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1.
Transl Psychiatry ; 11(1): 449, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471100

RESUMO

The neuropeptide oxytocin (OXT) and its receptor (OXTR) modulate interpersonal relationships, particularly mother-child interactions. DNA methylation (DNAm) changes of the OXTR gene were observed in individuals who experienced Childhood Maltreatment (CM). A modulatory role of single nucleotide polymorphisms (SNP) within OXTR in association with CM on the regulation of OXTR was also postulated. Whether these CM-induced epigenetic alterations are biologically inherited by the offspring remains unknown. We thus investigated possible intergenerational effects of maternal CM exposure on DNAm and OXTR gene expression, additionally accounting for the possible influence of three SNP: rs53576 and rs2254298 (OXTR gene), and rs2740210 (OXT gene). We used the Childhood Trauma Questionnaire to classify mothers into individuals with (CM+) or without CM (CM-). Maternal peripheral immune cells were isolated from venous blood (N = 117) and fetal immune cells from the umbilical cord (N = 113) after parturition. DNA methylation was assessed using MassARRAY. Taqman assays were performed for genotyping and gene expression analyses. Among mothers, CM was not associated with OXTR mean methylation or gene expression. However, four CpG sites showed different methylation levels in CM- compared to CM+. In mothers, the OXTR rs53576 and OXT rs2740210 allelic variations interacted with CM load on the OXTR mean methylation. Maternal and newborns' mean methylation of OXTR were positively associated within CM- dyads, but not in CM+ dyads. We show gene×environment interactions on the epigenetic regulation of the oxytocinergic signaling and show the intergenerational comparability of the OXTR DNAm might be altered in infants of CM+ mothers.


Assuntos
Maus-Tratos Infantis , Receptores de Ocitocina , Criança , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Mães , Ocitocina/genética , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445224

RESUMO

The tightly localized noradrenergic neurons (NA) in the locus coeruleus (LC) are well recognized as essential for focused arousal and novelty-oriented responses, while many children with autism spectrum disorder (ASD) exhibit diminished attention, engagement and orienting to exogenous stimuli. This has led to the hypothesis that atypical LC activity may be involved in ASD. Oxytocin (OXT) neurons and receptors are known to play an important role in social behavior, pair bonding and cognitive processes and are under investigation as a potential treatment for ASD. However, little is known about the neurotransmission from hypothalamic paraventricular (PVN) OXT neurons to LC NA neurons. In this study, we test, in male and female rats, whether PVN OXT neurons excite LC neurons, whether oxytocin is released and involved in this neurotransmission, and whether activation of PVN OXT neurons alters novel object recognition. Using "oxytocin sniffer cells" (CHO cells that express the human oxytocin receptor and a Ca indicator) we show that there is release of OXT from hypothalamic PVN OXT fibers in the LC. Optogenetic excitation of PVN OXT fibers excites LC NA neurons by co-release of OXT and glutamate, and this neurotransmission is greater in males than females. In male, but not in female animals, chemogenetic activation of PVN OXT neurons increases attention to novel objects.


Assuntos
Atenção , Locus Cerúleo/metabolismo , Neurônios/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Caracteres Sexuais , Transmissão Sináptica , Animais , Células CHO , Cricetulus , Feminino , Humanos , Masculino , Ocitocina/genética , Ratos , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445168

RESUMO

Oxytocin (OXT) is a neuropeptide involved in a plethora of behavioral and physiological processes. However, there is a prominent lack of 3D cell culture models that investigate the effects of OXT on a cellular/molecular level. In this study, we established a hypothalamic neuronal spheroid model to investigate the cellular response in a more realistic 3D setting. Our data indicate that the formation of spheroids itself does not alter the basic characteristics of the cell line and that markers of cellular morphology and connectivity are stably expressed. We found that both OXT and arginine vasopressin (AVP) treatment increase spheroid size (surface area and volume), as well as individual nucleus size, which serves as an indicator for cellular proliferation. The cellular response to both OXT and AVP seems mainly to be mediated by the AVP receptor 1a (V1aR); however, the OXT receptor (OXTR) contributes significantly to the observed proliferative effect. When we blocked the OXTR pharmacologically or knocked down the OXTR by siRNA, the OXT- or AVP-induced cellular proliferation decreased. In summary, we established a 3D cell culture model of the neuronal response to OXT and AVP and found that spheroids react to the treatment via their respective receptors but also via cross-talk between the two receptor types.


Assuntos
Hipotálamo/citologia , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Animais , Arginina Vasopressina/metabolismo , Linhagem Celular , Proliferação de Células , Hipotálamo/metabolismo , Ocitocina/metabolismo , Ratos , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo
4.
Handb Clin Neurol ; 180: 25-44, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225933

RESUMO

The hypothalamic neuropeptide oxytocin (OT) is critically involved in the modulation of socio-emotional behavior, sexual competence, and pain perception and anticipation. While intracellular signaling of OT and its receptor (OTR), as well as the functional connectivity of hypothalamic and extra-hypothalamic OT projections, have been recently explored, it remains elusive how one single molecule has pleotropic effects from cell proliferation all the way to modulation of complex cognitive processes. Moreover, there are astonishing species-dependent differences in the way OT regulates various sensory modalities such as touch, olfaction, and vision, which can be explained by differences in OTR expression in brain regions processing sensory information. Recent research highlights a small subpopulation of OT-synthesizing cells, namely, parvocellular cells, which merely constitute 1% of the total number of OT cells but act as "master cells' that regulate the activity of the entire OT system. In this chapter, we summarize the latest advances in the field of OT research with a particular focus on differences between rodents, monkeys and humans and highlight the main differences between OT and its "sister" peptide arginine-vasopressin, which often exerts opposite effects on physiology and behavior.


Assuntos
Ocitocina , Receptores de Ocitocina , Arginina Vasopressina , Encéfalo/metabolismo , Humanos , Neurotransmissores , Receptores de Ocitocina/metabolismo
5.
Neuropsychopharmacology ; 46(11): 1950-1957, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34127796

RESUMO

Preclinical and clinical evidence suggests that exogenous administration of oxytocin (OT) may hold promise as a therapeutic strategy for reducing heavy alcohol drinking. However, it remains unknown whether these effects are mediated by stimulation of endogenous sources of OT and signaling at oxytocin receptors (OTR) in brain or in the periphery. To address this question, we employed a targeted chemogenetic approach to examine whether selective activation of OT-containing neurons in the paraventricular nucleus of the hypothalamus (PVN) alters alcohol consumption in a binge-like drinking ("Drinking-in-the-Dark"; DID) model. Adult male Oxt-IRES-Cre mice received bilateral infusion of a Cre-dependent virus containing an excitatory DREADD (AAV8-hSyn-DIO-hM3Dq-mCherry) or control virus (AAV8-hSyn-DIO-mCherry) into the PVN. Chemogenetic activation of PVNOT+ neurons following clozapine-N-oxide injection reduced binge-like alcohol drinking in a similar manner as systemic administration of the neuropeptide. Pretreatment with a brain-penetrant OTR antagonist (L-368,899) reversed this effect while systemic administration of a peripherally restricted OTR antagonist (Atosiban) did not alter reduced alcohol drinking following chemogenetic activation of PVNOT+ neurons. Altogether, these data are the first to demonstrate that targeted activation of hypothalamic (endogenous) OT reduces alcohol consumption, providing further evidence that this neuropeptide plays a role in regulation of alcohol self-administration behavior. Further, results indicate that the ability OT to reduce alcohol drinking is mediated by signaling at OTR in the brain.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Ocitocina , Receptores de Ocitocina , Animais , Hipotálamo/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Ocitocina/metabolismo
6.
Cancer Sci ; 112(9): 3520-3532, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34115916

RESUMO

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.


Assuntos
Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/metabolismo , Piridinas/administração & dosagem , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Triazóis/administração & dosagem , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ocitocina/farmacologia , RNA Mensageiro/genética , Receptores de Ocitocina/genética , Transfecção , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Commun ; 12(1): 2900, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006875

RESUMO

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks.


Assuntos
Agressão/fisiologia , Arginina Vasopressina/metabolismo , Ocitocina/metabolismo , Núcleos Septais/metabolismo , Isolamento Social/psicologia , Agressão/efeitos dos fármacos , Animais , Arginina Vasopressina/farmacologia , Feminino , Microdiálise , Neurônios/metabolismo , Ocitocina/farmacologia , Ratos Wistar , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Núcleos Septais/citologia , Núcleos Septais/efeitos dos fármacos
8.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33891015

RESUMO

Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently receive more attention for their contributions to affiliative behavior, this mini-review discusses their roles in cardiovascular function broadly defined to include indirect effects that influence cardiovascular function. The traditional view is that neither AVP nor OXY contributes to basal cardiovascular function, although some recent studies suggest that this position might be re-evaluated. More evidence indicates that adaptations and neuroplasticity of AVP and OXY neurons contribute to cardiovascular pathophysiology.


Assuntos
Arginina Vasopressina/fisiologia , Pressão Sanguínea , Sistema Cardiovascular/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Ocitocina/fisiologia , Animais , Volume Sanguíneo , Doenças Cardiovasculares/etiologia , Humanos , Natriurese , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Caracteres Sexuais
9.
J Endocrinol ; 249(2): 135-148, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33705350

RESUMO

We explored the involvement of oxytocin receptor (Oxtr)/transient-receptor-potential-vanilloid-1 (TRPV1) genes and oxytocin (Oxt) on the adaptation of skeletal muscle to cold stress challenge in mice. Oxtr expression in hypothalamic paraventricular (PVN), supraoptic nuclei (SON), and hippocampus (HIPP) were evaluated by immunohistochemistry in parallel with the measurement of circulating Oxt. The Oxtr and TRPV1 gene expressions in soleus (SOL) and tibialis anterior (TA) muscles were investigated by RT-PCR. Histological studies of the cardiac muscle after cold stress were also performed. Male mice (n = 15) were divided into controls maintained at room temperature (RT = 24°C), exposed to cold stress (CS) at T = 4°C for 6 h , and 5 days. Immunohistochemical studies showed that Oxtr protein expression increased by two-fold (P = 0.01) in PVN and by 1.5-fold (P = 0.0001) in HIPP after 6 h- and 5 days of CS but decreased by 2-fold (P = 0.026) in SON in 5 days. Both Oxtr and TRPV1 gene expression increased after 6 h and 5 days of CS in SOL and TA muscles. Oxtr vs TRPV1 gene expression in SOL and TA muscles evaluated by regression analysis was linearly correlated following CS at 6 h and 5 days but not at control temperature of 24 ± 1°C, supporting the hypothesis of coupling between these genes. The circulating levels of Oxt are unaffected after 6 h of CS but decreased by 0.2-fold (P = 0.0141) after 5 days-CS. This is the first report that Oxtr and TRPV1 expressions are upregulated in response to cold acclimation in skeletal muscle. The up-regulation of Oxtr in PVN and HIPP balances the decrease of circulating Oxt.


Assuntos
Resposta ao Choque Frio , Músculo Esquelético/fisiologia , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Canais de Cátion TRPV/metabolismo , Aclimatação , Animais , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Camundongos , Receptores de Ocitocina/genética , Núcleo Supraóptico/metabolismo , Canais de Cátion TRPV/genética , Regulação para Cima
10.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672070

RESUMO

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.


Assuntos
Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Animais , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Ocitocina/metabolismo
11.
J Perinat Neonatal Nurs ; 35(1): 4-7, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33528179

RESUMO

Depression onset during and after pregnancy is prevalent and associated with significant implications for maternal, child, and family health. Although environmental risk factors important to the expression of pregnancy-related depression are well known, knowledge of the genetic underpinning is limited. Given the joint contribution of environmental and genetic factors to depression risk liability, DNA methylation presents itself as an ideal biomarker to investigate basic mechanisms and opportunities for translational research to care for pregnancy-related depression health outcomes. This article is an introduction to DNA methylation and its potential to serve as a marker of depression risk during pregnancy and the postpartum. This commentary discusses current clinical uses of DNA methylation-based testing and how it may be applied to perinatal depression clinical care and management.


Assuntos
Metilação de DNA , Depressão Pós-Parto/metabolismo , Precursores de Proteínas/metabolismo , Adulto , Depressão Pós-Parto/genética , Feminino , Humanos , Comportamento Materno , Assistência Perinatal , Gravidez , Receptores de Ocitocina/metabolismo
12.
Neurochem Res ; 46(4): 980-991, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33611682

RESUMO

Oxytocin (OT) neuronal activity is the key factor for breastfeeding and it can be disrupted by mother-baby separation. To explore cellular mechanisms underlying OT neuronal activity, we studied the role of protein kinase A (PKA) in OT neuronal activity in the supraoptic nucleus (SON) using a rodent model of pup deprivation (PD) Intermittent (IPD) or continuous (CPD) PD significantly reduced suckling duration and number of milk ejections in lactating rats, particularly those with CPD. In Western blots of the SON, PD increased expressions of OT receptor (OTR) and its immediate downstream effectors, Gαq and Gß subunits, particularly IPD, but reduced the expression of catalytic subunit of PKA (cPKA). In brain slices, inhibition of PKA blocked prostaglandin E2-evoked increase in firing activity including burst firing in OT neurons. In IPD dams, filamentous actin formed ring-like structures in the cytoplasmic region of OT neurons, which was reduced in CPD. Moreover, molecular association between actin and cPKA also reduced in PD dams. Incubation of brain slices with OT reduced the expression of cPKA, which was blocked by pretreatment with atosiban, an antagonist of OTR. These results indicate that PD disrupts OT neuronal activity through dissociating the Gq proteins and PKA in OTR-associated signaling cascade, which couples with reduced interactions between filamentous actin and PKA in OT neurons in the SON. This study highlights that PKA can be a novel target treating abnormal OT neuronal activity and its associated diseases.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Privação Materna , Neurônios/metabolismo , Ocitocina/metabolismo , Actinas/metabolismo , Animais , Feminino , Lactação/metabolismo , Masculino , Gravidez , Ratos Sprague-Dawley , Receptores de Ocitocina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Núcleo Supraóptico/metabolismo
13.
Clin Sci (Lond) ; 135(4): 597-611, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33564880

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. METHODS: We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. RESULTS: The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. CONCLUSIONS: Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.


Assuntos
Colite Ulcerativa/imunologia , Células Dendríticas/imunologia , Ocitocina/metabolismo , Ocitocina/farmacologia , Receptores de Ocitocina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Colite/induzido quimicamente , Células Dendríticas/metabolismo , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Ocitocina/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Ocitocina/genética , Transdução de Sinais
14.
J Hum Evol ; 152: 102949, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33578304

RESUMO

Humans have unique cognitive capacities that, compared with apes, are not only simply expressed as a higher level of general intelligence, but also as a quantitative difference in sociocognitive skills. Humans' closest living relatives, bonobos (Pan paniscus), and chimpanzees (Pan troglodytes), show key between-species differences in social cognition despite their close phylogenetic relatedness, with bonobos arguably showing greater similarities to humans. To better understand the evolution of these traits, we investigate the neurochemical mechanisms underlying sociocognitive skills by focusing on variation in genes encoding proteins with well-documented roles in mammalian social cognition: the receptors for vasopressin (AVPR1A), oxytocin (OXTR), serotonin (HTR1A), and dopamine (DRD2). Although these genes have been well studied in humans, little is known about variation in these genes that may underlie differences in social behavior and cognition in apes. We comparatively analyzed sequence data for 33 bonobos and 57 chimpanzees, together with orthologous sequence data for other apes. In all four genes, we describe genetic variants that alter the amino acid sequence of the respective receptors, raising the possibility that ligand binding or signal transduction may be impacted. Overall, bonobos show 57% more fixed substitutions than chimpanzees compared with the ancestral Pan lineage. Chimpanzees, show 31% more polymorphic coding variation, in line with their larger historical effective population size estimates and current wider distribution. An extensive literature review comparing allelic changes in Pan with known human behavioral variants revealed evidence of homologous evolution in bonobos and humans (OXTR rs4686301(T) and rs237897(A)), while humans and chimpanzees shared OXTR rs2228485(A), DRD2 rs6277(A), and DRD2 rs11214613(A) to the exclusion of bonobos. Our results offer the first in-depth comparison of neurochemical receptor gene variation in Pan and put forward new variants for future behavior-genotype association studies in apes, which can increase our understanding of the evolution of social cognition in modern humans.


Assuntos
Evolução Molecular , Pan paniscus/genética , Pan troglodytes/genética , Cognição Social , Animais , Encéfalo/metabolismo , Pan paniscus/metabolismo , Pan troglodytes/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo
15.
Nat Metab ; 3(2): 258-273, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33589843

RESUMO

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.


Assuntos
Sistema Nervoso Central/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Sistema Nervoso Periférico/fisiologia , Resposta de Saciedade/fisiologia , Animais , Ingestão de Alimentos , Feminino , Trato Gastrointestinal/inervação , Trato Gastrointestinal/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proglucagon/metabolismo , Receptores de Ocitocina/metabolismo , Nervo Vago/fisiologia
16.
Nat Neurosci ; 24(4): 529-541, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33589833

RESUMO

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.


Assuntos
Astrócitos/metabolismo , Núcleo Central da Amígdala/metabolismo , Emoções/fisiologia , Neurônios/metabolismo , Ocitocina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Núcleo Central da Amígdala/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/farmacologia , Ratos , Ratos Wistar , Receptores de Ocitocina/metabolismo
17.
Neuropsychopharmacology ; 46(5): 1045-1056, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495546

RESUMO

The neuropeptide oxytocin (OT) regulates important brain functions including feeding through activating OT receptors in multiple brain areas. Both OT fibers and OT receptors have been reported in the paraventricular thalamus (PVT), an area that was revealed to be important for the control of emotion, motivation, and food intake. However, the function and modulation of PVT OT signaling remain unknown. Here, we used a progressive ratio (PR) schedule of reinforcement to examine the role of PVT OT signaling in regulating the motivation for food and patch-clamp electrophysiology to study the modulation of OT on PVT neurons in brain slices. We demonstrate that PVT OT administration increases active lever presses to earn food rewards in both male and female mice under PR trials and OT receptor antagonist atosiban inhibits OT-induced increase in motivated lever presses. However, intra-PVT OT infusion does not affect food intake in normal conditions but attenuates hypophagia induced by stress and anxiety. Using patch-clamp recordings, we find OT induces long-lasting excitatory effects on neurons in all PVT regions, especially the middle to posterior PVT. OT not only evokes tonic inward currents but also increases the frequency of spontaneous excitatory postsynaptic currents on PVT neurons. The excitatory effect of OT on PVT neurons is mimicked by the specific OT receptor agonist [Thr4, Gly7]-oxytocin (TGOT) and blocked by OT receptor antagonist atosiban. Together, our study reveals a critical role of PVT OT signaling in promoting feeding motivation to attenuate stress-induced hypophagia through exciting PVT neurons.


Assuntos
Motivação , Ocitocina , Animais , Feminino , Masculino , Camundongos , Neurônios/metabolismo , Ocitocina/farmacologia , Receptores de Ocitocina/metabolismo , Tálamo/metabolismo
18.
Exp Mol Pathol ; 118: 104604, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434610

RESUMO

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.


Assuntos
Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Ocitocina/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Macrófagos/patologia , Ocitócicos/farmacologia , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Receptores de Ocitocina/metabolismo
19.
Psychopharmacology (Berl) ; 238(1): 293-304, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130926

RESUMO

RATIONALE: Anandamide is an endocannabinoid that contributes to certain aspects of social behavior, like play and reward, by binding to cannabinoid receptor type 1 (CB1). Most interesting is the recent discovery that anandamide may be mobilized by oxytocin receptor activation under certain contexts, particularly in the nucleus accumbens. OBJECTIVES: Given the established role of oxytocin and the nucleus accumbens in the neurobiology of pair-bonding, we investigated whether systemic administration of brain-permeable modulators of the endocannabinoid system could alter preferential partner contact in both male and female prairie voles. METHODS: Specifically, we tested whether intraperitoneal administration of the neutral CB1 antagonist AM4113 (4.0-16.0 mg/kg) or the anandamide hydrolysis inhibitor URB597 (5.0-20.0 mg/kg) could prevent or facilitate partner preference formation, respectively. To further investigate the specificity of effects on partner preference, we repeated our URB597 dosing regimen on an additional group of females and tested their anxiety-related behavior in both an elevated-plus maze and a light/dark test. RESULTS: AM4113 administration had no effect on partner preference. But while URB597 also had no effect on partner preference, low-dose females did increase absolute preferential contact with either the partner or the stranger; individual females spent significant contact time with either the partner or the stranger. None of our outcome measures in either anxiety test showed significant effects of treatment. CONCLUSIONS: Our results reveal that experimentally increasing anandamide levels in female prairie voles can increase social contact with both a familiar and novel male via unknown mechanisms that are likely separate from anxiety reduction.


Assuntos
Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Ligação do Par , Alcamidas Poli-Insaturadas/farmacologia , Comportamento Social , Animais , Ansiedade/metabolismo , Ansiedade/prevenção & controle , Ansiedade/psicologia , Ácidos Araquidônicos/administração & dosagem , Arvicolinae , Comportamento Animal , Benzamidas/farmacologia , Carbamatos/farmacologia , Endocanabinoides/administração & dosagem , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptores de Ocitocina/metabolismo
20.
Horm Behav ; 127: 104878, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148500

RESUMO

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.


Assuntos
Agressão/fisiologia , Hierarquia Social , Mesocricetus/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Arginina/metabolismo , Arginina Vasopressina/metabolismo , Cricetinae , Feminino , Hipotálamo Anterior/metabolismo , Masculino , Mesocricetus/metabolismo , Mesocricetus/psicologia , Ocitocina/metabolismo , Ligação Proteica , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Serotonina/metabolismo , Caracteres Sexuais , Comportamento Social
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