle with intense emotions, impulsivity, and maintaining stable relationships. Oxytocin, known as the "love hormone" or "bonding hormone," plays a crucial role in social bonding, trust, empathy, and emotional regulation and its dysregulation may contribute to BPD difficulties. This systematic review aims to analyze existing literature, examining the intricate interplay and encouraging future research and treatment strategies. Methods: A systematic search of Literature in PubMed, Embase and Psychinfo, without any language or time restriction, was performed until March 2024 combining thesaurus and free-search indexing terms related to "borderline personality disorder" and "oxytocin", producing 310 results (77 in PubMed, 166 in Embase and 67 in Psychinfo). Ninety-four full texts were analyzed, and 70 articles were included in qualitative analysis. Results: Oxytocin may influence attachment styles, parental behaviors, and stress responses, particularly in individuals with a history of childhood trauma. The interaction between oxytocin, genetics, early life experiences, and environmental factors contributes to the complexity of BPD. Genetic variations in the oxytocin receptor gene may influence social and emotional abilities and contribute to the development of psychopathology. Additionally, early adverse experiences, such as childhood maltreatment, can alter oxytocin functioning, impacting social cognition and emotional regulation. However, oxytocin's role in BPD treatment remains uncertain, with some studies suggesting potential benefits for specific symptoms like social threat avoidance, while others indicate adverse effects on nonverbal behavior and mentalizing. Conclusion: Understanding oxytocin's role in BPD offers insights into potential therapeutic interventions. While oxytocin-based treatments may hold promise for addressing specific symptoms, further research is needed. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Milk ejection disorders were induced by oxytocin receptor blockade. We tested the hypothesis that the degree of udder emptying at incomplete milk ejection can be estimated based on the concentration of various milk constituents in different milk fraction samples. To induce different levels of spontaneous udder emptying (SUE) 10 Holstein dairy cows were milked either with or without i.v. injection of the oxytocin receptor blocking agent atosiban (ATO). In ATOearly, 12 µg/kg BW ATO was injected immediately before and in ATOlate directly after a 1-min manual udder preparation. The normal milking routine served as the control treatment. In all 3 treatments the udder was completely emptied by the i.v. injection of 10 IU oxytocin (OT) at the end of spontaneous milk flow. During all experimental milkings 4 milk samples were taken in all treatments: at the start of udder preparation (foremilk; FM), immediately after cessation of spontaneous milk flow and cluster detachment by hand stripping (strip milk; SM), from spontaneous removed milk in bucket 1 (milk before OT; MBOT) and from the milk obtained after OT injection in bucket 2 (milk after OT; MAOT). Fat, protein, lactose, and electrolytes (Na, Cl, and K) were measured in each milk sample. In addition, electrical conductivity (EC) was determined in parallel to continuous milk flow recording. The treatments induced individual degrees of SUE; therefore, the final evaluations of data were based on SUE classes instead of treatments. The most pronounced differences of milk constituents at different degrees of SUE were found for the milk fat content. The fat content of SM and MBOT remained almost unchanged up to 60% SUE, but was considerably higher if >80% of the milk was spontaneously removed. The concentrations of Na and Cl were highest and of K lowest if less than 20% of milk was received in the different samples. The EC was higher in SM and MBOT if <20% of milk was received. In conclusion, the blockade of the OT effect influences primarily the fat content, which confirmed an OT-induced fat secretion during milking. Similar effects are likely found in situations of disturbed milk ejections, caused by a lack of or reduced release of OT in response to different degrees of tactile udder stimulation. Our results show that the measurement of fat content and the EC in SM samples collected after cluster detachment can be used to estimate the completeness of udder emptying. [ABSTRACT FROM AUTHOR]

Objective: Our primary objective was to investigate the variability of oxytocin (OT) and the GAMEN binding motif within the LNPEP oxytocinase in primates. Materials and Methods: We sequenced the LNPEP segment encompassing the GAMEN motif in 34 Platyrrhini species, with 21 of them also sequenced for the OT gene. Our dataset was supplemented with primate sequences of LNPEP, OT, and the oxytocin receptor (OTR) sourced from public databases. Evolutionary analysis and coevolution predictions were made followed by the macroevolution analysis of relevant amino acids associated with phenotypic traits, such as mating systems, parental care, and litter size. To account for phylogenetic structure, we utilized two distinct statistical tests. Additionally, we calculated binding energies focusing on the interaction between Callithtrix jacchus VAMEN and Pro8OT. Results: We identified two novel motifs (AAMEN and VAMEN), challenging the current knowledge of motif conservation in placental mammals. Coevolution analysis demonstrated a correlation between GAMEN, AAMEN, and VAMEN and their corresponding OTs and OTRs. Callithrix jacchus exhibited a higher binding energy between VAMEN and Pro8OT than orthologous molecules found in humans (GAMEN and Leu8OT). Discussion: The coevolution of AAMEN and VAMEN with their corresponding OTs and OTRs suggests a functional relationship that could have contributed to specific reproductive and adaptive behaviors, including paternal care, social monogamy, and twin births, prominent traits in Cebidae species, such as marmosets and tamarins. Our findings underscore the coevolution of taxon‐specific amino acids among the three studied molecules, shedding light on the oxytocinergic system as an adaptive epistatic repertoire in primates. [ABSTRACT FROM AUTHOR]

Background: Alexithymia is a trait involving difficulties in processing emotions. Genetic association studies have investigated candidate genes involved in alexithymia's pathogenesis. Therefore, the aim of the present study was to perform a systematic review of the genetic background associated with alexithymia. Methods: A systematic review of genetic studies of people with alexithymia was conducted. Electronic databases including PubMed, Scopus, and Web of Science were searched for the study purpose. We used the words "Alexithymia", "gene", "genetics", "variants", and "biomarkers". The present systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We found only candidate gene studies. A total of seventeen studies met the eligibility criteria, which comprised 22,361 individuals. The candidate genes associated with alexithymia were the serotoninergic pathway genes solute carrier family 6 member 4 (SLC6A4), serotonin 1A receptor (HTR1A), and serotonin 1A receptor (HTR2A); the neurotransmitter metabolism genes dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1), catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and oxytocin receptor (OXTR); and other pathway genes, vitamin D-binding protein (VDBP), tumor protein P53 regulated apoptosis inducing protein 1 (TP53AIP1), Rho GTPase Activating Protein 32 (ARHGAP32), and transmembrane protein 88B (TMEM88B). Conclusion: The results of this study showed that only case–control gene studies have been performed in alexithymia. On the basis of our findings, the majority of alexithymia genes and polymorphisms in this study belong to the serotoninergic pathway and neurotransmitter metabolism genes. These data suggest a role of serotoninergic neurotransmission in alexithymia. Nevertheless, more and future research is required to learn about the role of these genes in alexithymia. [ABSTRACT FROM AUTHOR]

High consumption of locally produced delicacies could expose nursing mothers to high monosodium glutamate (MSG) levels, frequently used as a necessary condiment in low-income countries. Thus, this study evaluated some novel preliminary changes in renal hormonal receptors, the aquaporin-3 channel, oxidative stress markers, and hematological indices induced by monosodium glutamate in lactating rats. Post-parturition, twenty-four (24) lactating Wistar rats were divided into four (4) groups of six rats each (n = 6). Oral administration of distilled water and MSG started three (3) days postpartum as follows: group 1: distilled water (1 ml/kg BW), group 2: MSG (925 mg/kg BW), group 3: MSG (1850 mg/kg BW), and group 4: MSG (3700 mg/kg BW). At the end of the experiment, which lasted fourteen (14) days, animals were sacrificed and samples of blood and tissues were obtained for biochemical analysis. MSG administration significantly (p < 0.05) increased ROS and MDA, with a significant (p < 0.05) decrease in kidney antioxidants. Serum creatinine, total, conjugated, and unconjugated bilirubin significantly (p < 0.05) increased with MSG administration. The prolactin receptor was significantly reduced (p < 0.05), while the oxytocin receptor and aquaporin-3 channel were significantly (p < 0.05) increased in the MSG-administered groups. There were significant (p < 0.05) changes in the hematological indices of the MSG-administered animals. Thus, the findings of this study suggest that high MSG consumption causes hematological alterations and may alter renal function via increased ROS production and dysregulation of the AQP-3 channel, prolactin, and oxytocin receptors in the kidneys of lactating Wistar rats. [ABSTRACT FROM AUTHOR]

Introduction: The social defeat paradigm is the most representative animal model to study social anxiety disorder (SAD) and its underlying neuronal mechanisms. We have previously reported that defeat progressively reduces oxytocin receptors (OXTR) in limbic regions of the brain over an eight-week period in female prairie voles (Microtus ochrogaster). Oxytocin receptors activate the mitogen-activated protein kinase (MAPK) pathway, which has been previously associated with the anxiolytic effects of oxytocin. Here, we assessed the functional significance of OXTR in stress-induced social avoidance and the response of the MAPK signaling pathway in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and basolateral amygdala (BLA) of female prairie voles. Methods: In experiment 1, Sexually naïve adult female prairie voles were defeated for three consecutive days and tested a week after for social preference/avoidance (SPA) test. Control subjects were similarly handled without defeat conditioning. In experiment 2, sexually and stress naïve adult female prairie voles were bilaterally injected into the NAc, ACC, or the BLA with a CRISPR/Cas9 virus targeting the Oxtr coding sequence to induce OXTR knockdown. Two weeks post-surgery, subjects were tested for SPA behavior. Viral control groups were similarly handled but injected with a control virus. A subgroup of animals from each condition in both experiments were similarly treated and euthanized without being tested for SPA behavior. Brains were harvested for OXTR autoradiography, western blot analysis of MAPK proteins and quantification of local oxytocin content in the NAc, BLA, ACC, and PVN through ELISA. Results: Social defeat reduced OXTR binding in the NAc and affected MAPK pathway activity and oxytocin availability. These results were region-specific and sensitive to exposure to the SPA test. Additionally, OXTR knockdown in the NAc, ACC, and BLA induced social avoidance and decreased basal MAPK activity in the NAc. Finally, we found that OXTR knockdown in these regions was associated with less availability of oxytocin in the PVN. Conclusion: Dysregulation of the oxytocin system and MAPK signaling pathway in the NAc, ACC, and BLA are important in social behavior disruptions in female voles. This dysregulation could, therefore, play an important role in the etiology of SAD in women. [ABSTRACT FROM AUTHOR]

In rodents, oxytocin (Oxt) contributes to the onset of maternal care by shifting the perception of pups from aversive to attractive. Both Oxt receptor knockout (Oxtr -/-) and forebrain-specific Oxtr knockout (FB/FB) dams abandon their first litters, likely due to a failure of the brain to 'switch' to a more maternal state. Whether this behavioral shift is neurochemically similar in virgin females, who can display maternal behaviors when repeatedly exposed to pups, or what neuroanatomical substrate is critical for the onset of maternal care remains unknown. To understand similarities and differences in Oxtr signaling in virgin pup-sensitized Oxtr FB/FB as opposed to post-parturient Oxtr -/- and Oxtr FB/FB dams, maternal behavior (pup-sensitized females only) and immediate early gene activation were assessed. Pup-sensitized Oxtr FB/FB females retrieved pups faster on day one of testing and had reduced c-Fos expression in the dorsal lateral septum as compared to virgin pup-sensitized Oxtr +/+ females. This differs from what was observed in post-parturient Oxtr -/- and Oxtr FB/FB dams, where increased c-Fos expression was observed in the nucleus accumbens (NAcc) shell. Based on these data, we then disrupted Oxtr signaling in the NAcc shell or the posterior paraventricular thalamus (pPVT) (control region) of female Oxtr floxed mice using a Cre recombinase expressing adenoassociated virus. Knockout of the Oxtr only in the NAcc shell prevented the onset of maternal care post-parturient females. Our data suggest that a pupsensitized brain may differ from a post-parturient brain and that Oxtr signaling in the NAcc shell is critical to the onset of maternal behavior. [ABSTRACT FROM AUTHOR]

Background: Dysfunctional uterine peristalsis seems to play a pivotal role in hindering embryo implantation among women diagnosed with adenomyosis. This research aims to investigate whether administering an oxytocin receptor antagonist during a frozen embryo transfer (FET) cycle using a hormone replacement therapy (HRT) protocol can enhance in vitro fertilization (IVF) outcomes for infertile women affected by adenomyosis. Methods: Between January 2018 and June 2022, our reproductive center conducted IVF-FET HRT cycles for infertile women diagnosed with adenomyosis. Propensity score matching was employed to select matched subjects between the two groups in a 1:1 ratio. Following this, 168 women received an oxytocin receptor antagonist during FET, constituting the study group, while the matched 168 women underwent FET without this antagonist, forming the control group. We conducted comparative analyses of baseline and cycle characteristics between the two groups, along with additional subgroup analyses. Results: The study group exhibited notably lower rates of early miscarriage compared to the control group, although there were no significant differences in clinical pregnancy rates, ongoing pregnancy rates, and live birth rates between the two groups. Multivariate analysis revealed a negative correlation between the use of oxytocin receptor antagonists and early miscarriage rates in women with adenomyosis. Subgroup analyses, categorized by age, infertility types, and embryo transfer day, showed a substantial decrease in early miscarriage rates within specific subgroups: women aged ≥ 37 years, those with secondary infertility, and individuals undergoing day 3 embryo transfers in the study group compared to the control group. Furthermore, subgroup analysis based on adenomyosis types indicated significantly higher clinical pregnancy rates, ongoing pregnancy rates and live birth rates in the study group compared to the control group among women with diffuse adenomyosis. Conclusions: Administering an oxytocin receptor antagonist during FET may reduce the early miscarriage rates in women with adenomyosis. [ABSTRACT FROM AUTHOR]

• Maternal obesity alters the neurological and behavioral phenotype in the offspring. • Treatment with cannabidiol rescues anxiety and social disturbances in the offspring. • Both perinatal maternal obesity and CBD present sexually dimorphic influences. • CBD modulates glial reactivity, oxytocin, glutamate and endocannabinoid signaling. Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system. [ABSTRACT FROM AUTHOR]

Simple Summary: Today, sows produce larger litter sizes than they did several years ago. Modern hyperprolific sows with greater parity numbers experience longer farrowing durations and require more farrowing assistance compared to those with lower parity numbers. Among reproductive hormones, oxytocin plays a critical role during parturition and is often given to sows during farrowing to shorten its duration. Oxytocin is a uterotonic hormone originating from the hypothalamus and released from the posterior pituitary gland, and it is important for the expulsion of fetuses. Aging is a well-known factor that affects productivity and increases farrowing duration in modern prolific sows. In the current study, we demonstrated a decrease in the immunolocalization of oxytocin receptors in the uterine tissue of older sows, supporting a previous study that showed weaker uterine contractions in sows with a greater parity number, which possibly affects the duration of farrowing. This study investigated the gross morphology of reproductive organs and oxytocin receptor distribution across different parities in hyperprolific sows. A total of thirty-two reproductive organs from Landrace × Yorkshire crossbred sows were categorized into three groups based on parity numbers: 1 (n = 10), 2–5 (n = 12), and ≥6 (n = 10). All sows were culled due to management problems, and none had reproductive disorders. A gross morphology examination of the ovaries, uterus, and the rest of the reproductive tract was conducted. Using immunohistochemistry, the levels of oxytocin receptor were evaluated in five layers of the uterus, the epithelial, superficial glandular, deep glandular, and circular and longitudinal smooth muscles of the myometrium, and were quantified using an H-score. On average, the age and body weight of sows and the total number of piglets born per litter were 799.8 ± 327.8 days, 213.2 ± 31.7 kg, and 15.5 ± 4.8, respectively. The numbers of ovulations in sows in parity number 1 (19.9 ± 2.4) were lower than those in sows in parity numbers 2–5 (29.7 ± 2.0, p = 0.004) and ≥6 (27.7 ± 2.1, p = 0.022). The uterine weights of sows in parity number 1 (902.9 ± 112.5 g) were lower than those of parity numbers 2–5 (1442.1 ± 111.8 g, p = 0.001) and ≥6 (1394.3 ± 125.1 g, p = 0.004). The length of the uterus in sows with parity number 1 (277.9 ± 26.1 cm) was shorter than those in sows with parity numbers 2–5 (354.6 ± 25.9 cm, p = 0.033) and tended to be shorter than those in sows with parity numbers ≥ 6 (346.6 ± 29.0 cm, p = 0.068). The immunolocalization of oxytocin receptors could be detected in various parts of the porcine endometrium and myometrium. Among the five tissue layers of the uterus, the H-score of oxytocin receptors in the deep uterine glands was greater than in the superficial uterine glands (p = 0.023) and the circular muscle layer of the myometrium (p = 0.011), but it did not differ from the epithelial layer of the endometrium (p = 0.428) or the longitudinal muscle layer of the myometrium (p = 0.081). Sows with parity numbers ≥ 6 had a lower oxytocin receptor H-score than those with parity numbers 1 (p < 0.001) and 2–5 (p < 0.001). In conclusion, these data emphasize the notable variations in several reproductive parameters and the levels of oxytocin receptor within the uterus of hyperprolific sows. Across the majority of uterine tissue layers, there was a marked decrease in the H-score of the oxytocin receptor in the older sows. [ABSTRACT FROM AUTHOR]

The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar inflammation induces social avoidance in mice. Oxytocin regulates social relationship and expression pattern of the oxytocin receptor in the brain is related to social behaviors. However, the expression patterns of the oxytocin receptor in the cerebellum remain controversial. Here, we report that the expression patterns of the oxytocin receptor in the cerebellum are highly variable among knock-in transgenic lines. We used Oxtr-Cre knock-in mice combined with a fluorescent reporter line and found that oxytocin receptor expression in Bergmann glia was more variable than that in Purkinje cells. We found that physical damage with inflammation induced the selective upregulation of the oxytocin receptor in Bergmann glia. Our findings indicate high variability in oxytocin receptor expression in the cerebellum and suggest that the oxytocin receptor can affect neural processing in pathological conditions, such as inflammation. [ABSTRACT FROM AUTHOR]

Arginine vasopressin (AVP) and oxytocin (OT) are well-known as neuropeptides that regulate various social behaviors in mammals. However, little is known about their role in mouse female sexual behavior. Thus, we investigated the role of AVP (v1a and v1b) and OT receptors on female sexual behavior. First, we devised a new apparatus, the bilevel chamber, to accurately observe female mouse sexual behavior. This apparatus allowed for a more precisely measurement of lordosis as receptivity and rejection-like behavior (newly defined in this study), a reversed expression of proceptivity. To address our research question, we evaluated female sexual behavior in mice lacking v1a (aKO), v1b (bKO), both v1a and v1b (dKO), and OT (OTRKO) receptors. aKO females showed decreased rejection-like behavior but a normal level of lordosis, whereas bKO females showed almost no lordosis and no change in rejection-like behavior. In addition, dKO females showed normal lordosis levels, suggesting that the v1b receptor promotes lordosis, but not necessarily, while the v1a receptor latently suppresses it. In contrast, although OTRKO did not influence lordosis, it significantly increased rejection-like behavior. In summary, the present results demonstrated that the v1a receptor inhibits proceptivity and receptivity, whereas the v1b and OT receptors facilitate receptivity and proceptivity, respectively. [ABSTRACT FROM AUTHOR]

Social buffering is the phenomenon in which the presence of an affiliative conspecific mitigates stress responses. We previously demonstrated that social buffering completely ameliorates conditioned fear responses in rats. However, the neuromodulators involved in social buffering are poorly understood. Given that opioids, dopamine, oxytocin and vasopressin play an important role in affiliative behaviour, here, we assessed the effects of the most well‐known antagonists, naloxone (opioid receptor antagonist), haloperidol (dopamine D2 receptor antagonist), atosiban (oxytocin receptor antagonist) and SR49059 (vasopressin V1a receptor antagonist), on social buffering. In Experiment 1, fear‐conditioned male subjects were intraperitoneally administered one of the four antagonists 25 min prior to exposure to a conditioned stimulus with an unfamiliar non‐conditioned rat. Naloxone, but not the other three antagonists, increased freezing and decreased walking and investigation as compared with saline administration. In Experiment 2, identical naloxone administration did not affect locomotor activity, anxiety‐like behaviour or freezing in an open‐field test. In Experiment 3, after confirming that the same naloxone administration again increased conditioned fear responses, as done in Experiment 1, we measured Fos expression in 16 brain regions. Compared with saline, naloxone increased Fos expression in the paraventricular nucleus of the hypothalamus and decreased Fos expression in the nucleus accumbens shell, anterior cingulate cortex and insular cortex and tended to decrease Fos expression in the nucleus accumbens core. Based on these results, we suggest that naloxone blocks social buffering of conditioned fear responses in male rats. [ABSTRACT FROM AUTHOR]

Epidemiological data suggest that moderate hyperoxemia may be associated with an improved outcome after traumatic brain injury. In a prospective, randomized investigation of long-term, resuscitated acute subdural hematoma plus hemorrhagic shock (ASDH + HS) in 14 adult, human-sized pigs, targeted hyperoxemia (200 < PaO2 < 250 mmHg vs. normoxemia 80 < PaO2 < 120 mmHg) coincided with improved neurological function. Since brain perfusion, oxygenation and metabolism did not differ, this post hoc study analyzed the available material for the effects of targeted hyperoxemia on cerebral tissue markers of oxidative/nitrosative stress (nitrotyrosine expression), blood–brain barrier integrity (extravascular albumin accumulation) and fluid homeostasis (oxytocin, its receptor and the H2S-producing enzymes cystathionine-β-synthase and cystathionine-γ-lyase). After 2 h of ASDH + HS (0.1 mL/kgBW autologous blood injected into the subdural space and passive removal of 30% of the blood volume), animals were resuscitated for up to 53 h by re-transfusion of shed blood, noradrenaline infusion to maintain cerebral perfusion pressure at baseline levels and hyper-/normoxemia during the first 24 h. Immediate postmortem, bi-hemispheric (i.e., blood-injected and contra-lateral) prefrontal cortex specimens from the base of the sulci underwent immunohistochemistry (% positive tissue staining) analysis of oxidative/nitrosative stress, blood–brain barrier integrity and fluid homeostasis. None of these tissue markers explained any differences in hyperoxemia-related neurological function. Likewise, hyperoxemia exerted no deleterious effects. [ABSTRACT FROM AUTHOR]

Objective: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)—a densely innervated tissue layer covering the calvarial skull—has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. Methods: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. Results: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model—an effect that was preventable by the administration of an OTR antagonist. Conclusion: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin. [ABSTRACT FROM AUTHOR]

Introduction: Dysfunctions in the oxytocin system have been reported in patients with borderline personality disorder (BPD). Deficits could be related to interpersonal hypersensitivity, which has been previously associated with failures in social cognition (SC) in this disorder, especially in Theory of Mind (ToM) skills. The aim of this work is to study the links between the oxytocin system and SC impairments in patients with BPD. Method: Plasma oxytocin levels (OXT) and protein expression of oxytocin receptors in blood mononuclear cells (OXTR) were examined in 33 patients with a diagnosis of BPD (age: M 28.85, DT = 8.83). Social cognition was assessed using the Movie for the Assessment of Social Cognition (MASC). Statistical associations between biochemical factors and different response errors in MASC were analyzed through generalized linear regression controlling for relevant clinical factors. Results: Generalized linear regression showed a significant relationship between lower OXTR and overmentalization in BPD patients (OR = 0.90). Conclusions: This work supports the relationship between alterations in the oxytocin system and ToM impairments observed in BPD patients, enhancing the search for endophenotypes related to the phenotypic features of the disorder to improve current clinical knowledge and address more specific therapeutic targets. [ABSTRACT FROM AUTHOR]

The article explores the role of oxytocin in regulating parental care and infanticidal behaviors in virgin mandarin voles. Oxytocin, known as the 'love hormone', influences social bonding and attachment. The study reveals that oxytocin projections from the paraventricular nucleus to the medial prefrontal cortex play a crucial role in promoting nurturing behaviors or aggressive responses towards pups, depending on the context and individual. The findings shed light on the neural circuits underlying parental and aggressive behaviors in mandarin voles, offering insights into potential sex-specific mechanisms and avenues for further research. [Extracted from the article]

Autism spectrum disorders (ASDs) are known to present sex-specific differences. At the same time, understanding how maternal behaviours are affected by pathogenic mutations is crucial to translate research efforts since rearing may recursively modulate neurodevelopment phenotype of the progeny. In this work, we focused on the effects of Gprasp2 deletion in females and its impact in progeny care and development. Female mice, wild-type (WT), Gprasp2+/− (HET) or Gprasp2−/− (KO) mutants and their progeny were used and behavioural paradigms targeting anxiety, memory, maternal care, and other social behaviours were performed. Analysis of communication was carried out through daily recordings of ultrasonic vocalizations in isolated pups and cross-fostering experiments were performed to understand the effect of maternal genotype in pup development. We found that Gprasp2−/− females presented striking impairments in social and working memory. Females also showed disruptions in maternal care, as well as physiological and molecular alterations in the reproductive system and hypothalamus, such as the structure of the mammary gland and the expression levels of oxytocin receptor (OxtR) in nulliparous versus primiparous females. We observed alterations in pup communication, particularly a reduced number of calls in Gprasp2 KO pups, which resulted from an interaction effect of the dam and pup genotype. Cross-fostering mutant pups with wild-type dams rescued some of the early defects shown in vocalizations, however, this effect was not bidirectional, as rearing WT pups with Gprasp2−/− dams was not sufficient to induce significant phenotypical alterations. Our results suggest Gprasp2 mutations perturb social and working memory in a sex-independent manner, but impact female-specific behaviours towards progeny care, female physiology, and gene expression. These changes in mutant dams contribute to a disruption in early stages of progeny development. More generally, our results highlight the need to better understand GxE interactions in the context of ASDs, when female behaviour may present a contributing factor in postnatal neurodevelopmental trajectory. [ABSTRACT FROM AUTHOR]

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decisionmaking network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior. [ABSTRACT FROM AUTHOR]

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m² or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner. [ABSTRACT FROM AUTHOR]

Although previous research has established a link between the variant rs53576 of the oxytocin receptor gene (OXTR) and social behaviors, our understanding of its long-term impact on mental health from early childhood to adolescence remains limited. This study aimed to explore the potential link between children's involvement in recreational activities with parents during early childhood, their OXTR rs53576 genotype, and the subsequent development of psychopathology. It involved gathering data during three different stages: early childhood (T1), middle childhood (T2), and adolescence (T3). During T1, the parents of 144 Chinese participants aged 4 to 6 years (48.6% boys) completed a scale on frequency of parent-child recreational activities. Three years later (T2), parents were re-surveyed about the participant's conduct problems, which was assessed using the Strength and Difficulties Questionnaire. Seven years later (T3), the participants completed the Depression scale of the Depression Anxiety and Stress Scale – 21 to evaluate their levels of depressive symptoms. Additionally, buccal swab samples were collected and genotyped for OXTR rs53576. OXTR rs53576 genotypes were found to interact with the frequency of parent-child recreational activities to predict future conduct problems (β=-1.38, p = 0.028). Increased conduct problems were in turn associated with a higher level of subsequent depressive symptoms during adolescence (r = 0.22, p < 0.05). Engaging in recreational activities with parents during early childhood is important for the overall well-being of children, particularly for those who demonstrate a tendency of being sociable. Early childhood interventions should educate and assist parents in designing unstructured play based on their young children's sociability. [ABSTRACT FROM AUTHOR]

Social isolation is a state of lack of social connections, involving the modulation of different molecular signalling cascades and associated with high risk of mental health issues. To investigate if and how gene expression is modulated by social experience at the central level, we analyzed the effects of 5 weeks of social isolation in rats focusing on endocannabinoid system genes transcription in key brain regions involved in emotional control. We observed selective reduction in mRNA levels for fatty acid amide hydrolase (Faah) and cannabinoid receptor type 1 (Cnr1) genes in the amygdala complex and of Cnr1 in the prefrontal cortex of socially isolated rats when compared to controls, and these changes appear to be partially driven by trimethylation of Lysine 27 and acetylation of Lysine 9 at Histone 3. The alterations of Cnr1 transcriptional regulation result also directly correlated with those of oxytocin receptor gene. We here suggest that to counteract the effects of SI, it is of relevance to restore the endocannabinoid system homeostasis via the use of environmental triggers able to revert those epigenetic mechanisms accounting for the alterations observed. [ABSTRACT FROM AUTHOR]

Antibodies are one of the most utilized tools in biomedical research. However, few of them are rigorously evaluated, as there are no accepted guidelines or standardized methods for determining their validity before commercialization. Often, an antibody is considered validated if it detects a band by Western blot of the expected molecular weight and, in some cases, if blocking peptides result in loss of staining. Neither of these approaches are unquestionable proof of target specificity. Since the oxytocin receptor has recently become a popular target in neuropsychiatric research, the need for specific antibodies to be used in brain has arisen. In this work, we have tested the specificity of six commercially available oxytocin receptor antibodies, indicated by the manufacturers to be suitable for Western blot and with an available image showing the correct size band (45-55 KDa). Antibodies were first tested by Western blot in brain lysates of wild-type and oxytocin receptor knockout mice. Uterus tissue was also tested as control for putative differential tissue specificity. In brain, the six tested antibodies lacked target specificity, as both wild-type and receptor knockout samples resulted in a similar staining pattern, including the expected 45-55 KDa band. Five of the six antibodies detected a selective band in uterus (which disappeared in knockout tissue). These five specific antibodies were also tested for immunohistochemistry in uterus, where only one was specific. However, when the uterine-specific antibody was tested in brain tissue, it lacked specificity. In conclusion, none of the six tested commercial antibodies are suitable to detect oxytocin receptor in brain by either Western blot or immunohistochemistry, although some do specifically detect it in uterus. The present work highlights the need to develop standardized antibody validation methods, including a proper negative control, in order to grant quality and reproducibility of the generated data. [ABSTRACT FROM AUTHOR]

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway. [ABSTRACT FROM AUTHOR]

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue. A study on the evolution of the oxytocin system illustrates the varied role of this neuropeptide in physiology and behavior [ABSTRACT FROM AUTHOR]

Pregnancy and delivery are physiological conditions that are marked by abrupt alterations to hormones, immunological and molecular characters. The current study aimed to evaluate oxytocin (OT), prolactin (PRL), cortisol and insulin growth factor-2 (IGF-2) levels as physiological biomarkers; programmed cell death protein1 (PD-1), programmed cell death ligand-1 (PD-L1),interleukin-6 (IL-6) as immunological biomarkers, and single nucleotide polymorphisms (SNPs; rs53576 and rs2254298) of oxytocin receptor gene OXTR as molecular factors in samples of Iraqi women undergoing caesarean section (CS) and normal delivery (ND). Blood samples were collected from 96 pregnant women at term with ages ranging between 16-43 years. Regarding the physiological biomarkers, the study findings indicated that the change in OT, cortisol and IGF-2 between CS and ND groups was not significant, While the PRL level indicated a highly significant (P≤0.001) decrease in the CS group, especially in comparison with the ND group. Immunological biomarkers demonstrated a significant (P≤05) elevation for PD-1 as well as for PDL1 in the CS group as compared to the ND group. However, PD-1/PD-L1 ratio revealed a high significant (P≤0.001) rise in CS compared with ND. The IL-6 results revealed a significant (P≤0.001) reduction in the CS groups compared to the ND group. And regarding the SNP of OXTR (rs53576), the findings revealed no notable association in genotypes CC, TC and TT between both groups. In addition, the mutant C allele and the wild T allele revealed no significant association between CS and ND groups [OR=1.26 (0.68-2.3%)]. The SNP results of OXTR (rs2254298) showed a high positive association (P≤0.001) in genotypes GG, AG and AA between CS and ND groups. Also, the mutant G allele and the wild A allele revealed high significance (P≤0.001) between both groups [OR=5.3 (2.8-9.76%)]. [ABSTRACT FROM AUTHOR]

How couples communicate during conflict interactions can have important implications for their relational well-being. The theory of resilience and relational load provides a valuable lens for exploring the associations among couples' language use during conflict conversations and the extent to which such conversations are perceived as threatening to one's relationship, as well as whether genetic markers moderate such associations. Forty-seven mixed-sex couples had a conversation about a topic causing conflict in their relationship and provided saliva samples that were tested for their genotype (GG, AA, or AG) for oxytocin receptor gene rs53576. The results revealed that neither the use of communal language nor positive emotion words were associated with perceiving the conversation as less threatening to their relationship. Genetic variation did not moderate the associations with either positive emotion word use or communal language. However, a three-way interaction between sex, OXTR, and positive emotion word use emerged in the post hoc analyses, indicating that positive emotion word use was negatively associated with threat appraisals for women with a GG genotype, and positively associated with threat appraisals for men with a GG genotype. Implications for mixed-sex couples' communication and research on language use during conflict conversations are discussed. [ABSTRACT FROM AUTHOR]

Chronic exposure to trauma and violence can promote aggressive behavior. Oxytocin and variants in the oxytocin receptor (OXTR) gene may play a role in the etiology of proactive, that is, goal‐oriented instrumental aggression, or reactive aggression, which typically occurs in response to emotionally triggering situations. The current study builds on previous findings that experienced and witnessed trauma in childhood predicts higher levels of appetitive aggression, a form of proactive aggression characterized by the enjoyment of participating in violent behavior. The current study explores the role of OXTR rs2254298 and rs53576 variants in appetitive and reactive aggression. Adult males living in Cape Town, South Africa, and at risk for violent behavior completed the Appetitive Aggression Scale (AAS) and Buss–Perry Aggression Questionnaire (BPAQ). OXTR rs2254298 and rs53576 were successfully genotyped via restriction fragment length polymorphism (RFLP) analysis in 238 and 239 participants, respectively. Regression analysis showed that rs2254298 G/G and A/G genotypes and the rs53576 A/G genotype were significantly associated with lower AAS scores (p <.001) compared to the A/A genotype. Additionally, genotype interaction analyses conducted in 232 participants, found that the combination of rs2254298 A/G and rs53576 G/G genotypes produced opposite effects on appetitive and reactive aggression. Specifically, this combination was associated with a 0.29‐point increase in AAS scores (p =.032) and a 0.13‐point decrease in BPAQ scores (p =.037) when compared to A‐allele homozygosity for both variants. These results suggest that genetic variation in a signaling system involved in influencing environmental and social salience may contribute to appetitive aggression. [ABSTRACT FROM AUTHOR]

The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the "metabolic syndrome". We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing. [ABSTRACT FROM AUTHOR]

It is known that the neurohormone oxytocin plays an important role in the pathogenesis of mental illness and also models the relationship between stress factors, especially those acting in the early stages of development, and the development of mental disorders. On the basis of these data, we investigated the effects of the interaction of the environmental factor, in the capacity of which the childhood adversity (CA) and the oxytocin receptor (OXTR) genotypes in the polymorphic sites rs4686302 and rs7632287 were considered, on the severity of negative symptoms of schizophrenia. The study involved 592 patients with schizophrenia (code F20, according to ICD-10). Information about the presence of CA was obtained from case histories and patient interviews. Analysis of covariance (GML) was used for statistical data processing; in post hoc pairwise comparison, Tukey's test was used. A significant effect of the interaction between CA and OXTR gene polymorphism rs7632287 (G/A) on the severity of negative symptoms in patients with schizophrenia was revealed. In patients without CA, polymorphisms did not have a significant effect on the studied phenotype. Thus, our study showed for the first time that the rs7632287 (G/A) polymorphism and CA have a mutual effect on the severity of negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Overactive bladder (OAB) is an age-related disorder characterised by unstable bladder contractions resulting in disruptive lower urinary tract symptoms (LUTS), thus creating a profound impact on an individual's quality of life. The development of LUTS may be linked to the overexpression of oxytocin receptors (OXTRs) within the bladder detrusor muscle, resulting in increased baseline myogenic tone. Thus, it is hypothesised that targeting OXTRs within the bladder using oxytocin antagonists may attenuate myogenic tone within the bladder, thereby providing a new therapeutic avenue for treating OAB. Organ bath contractility and immunohistochemistry techniques were conducted on bladder tissue sourced from young rats (7–8 weeks and 10–12 weeks) and older rats (4–5 months and 7–9 months). Organ bath studies revealed that oxytocin (OT) significantly increased bladder contractions, which were significantly attenuated by [β-Mercapto-β,β-cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]-Oxytocin) (1 µM) (**** p < 0.0001) and atosiban (10 µM) in both young and older rats (** p < 0.01); in contrast, cligosiban (1 µM and 10 µM) did not inhibit OT-induced contractions in both young and older rats (p ≥ 0.05). Interestingly, cligosiban (1 µM and 10 µM) significantly reduced the frequency of spontaneous contractions within the bladder of both young (*** p < 0.001) and older rats (**** p < 0.0001), while atosiban (10 µM) only demonstrated this effect in older rats (** p < 0.01). Furthermore, immunohistochemistry (IHC) analysis revealed significant colocalization of nuclear-specific oxytocin receptors (OXTRs) in the contractile (smooth muscle) cells within young (** p < 0.01) and older rats (* p < 0.05), indicating OT may be a key modulator of bladder contractility. [ABSTRACT FROM AUTHOR]

Considerable global demand exists for the development of novel drugs for the treatment of alopecia. A recent report demonstrated that oxytocin promotes hair growth activity in human dermal papilla (DP) cells; however, its application in drugs or cosmetic products is challenging because rapid degradation and relatively large molecular weight prevent long-term topical administration on the scalp. Here, we examined cinnamic acid, a small molecule activator for oxytocin receptor (OXTR) expression. Treatment with cinnamic acid led to upregulation of OXTR and trichogenic gene expression in human DP cells. Furthermore, inhibition of OXTR with an antagonist, L-371,257, suppressed hair growth-related gene expression in DP cells. These findings suggest that cinnamic acid enhances the hair growth ability of DP cells via oxytocin signaling. Additionally, we tested the hair growth-promoting effects of cinnamic acid using hair follicle organoids in vitro and observed that cinnamic acid significantly promoted the growth of hair peg-like sprouting. These promising results may be useful for developing hair growth-promoting products targeting oxytocin. [ABSTRACT FROM AUTHOR]