Oxytocin Expression Research Articles

The effect of macrophage polarization on the expression of the oxytocin signalling system in enteric neurons

BackgroundThe aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons.MethodsIn this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages.ResultsThe data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1β, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-β) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type.ConclusionsThis is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

Population variation alters aggression-associated oxytocin and vasopressin expressions in brains of Brandt\u2019s voles in field conditions

Density-dependent change in aggressive behavior contributes to the population regulation of many small rodents, but the underlying neurological mechanisms have not been examined in field conditions. We hypothesized that crowding stress and aggression-associated oxytocin (OT) and arginine vasopressin (AVP) in specific regions of the brain may be closely related to aggressive behaviors and population changes of small rodents. We analyzed the association of OT and AVP expression, aggressive behavior, and population density of Brandt’s voles in 24 large semi-natural enclosures (0.48 ha each) in Inner Mongolia grassland. We tested the effects of population density on the OT/AVP system and aggressive behavior by experimentally manipulating populations of Brandt’s voles in the grassland enclosures. High density was positively and significantly associated with more aggressive behavior, and increased expression of mRNA and protein of AVP and its receptor, but decreased expression of mRNA and protein of OT and its receptor in specific brain regions of the voles. Our study suggests that changes in OT/AVP expression are likely a result of the increased psychosocial stress that these voles experience during overcrowding, and thus the OT/AVP system can be used as indicators of density-dependent stressors in Brandt’s voles.

Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats.

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

The effects of P. atlantica as a libido booster and sexual enhancer on the reproductive system of male rats

Background and aimAlongside the advancement of various modern treatments, attention has recently been focused on finding alternative infertility treatments based on diet and herbal medicine. Pistacia atlantica (wild pistachio; Baneh) is a plant species traditionally known as a libido booster and sexual enhancer. Experimental procedureThe study aim was to evaluate the effects of a P. atlantica-enriched diet on the functions of the reproductive system of male rats. Results and conclusionResults revealed that the diet containing 20% P. atlantica doubled testosterone levels in the treatment group compared to the control. It decreased the total bodyweight, while significantly increased the ratios of the seminal vesicles, testis, and epididymis to the bodyweight of rats. The sperm count in the treatment group was 4.8 × 106/mL, which was significantly more than the control group (4.2 × 106/mL). Furthermore, the utilization of P. atlantica significantly raised HDL levels, though it reduced the LDL and TG levels and the concentration of testis MDA. Concerning other factors, the 20% of P. atlantica considerably increased the serum level of Zinc and vitamin D. Histomorphometric analysis revealed that the diet increased the testicular capsule thickness, whereas it did not cause any significant change in the diameter of the seminiferous tubule, the number of Leydig cells, and Sertoli cells. Additionally, the repopulation index, tubular differentiation index, and spermiogenesis index increased in the treatment group. Molecular analysis showed that the prescribed diet increased the expression of both oxytocin (OXT) and its receptor (OXTR) genes, improving the reproductive system function.

Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats.

Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a "two-hit" stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.

The Effect of Oxytocin on Intracellular Ca2+ Release in Cardiac Cells.

Ca2+ signaling is vital for the proper functioning of all cells, including cells of the cardiovascular system. Membrane receptors for many hormones trigger intracellular Ca2+ signaling via the activation of phospholipase C and production of inositol-1,4,5-trisphosphate (InsP3). Several research groups have demonstrated the expression of oxytocin (OXT) and oxytocin receptors (OXTR) in the heart and suggested a cardioprotective role of OXT against several pathological conditions. Here we describe the protocol for measuring the effects of oxytocin on intracellular Ca2+ dynamics in newborn rat cardiac myocytes and cardiac fibroblasts maintained in short-term culture.

Support for the parental practice hypothesis: Subadult prairie voles exhibit similar behavioral and neural profiles when alloparenting kin and non-kin

Parental care is critical for offspring survival in altricial species. Although parents are the most common caregivers, other individuals (e.g., older siblings) can also provide alloparental care. Some have argued that animals engage in alloparental behavior to practice providing care for their eventual offspring, whereas others have argued that alloparental behavior enhances indirect fitness. Proximate measures have the potential to test ultimate functions of behavior. A focus on neural expression of oxytocin and vasopressin (two neuropeptides modulating alloparental care) or neural activation following exposure to related and unrelated individuals could reveal whether practice or investment in indirect fitness explains alloparental behavior. This study examined alloparental behaviors and neural responses in prairie voles (Microtus ochrogaster), a species that engages in alloparental behavior. Subadult (independent, yet sexually immature) male prairie voles were exposed to one of four stimuli: same-age sibling, neonatal sibling, unrelated neonate, or inanimate neonate-sized object. We assessed alloparental behaviors and quantified cFos protein expression in oxytocin and vasopressin neuronal populations of the paraventricular nucleus of the hypothalamus and the supraoptic nucleus of the hypothalamus in response to stimulus exposure. We detected no differences in cFos and nonapeptide co-localization among stimulus groups. Subjects performed similar amounts of alloparental care toward related and unrelated neonates, but not other subadults or inanimate objects. Notably, caregiving did not differ based on kin-status. The lack of difference in alloparenting toward related and non-related neonates suggests that alloparental care in prairie voles primarily serves to provide subadults with parental practice.

Vasopressin and oxytocin expression in hypothalamic supraoptic nucleus and plasma electrolytes changes in water-deprived male Meriones libycus

ABSTRACT In mammals, plasmatic osmolality needs to be stable, and it is highly related to the hydric state of the animals which depends on the activity of the hypothalamic neurohypophysial system and more particularly by vasopressin secretion. Meriones, a desert rodent, can survive even without drinking for more than one month. The mechanism(s) by which they survive under these conditions remains poorly understood. In this study, we examine the water’s deprivation consequences on the: (1) anatomy, morphology, and physiology of the hypothalamic supraoptic nucleus, (2) body mass and plasma electrolytes changes in male desert rodents ‘Meriones libycus’ subjected to water deprivation for 30 days. The effect of water deprivation was evaluated on the structural and cellular organization of the supraoptic nucleus by morphological observations and immunohistochemical approaches, allowing the labeling of AVP but also oxytocin. Our finding demonstrated that upon water deprivation (1) the body weight decreased and reached a plateau after a month of water restriction. (2) The plasmatic osmolality began to decrease and return to values similar to control animals at day 30. (3) The SON, both in hydrated and water-deprived animals, is highly developed.(4) The AVP labeling in the SON increased upon dehydration at variance with OT. These changes observed in body mass and plasma osmolality reveal an important adaptive process of male Meriones in response to prolonged water deprivation. Overall, this animal represents an interesting model for the study of water body homeostasis and the mechanisms underlying the survival of desert rodents to xeric environments.

Interactive effects of compounding multidimensional stressors on maternal and male and female rat offspring outcomes

Exposure to adverse childhood experiences (ACEs) is a risk factor for the development of psychiatric disorders in addition to cardiovascular associated diseases. This risk is elevated when the cumulative burden of ACEs is increased. Laboratory animals can be used to model the changes (as well as the underlying mechanisms) that result in response to adverse events. In this study, using male and female Sprague Dawley rats, we examined the impact of increasing stress burden, utilizing both two adverse early life experiences (parental/offspring high fat diet + limited bedding exposure) and three adverse early life experiences (parental/offspring high fat diet + limited bedding exposure + neonatal inflammation), on maternal care quality and offspring behavior. Additionally, we measured hormones and hippocampal gene expression related to stress. We found that the adverse perinatal environment led to a compensatory increase in maternal care. Moreover, these dams had reduced maternal expression of oxytocin receptor, compared to standard housed dams, in response to acute stress on postnatal day (P)22. In offspring, the two-hit and three-hit models resulted in a hyperlocomotor phenotype and increased body weights. Plasma leptin and hippocampal gene expression of corticotropin releasing hormone (Chrh)1 and Crhr2 were elevated (males) while expression of oxytocin was reduced (females) following acute stress. On some measures (e.g., hyperlocomotion, leptin), the magnitude of change was lower in the three-hit compared to the two-hit model. This suggests that multiple early adverse events can have interactive, and often unpredictable, impacts, highlighting the importance of modeling complex interactions amongst stressors during development.

HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus

Many persons infected with HIV-1 (PWH) and opioid-dependent individuals experience deficits in sociability that interfere with daily living. Sociability is regulated by the prefrontal cortico-hippocampal-amygdalar circuit. Within this circuit HIV-1 trans-activator of transcription (HIV-1 Tat) and opioids can increase dendritic pathology and alter neuronal firing. Changes in sociability are also associated with dysregulation of hypothalamic neuropeptides such as oxytocin or corticotropin releasing factor (CRF) in the prefrontal cortico-hippocampal-amygdalar circuit. Accordingly, we hypothesized that the interaction of HIV-1 Tat and morphine would impair inter-male social interactions and disrupt oxytocin and CRF within the PFC and associated circuitry. Male mice were exposed to HIV-1 Tat for 8 weeks and administered saline or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of HIV-1 Tat exposure. Tat attenuated aggressive interactions with an unknown intruder, whereas morphine decreased both non-aggressive and aggressive social interactions in the resident-intruder test. However, there was no effect of Tat or morphine on non-reciprocal interactions in the social interaction and novelty tests. Tat, but not morphine, decreased oxytocin levels in the PFC and amygdala, whereas both Tat and morphine decreased the percentage of oxytocin-immunoreactive neurons in the hypothalamic paraventricular nucleus (PVN). In Tat(+) or morphine-exposed mice, regional levels of CRF and oxytocin correlated with alterations in behavior in the social interaction and novelty tests. Overall, decreased expression of oxytocin in the prefrontal cortico-hippocampal-amygdalar circuit is associated with morphine- and HIV-Tat-induced deficits in social behavior.

Oxytocin Regulates Synaptic Transmission in the Sensory Cortices in a Developmentally Dynamic Manner.

The development and stabilization of neuronal circuits are critical to proper brain function. Synapses are the building blocks of neural circuits. Here we examine the effects of the neuropeptide oxytocin on synaptic transmission in L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). We find that perfusion of oxytocin onto acute brain slices significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSC) of S1BF L2/3 pyramidal neurons at P10 and P14, but reduces it at the later ages of P22 and P28; the transition occurs at around P18. Since oxytocin expression is itself regulated by sensory experience, we also examine whether the effects of oxytocin on excitatory synaptic transmission correlate with that of sensory experience. We find that, indeed, the effects of sensory experience and oxytocin on excitatory synaptic transmission of L2/3 pyramidal neurons both peak at around P14 and plateau around P18, suggesting that they regulate a specific form of synaptic plasticity in L2/3 pyramidal neurons, with a sensitive/critical period ending around P18. Consistently, oxytocin receptor (Oxtr) expression in glutamatergic neurons of the upper layers of the cerebral cortex peaks around P14. By P28, however, Oxtr expression becomes more prominent in GABAergic neurons, especially somatostatin (SST) neurons. At P28, oxytocin perfusion increases inhibitory synaptic transmission and reduces excitatory synaptic transmission, effects that result in a net reduction of neuronal excitation, in contrast to increased excitation at P14. Using oxytocin knockout mice and Oxtr conditional knockout mice, we show that loss-of-function of oxytocin affects baseline excitatory synaptic transmission, while Oxtr is required for oxytocin-induced changes in excitatory synaptic transmission, at both P14 and P28. Together, these results demonstrate that oxytocin has complex and dynamic functions in regulating synaptic transmission in cortical L2/3 pyramidal neurons. These findings add to existing knowledge of the function of oxytocin in regulating neural circuit development and plasticity.

Effects of gonadal status and the estrogen milieu on hypothalamic oxytocin gene expression and serum oxytocin levels in female rats

Oxytocin (OT) and its receptor (OTR) play various roles in the central and peripheral regulation of appetite and body weight. Previously, we have shown that the administration of OT markedly decreased appetite and body weight gain in ovariectomized (OVX) obese rats. In addition, recent studies have shown that the endogenous OT system is also affected by endogenous or exogenous estrogen. In this study, we showed that ovariectomy decreased rats' hypothalamic OT/OTR mRNA and serum OT levels, but did not affect their visceral fat OTR mRNA levels. The chronic administration of estradiol (E2) abrogated these ovariectomy-induced changes; i.e., it increased the rats' hypothalamic OT/OTR mRNA and serum OT levels, and may be associated with reductions in food intake and body weight gain. In addition, acute E2 administration increased the rats' hypothalamic OTR mRNA and serum OT levels, but did not affect their hypothalamic OT mRNA levels. Taken together, these results suggest that endogenous OT and/or OTR expression might be positively regulated by E2 and that the suppressive effects of E2 on appetite and body weight gain might be mediated, at least in part, by the OT system. Thus, we consider that OT might be a target hormone to pursue subsequent interventions of menopause for menopause-induced metabolic disorders.

Oxytocin excites BNST interneurons and inhibits BNST output neurons to the central amygdala

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear. However, the role of OTR in the modulation of BNSTDL activity remains elusive. BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties into three types. Using in vitro patch-clamp recordings in male rats, we demonstrate that OT selectively excites and increases spontaneous firing rate of Type I BNSTDL neurons. As a consequence, OT increases the frequency, but not amplitude, of spontaneous inhibitory post-synaptic currents (sIPSCs) selectively in Type II neurons, an effect abolished by OTR antagonist or tetrodotoxin, and reduces spontaneous firing rate in these neurons. These results suggest an indirect effect of OT in Type II neurons, which is mediated via OT-induced increase in firing of Type I interneurons. As Type II BNSTDL neurons were shown projecting to the central amygdala (CeA), we also recorded from retrogradely labeled BNST→CeA neurons and we show that OT increases the frequency of sIPSC in these Type II BNST→CeA output neurons. In contrast, in Type III neurons, OT reduces the amplitude, but not frequency, of both sIPSCs and evoked IPSCs via a postsynaptic mechanism without changing their intrinsic excitability. We present a model of fine-tuned modulation of BNSTDL activity by OT, which selectively excites BNSTDL interneurons and inhibits Type II BNST→CeA output neurons. These results suggest that OTR in the BNST might facilitate cued fear by inhibiting the BNST→CeA neurons.

Oxytocin receptor is a potential biomarker of the hyporesponsive HPA axis subtype of PTSD and might be modulated by HPA axis reactivity traits in humans and mice

This study aimed to identify yet unavailable blood biomarkers for the responsive and the hyporesponsive hypothalamic-pituitary-adrenal (HPA) axis subtypes of posttraumatic stress disorder (PTSD). As, I, we recently discovered the intranasal neuropeptide oxytocin to reduce experimentally provoked PTSD symptoms, II, expression of its receptor (OXTR) has hitherto not been assessed in PTSD patients, and III, oxytocin and OXTR have previously been related to the HPA axis, we considered both as suitable candidates. During a Trier Social Stress Test (TSST), we compared serum oxytocin and blood OXTR mRNA concentrations between female PTSD patients, their HPA axis reactivity subtypes and sex and age-matched healthy controls (HC). At baseline, both candidates differentiated the hyporesponsive HPA axis subtype from HC, however, only baseline OXTR mRNA discriminated also between subtypes. Furthermore, in the hyporesponsive HPA axis subgroup, OXTR mRNA levels correlated with PTSD symptoms and changed markedly during the TSST. To assess the influence of (traumatic) stress on the cerebral expression of oxytocin and its receptor and to test their suitability as biomarkers for the mouse PTSD-like syndrome, we then analyzed oxytocin, its mRNA (Oxt) and Oxtr mRNA in three relevant brain regions and Oxt in blood of a PTSD mouse model. To further explore the HPA axis reactivity subtype dependency of OXTR, we compared cerebral OXTR protein expression between mice exhibiting two different HPA axis reactivity traits, i.e., FK506 binding protein 51 knockout vs. wildtype mice. In summary, blood OXTR mRNA emerged as a potential biomarker of the hyporesponsive HPA axis PTSD subtype and prefrontal cortical Oxtr and Oxt of the mouse PTSD-like syndrome. Moreover, we found first translational evidence for a HPA axis responsivity trait-dependent regulation of OXTR expression. The lack of a cohort of the (relatively rare) hyporesponsive HPA axis subtype of HC is a limitation of our study.

Temporal Profiling of Molecular Alterations in the Hypothalamic Paraventricular Nucleus During Angiotensin‐II Hypertension

The hypothalamic paraventricular nucleus (PVN) plays a central role in cardiovascular regulation including hypertension development in response to elevations in angiotensin-II (Ang-II). Upstream circumventricular nuclei located outside of the blood-brain-barrier sense circulating Ang-II and influence PVN endocrine and autonomic regulation via efferent synaptic projections. Despite progress in unraveling the function of circumventricular-PVN networks in neurogenic hypertension development, the underlying PVN mechanisms responsible for hypertension development remain unclear. In particular, most investigations have examined PVN alterations during established hypertension, which limits insight into molecular changes that may occur prior to hypertension development. Based on this, we performed a detailed temporal profiling of key molecular targets in the PVN during Ang-II hypertension progression. Male C57Bl/6J mice were implanted with subcutaneous osmotic minipumps for chronic delivery of low dose Ang-II (600 ng/kg/min). Brains were harvested for immunohistochemistry analysis of target molecules across rostral to caudal subregions of the PVN (n=3-4/group) at baseline (day 0), pre-hypertensive (days 3 and 7), and established-hypertension (day 14) timepoints. Previous work has suggested a role for arginine vasopressin (AVP) in Ang-II-induced hypertension. In line with this, AVP immunoreactivity in the PVN was elevated within 3 days of Ang-II infusion; this was evident only in the caudal PVN (day 3 fold change: 2.5±0.2, density/cell, p<0.05), whereas AVP expression in the rostral and medial portions was unchanged. Interestingly, caudal AVP immunoreactivity returned to basal levels by day 7 and remained low for the remainder of the protocol. In contrast to AVP, oxytocin expression was unchanged across the rostral to caudal PVN during 2-week Ang-II hypertension development. We also measured preproenkephalin (PPE) immunoreactivity, and found a progressive increase throughout the entire PVN with elevations initiated at pre-hypertensive times (day 7 fold change: 2.0±0.1, density/area, p=0.08) that were sustained during established hypertension (day 14 fold change: 2.6±0.3, density/area, p<0.05). To test possible involvement of the arcuate nucleus, which transmits circulating information from the median eminence to the PVN, in Ang-II hypertension, we measured alpha-melanocortin stimulating hormone (alpha-MSH) levels. Histological analysis for alpha-MSH immunoreactivity in the PVN, as an indicator of synaptic innervation strength from arcuate nucleus proopiomelanocortin neurons, revealed no changes during Ang-II infusion. Collectively, these findings indicate elevations in PVN AVP and PPE, but not oxytocin and alpha-MSH, in response to elevations in circulating Ang-II. Furthermore, the temporal responses suggest that different PVN molecules may be responsible for the initiation (e.g. AVP) versus maintenance (e.g. PPE) of Ang-II hypertension.

Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury.

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the OXT receptor (OXTR) mRNAs in the hypothalamus and mPFC, respectively, intranasal administration of OXT before behavioral testing was found to reduce impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals. These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits.

Oxytocin antagonist induced visceral pain and corticotropin-releasing hormone neuronal activation in the central nucleus of the amygdala during colorectal distention in mice

Activation of neurons containing oxytocin and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, the anterior cingulate cortex (ACC), and the central nucleus of the amygdala (CeA) during colorectal distention (CRD) is likely to play a crucial role in animal models of irritable bowel syndrome (IBS). Earlier studies in rodents showed that the microbiome is involved in social behavior via oxytocin expression in the brain. However, the detailed mechanism of visceral sensation and oxytocin is largely unknown. We tested the following hypotheses: (1) that oxytocin neurons in the PVN are activated by CRD, and (2) that the activation of oxytocin neurons by CRD is related to anxiety-like behavior, visceral perception, and an activation of CRH CeA neurons or ACC neurons. Oxytocin antagonist caused visceral hypersensitivity and anxiety-like behavior. In the PVN, oxytocin neurons were activated by CRD. Noxious CRD activated the CeA, basolateral nucleus of the amygdala (BLA), and ACC. High-dose oxytocin antagonist suppressed ACC activity and activated CRH CeA neurons. These results support our hypotheses. Oxytocin likely regulates CRH CeA neurons in an inhibitory manner and the ACC in an excitatory manner. Further research into the interaction of oxytocin and CRH in visceral pain and anxiety is warranted.

Oxytocin Receptors Inhibit Output Neurons of the Bed Nucleus of the Stria Terminalis (BNST) and Promote Fear Responses to Predictable Threats

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear measured in the fear-potentiated startle. However, the mechanisms of these OT effects in the BNSTDL remain elusive.

Maternal Exposure to Dibutyl Phthalate (DBP) or Diethylstilbestrol (DES) Leads to Long-Term Changes in Hypothalamic Gene Expression and Sexual Behavior.

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8–12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.

Identification of peripheral oxytocin-expressing cells using systemically applied cell-type specific adeno-associated viral vector.

Oxytocin is primarily synthesised in the brain and is widely known for its role in lactation and parturition after being released into the blood from the posterior pituitary gland. Nevertheless, peripheral tissues have also been reported to express oxytocin. Using systemic injection of a recombinant adeno-associated virus vector, we investigated the expression of the green fluorescent protein Venus under the control of the oxytocin promoter in the gastrointestinal tract, pancreas and testes of adult rats. Here, we confirm that the vector infects oxytocin neurones of the enteric nervous system in ganglia of the myenteric and submucosal plexuses. Venus was detected in 25%-60% of the ganglia in the myenteric and submucosal plexuses identified by co-staining with the neuronal marker PGP9.5. Oxytocin expression was also detected in the islets of Langerhans in the pancreas and the Leydig cells of the testes. Our data illustrate that peripheral administration of the viral vector represents a powerful method for selectively labelling oxytocin-producing cells outside the brain.