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During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.
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Ocitocina , Células Ganglionares da Retina , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/metabolismoRESUMO
The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2-/- model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2-/- mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2-/- mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.
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Microbioma Gastrointestinal , Locomoção , Comportamento Social , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Transplante de Microbiota Fecal , Fezes/microbiologia , Limosilactobacillus reuteri/metabolismo , Limosilactobacillus reuteri/fisiologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/microbiologia , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/terapia , Análise de Componente Principal , Agitação Psicomotora/patologia , Transmissão SinápticaRESUMO
Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.
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Complexo Nuclear Basolateral da Amígdala/fisiologia , Reação de Fuga , Adulto , Animais , Medo , Feminino , Reação de Congelamento Cataléptica , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto , Especificidade da EspécieRESUMO
Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial and temporal enrichment of oxytocin receptor expression within adult-born neurons in the murine olfactory bulb, with oxytocin receptor expression peaking during activity-dependent integration. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, we demonstrate that oxytocin receptor signaling promotes synaptic maturation of newly integrating adult-born neurons by regulating their morphological development and expression of mature synaptic AMPARs and other structural proteins.
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Ocitocina , Receptores de Ocitocina , Camundongos , Animais , Ocitocina/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Neurônios/fisiologia , Bulbo Olfatório/metabolismo , NeurogêneseRESUMO
Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.
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Ocitocina , Vasopressinas , Animais , Humanos , Receptores de VasopressinasRESUMO
Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin's role in the brain. Herein, we describe a near-infrared oxytocin nanosensor (nIROXT), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROXT leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 µm in the paraventricular nucleus of C57BL/6 mice, which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs, such as nIROXT, are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.
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Encéfalo , Camundongos Endogâmicos C57BL , Nanotubos de Carbono , Imagem Óptica , Ocitocina , Vasopressinas , Animais , Ocitocina/metabolismo , Camundongos , Imagem Óptica/métodos , Vasopressinas/metabolismo , Nanotubos de Carbono/química , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Masculino , Receptores de Ocitocina/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/métodosRESUMO
Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.g., migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence, in vivo electrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using Fluoro-Ruby) from the PVN to the WDR cells filled with Neurobiotin were observed. Moreover, colocalization between OTR and calcitonin gene-related peptide (CGRP) or OTR and GABA was found near Neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (True-Blue, TB) and infraorbital nerves (Fluoro-Gold, FG) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells.
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Estimulação Elétrica , Ocitocina , Núcleo Hipotalâmico Paraventricular , Ratos Wistar , Receptores de Ocitocina , Transmissão Sináptica , Animais , Masculino , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Ocitocina/metabolismo , Ocitocina/análogos & derivados , Ratos , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Transmissão Sináptica/fisiologia , Nociceptores/fisiologia , Nociceptores/metabolismo , Nociceptividade/fisiologia , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos dos fármacos , Meninges/fisiologia , Inibição Neural/fisiologiaRESUMO
Oxytocin has recently gained significant attention because of its role in the pathophysiology and management of dominant neuropsychiatric disorders. Oxytocin, a peptide hormone synthesized in the hypothalamus, is released into different brain regions, acting as a neurotransmitter. Receptors for oxytocin are present in many areas of the brain, including the hypothalamus, amygdala, and nucleus accumbens, which have been involved in the pathophysiology of depression, anxiety, schizophrenia, autism, Alzheimer's disease, Parkinson's disease, and attention deficit hyperactivity disorder. Animal studies have spotlighted the role of oxytocin in social, behavioral, pair bonding, and mother-infant bonding. Furthermore, oxytocin protects fetal neurons against injury during childbirth and affects various behaviors, assuming its possible neuroprotective characteristics. In this review, we discuss some of the concepts and mechanisms related to the role of oxytocin in the pathophysiology and management of some neuropsychiatric, neurodegenerative, and neurodevelopmental disorders.
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Transtorno Autístico , Ocitocina , Animais , Ocitocina/fisiologia , Comportamento Social , Ansiedade , EncéfaloRESUMO
Mastitis is the most frequent disease of cows and has well-recognized detrimental effects on animal wellbeing and dairy farm profitability. With the advent of the postantibiotic era, alternative antibiotic agents, especially probiotics, have received increasing attention in the treatment of mastitis. Based on research showing that Lactobacillus reuteri (L. reuteri) has anti-inflammatory effects, this study explored the protective effects and mechanisms of L. reuteri against mastitis induced by Staphylococcus aureus (S. aureus) in mice. First, mice with S. aureus-induced mastitis were orally administered L. reuteri, and the inflammatory response in the mammary gland was observed. The results showed that L. reuteri significantly inhibited S. aureus-induced mastitis. Moreover, the concentration of oxytocin (OT) and protein expression of oxytocin receptor (OTR) were measured, and inhibition of OTR or vagotomy reversed the protective effect of L. reuteri or its culture supernatant (LCS) on S. aureus-induced mastitis. In addition, in mouse mammary epithelial cells (MMECs), OT inhibited the inflammation induced by S. aureus by inhibiting the protein expression of OTR. It was suggested that L. reuteri protected against S. aureus-induced mastitis by releasing OT. Furthermore, microbiological analysis showed that the composition of the microbiota was altered, and the relative abundance of Lactobacillus was significantly increased in gut and mammary gland after treatment with L. reuteri or LCS. In conclusion, our study found the L. reuteri inhibited the mastitis-induced by S. aureus via promoting the release of OT, and treatment with L. reuteri increased the abundance of Lactobacillus in both gut and mammary gland.
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Microbioma Gastrointestinal , Limosilactobacillus reuteri , Mastite , Infecções Estafilocócicas , Feminino , Humanos , Animais , Bovinos , Camundongos , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Staphylococcus aureus , Mastite/terapia , Receptores de Ocitocina , LactobacillusRESUMO
The formation of social memory between individuals of the opposite sex is crucial for expanding mating options or establishing monogamous pair bonding. A specialized neuronal circuit that regulates social memory could enhance an individual's mating opportunities and provide a parallel pathway for computing social behaviors. While the influence of light exposure on various forms of memory, such as fear and object memory, has been studied, its modulation of social recognition memory remains unclear. Here, we demonstrate that acute exposure to light impairs social recognition memory (SRM) in mice. Unlike sound and touch stimuli, light inhibits oxytocin neurons in the supraoptic nucleus (SON) via M1 SON-projecting intrinsically photosensitive retinal ganglion cells (ipRGCs) and GABAergic neurons in the perinuclear zone of the SON (pSON). We further show that optogenetic activation of SON oxytocin neurons using channelrhodopsin is sufficient to enhance SRM performance, even under light conditions. Our findings unveil a dedicated neuronal circuit through which luminance affects SRM, utilizing a non-image-forming visual pathway, distinct from the canonical modulatory role of the oxytocin system.
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Studies from a variety of species indicate that argininevasopressin (AVP) and its V1a receptor (Avpr1a) play a critical role in the regulation of a range of social behaviors by their actions in the social behavior neural network. To further investigate the role of AVPRs in social behavior, we performed CRISPR-Cas9mediated editing at the Avpr1a gene via pronuclear microinjections in Syrian hamsters (Mesocricetus auratus), a species used extensively in behavioral neuroendocrinology because they produce a rich suite of social behaviors. Using this germ-line gene-editing approach, we generated a stable line of hamsters with a frame-shift mutation in the Avpr1a gene resulting in the null expression of functional Avpr1as. Avpr1a knockout (KO) hamsters exhibited a complete lack of Avpr1a-specific autoradiographic binding throughout the brain, behavioral insensitivity to centrally administered AVP, and no pressor response to a peripherally injected Avpr1a-specific agonist, thus confirming the absence of functional Avpr1as in the brain and periphery. Contradictory to expectations, Avpr1a KO hamsters exhibited substantially higher levels of conspecific social communication (i.e., odor-stimulated flank marking) than their wild-type (WT) littermates. Furthermore, sex differences in aggression were absent, as both male and female KOs exhibited more aggression toward same-sex conspecifics than did their WT littermates. Taken together, these data emphasize the importance of comparative studies employing gene-editing approaches and suggest the startling possibility that Avpr1a-specific modulation of the social behavior neural network may be more inhibitory than permissive.
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Sistemas CRISPR-Cas , Receptores de Vasopressinas , Agressão/fisiologia , Animais , Arginina/metabolismo , Arginina Vasopressina/genética , Cricetinae , Mesocricetus , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Comportamento SocialRESUMO
Mentalizing is a core faculty of human social behaviors that involves inferring the cognitive states of others. This process necessitates adopting an allocentric perspective and suppressing one's egocentric perspective, referred to as self-other distinction (SOD). Meanwhile, individuals may project their own cognitive states onto others in prosocial behaviors, a process known as self-other mergence (SOM). It remains unclear how the two opposing processes coexist during mentalizing. We here combined functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) techniques with intranasal oxytocin (OTint) as a probe to examine the SOM effect in healthy male human participants, during which they attributed the cognitive states of decision confidence to an anonymous partner. Our results showed that OTint facilitated SOM via the left temporoparietal junction (lTPJ), but did not affect neural representations of internal information about others' confidence in the dorsomedial prefrontal cortex, which might be dedicated to SOD, although the two brain regions, importantly, have been suggested to be involved in mentalizing. Further, the SOM effect induced by OTint was fully mediated by the lTPJ activities and became weakened when the lTPJ activities were suppressed by rTMS. These findings suggest that the lTPJ might play a vital role in mediating SOM during mentalizing.SIGNIFICANCE STATEMENT Every human mind is unique. It is critical to distinguish the minds of others from the self. On the contrary, we often project the current mental states of the self onto others; that is to say, self-other mergence (SOM). The neural mechanism underlying SOM remains unclear. We here used intranasal oxytocin (OTint) as a probe to leverage SOM, which is typically suppressed during mentalizing. We revealed that OTint specifically modulated the left temporoparietal junction (lTPJ) neural activities to fully mediate the SOM effect, while suppressing the lTPJ neural activities by transcranial magnetic stimulations causally attenuated the SOM effect. Our results demonstrate that the lTPJ might mediate SOM during social interactions.
Assuntos
Mentalização , Teoria da Mente , Humanos , Masculino , Ocitocina , Estimulação Magnética Transcraniana/métodos , Encéfalo , Córtex Pré-Frontal/fisiologia , Mapeamento Encefálico , Imageamento por Ressonância Magnética , Teoria da Mente/fisiologiaRESUMO
To assess the influence of physical training on neuronal activation and hypothalamic expression of vasopressin and oxytocin in spontaneously hypertensive rats (SHR), untrained and trained normotensive rats and SHR were submitted to running until fatigue while internal body and tail temperatures were recorded. Hypothalamic c-Fos expression was evaluated in thermoregulatory centers such as the median preoptic nucleus (MnPO), medial preoptic nucleus (mPOA), paraventricular nucleus of the hypothalamus (PVN), and supraoptic nucleus (SON). The PVN and the SON were also investigated for vasopressin and oxytocin expressions. Although exercise training improved the workload performed by the animals, it was reduced in SHR and followed by increased internal body temperature due to tail vasodilation deficit. Physical training enhanced c-Fos expression in the MnPO, mPOA, and PVN of both strains, and these responses were attenuated in SHR. Vasopressin immunoreactivity in the PVN was also increased by physical training to a lesser extent in SHR. The already-reduced oxytocin expression in the PVN of SHR was increased in response to physical training. Within the SON, neuronal activation and the expressions of vasopressin and oxytocin were reduced by hypertension and unaffected by physical training. The data indicate that physical training counterbalances in part the negative effect of hypertension on hypothalamic neuronal activation elicited by exercise, as well as on the expression of vasopressin and oxytocin. These hypertension features seem to negatively influence the workload performed by SHR due to the hyperthermia derived from the inability of physical training to improve heat dissipation through skin vasodilation.
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Hipertensão , Corrida , Ratos , Animais , Ratos Endogâmicos SHR , Ocitocina/metabolismo , Ocitocina/farmacologia , Hipotálamo/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Vasopressinas/metabolismo , Hipertensão/metabolismo , FadigaRESUMO
Ultraviolet B (UVB) radiation induces cutaneous inflammation, leading to thermal and mechanical hypersensitivity. Here, we examine the mechanical properties and profile of tactile and nociceptive peripheral afferents functionally disrupted by this injury and the role of oxytocin (OXT) as a modulator of this disruption. We recorded intracellularly from L4 afferents innervating the irradiated area (5.1 J/cm2) in 4-6 old week male mice (C57BL/6J) after administering OXT intraperitoneally, 6 mg/Kg. The distribution of recorded neurons was shifted by UVB radiation to a pattern observed after acute and chronic injuries and reduced mechanical thresholds of A and C- high threshold mechanoreceptors while reducing tactile sensitivity. UVB radiation did not change somatic membrane electrical properties or fiber conduction velocity. OXT systemic administration rapidly reversed these peripheral changes toward normal in both low and high-threshold mechanoreceptors and shifted recorded neuron distribution toward normal. OXT and V1aR receptors were present on the terminals of myelinated and unmyelinated afferents innervating the skin. We conclude that UVB radiation, similar to local tissue surgical injury, cancer metastasis, and peripheral nerve injury, alters the distribution of low and high threshold mechanoreceptors afferents and sensitizes nociceptors while desensitizing tactile units. Acute systemic OXT administration partially returns all of those effects to normal.
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Nociceptividade , Ocitocina , Camundongos , Masculino , Animais , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Camundongos Endogâmicos C57BL , Tato/fisiologia , Pele/inervação , Mecanorreceptores , Nociceptores/fisiologiaRESUMO
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age, representing the primary cause of anovulatory infertility. The nonapeptide oxytocin (OT) plays an important role in cognitive, emotional, and reproductive functions in human beings. Oxytocin receptors are expressed in several body parts, including the ovaries. Despite this, the possible role played by oxytocin in symptoms of PCOS is not clear. The present systematic review aimed at understanding the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. After a systematic search in the principal databases, eight studies, five human and three animal, were included. Four human studies and one animal study highlighted the role played by oxytocin in fertility issues related to PCOS. Three human and two animal studies investigated the role of body weight and OT levels. Studies that analyzed oxytocin basal levels in women agreed that PCOS is associated with a reduction in the serum level of oxytocin. Two human studies and one animal study agreed about lower levels of oxytocin, confirming a possible implication of the dysfunction of OT in the pathogenesis of PCOS.
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Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen-glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT's potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT's precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection.
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Cyclic ADP-ribose (cADPR) has emerged as a calcium-regulating second messenger in smooth muscle cells. CD38 protein possesses ADP-ribosyl cyclase and cADPR hydrolase activities and mediates cADPR synthesis and degradation. We have previously shown that CD38 expression is regulated by estrogen and progesterone in the myometrium. Considering hormonal regulation in gestation, the objective of the present study was to determine the role of CD38/cADPR signaling in the regulation of intracellular calcium upon contractile agonist stimulation using immortalized pregnant human myometrial (PHM1) cells. Western blot, immunofluorescence, and biochemical studies confirmed CD38 expression and the presence of ADP-ribosyl cyclase (2.6 ± 0.1 pmol/mg) and cADPR hydrolase (26.8 ± 6.8 nmoles/mg/h) activities on the PHM1 cell membrane. Oxytocin, PGF2α, and ET-1 elicited [Ca2+]i responses, and 8-Br-cADPR, a cADPR antagonist significantly attenuated agonist-induced [Ca2+]i responses between 20% and 46% in average. The findings suggest that uterine contractile agonists mediate their effects in part through CD38/cADPR signaling to increase [Ca2+]i and presumably uterine contraction. As studies in humans are limited by the availability of myometrium from healthy donors, PHM1 cells form an in vitro model to study human myometrium.
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Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.
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Síndrome de Prader-Willi , Humanos , Camundongos , Animais , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/psicologia , Microglia , Proteínas de Transporte/genética , Fenótipo , Fagossomos , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 µg), kisspeptin + astressin 2B (1 µg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.
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Sistema Hipotálamo-Hipofisário , Kisspeptinas , Sistema Hipófise-Suprarrenal , Ratos Wistar , Animais , Masculino , Kisspeptinas/administração & dosagem , Kisspeptinas/farmacologia , Kisspeptinas/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Fragmentos de Peptídeos/administração & dosagem , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Corticosterona/sangue , Vasotocina/farmacologia , Vasotocina/administração & dosagem , Testosterona/sangue , Injeções Intraventriculares , Gônadas/metabolismo , Gônadas/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Liberador da Corticotropina , OligopeptídeosRESUMO
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.