O objetivo deste estudo foi avaliar os efeitos imediatos da administração da ocitocina (OT) na ansiedade de performance musical (APM) em cantores profissionais, tendose como parâmetro o \"Teste de Simulação de Canto em Público\" (TSCP). Realizouse um ensaio clínico randomizado, duplo cego, cross-over controlado por placebo, tendo como sujeitos 50 cantores profissionais homens, sendo 16% eruditos e 84% populares, com idade média de 28,86 anos e tempo de experiência média de 10,96 anos. Todos os cantores realizaram autoadministração de dose única de 24UI de OT ou placebo por meio de um spray nasal, em sessões diferentes, de acordo com o grupo que foram alocados. Após 51 minutos da administração da OT ou placebo, tempo que coincidiu com o pico de concentração da OT, os cantores realizaram o TSCP, que consistiu em uma performance musical, com interpretação à capela de uma música de livre escolha, por quatro minutos em ambiente controlado. Foram analisadas medidas de indicadores de humor, de desempenho da performance, sinas e sintomas vocais, por meio de escalas de autoavaliação, e análise das medidas acústicas vocais utilizando o software Multi-Dimensional Voice Program Advanced, ao longo de seis fases: Medida Inicial (MI), Medida Basal (MB), Medida Antecipatória (MA), Medida de desempenho (MD), Medida Pós-estresse 0 (MPe0), e Medida Pós-estresse 1 (MPe1). Foi realizada análise de variância ANOVA 2x2 para modelos de estudos cross-over com comparação intra e interssujeitos. Os resultados indicaram que houve efeito do tratamento com OT quando comparado com o placebo durante o TSCP, melhorando a autoavaliação do desempenho nas fases MD, MPe0 e MPe1. Não houve mudanças nos indicadores de humor, sinais e sintomas vocais e nas medidas acústicas vocais avaliadas nos cantores ao longo do TSCP. Para as medidas avaliadas não se evidenciou efeito de sequência e de período. As medidas de separabilidade evidenciaram que o 29% para as medidas de autoavaliação e o 23% para as medidas acústicas da voz, corresponde ao efeito do tratamento com OT, sendo estimada independentemente do efeito carry-over. Em conclusão, a OT apresentou efeito ansiolítico, evidenciando melhora na autoavaliação do desempenho, com ausência de reações adversas quanto aos sinais e sintomas vocais e às medidas acústicas da voz. / The aim of this study was to evaluate the immediate effects of administration of Oxytocin (OT) in the musical performance anxiety (MPA) in professional singers, having the \'Test of Public Singing Simulation\' (TPSS) as parameter. We conducted a double-blind cross-over randomized placebo-controlled clinical trial, with 50 professional male singers as subjects, of whom 16% were erudite singers and 84% were popular singers, with an average age of 28.86 and an average period of experience of 10.96 years. All singers self-administered an only dose of 24UI of OT or placebo via a nasal spray, in different sessions, according to the group they were placed with. After 51 minutes of the OT or placebo administration, time that coincident of peak concentration of OT, the TPSS was performed, which consisted of an acapella musical interpretation of a free choice song for 4 minutes in a controlled environment. Measures of mood indicators were analyzed, as well as performance, vocal signs and symptoms, with self-assessment scales and analysis of voice acoustic measures using Multi-Dimensional Voice Program Advanced software during six stages: Initial Measure (MI), Basal Measure (MB), Anticipatory (MA), Performance Measure (MD), Post-stress 0 Measure (MPe0) and Post-stress 1 Measure (MPe1). An analysis of the ANOVA 2x2 variation was performed for crossover study models with intra- and inter- subject comparisons. The results indicated an effect in the OT treatment when compared with placebo during the TPSS, improving the in stages MD, MPe0 and MPe1. There were no changes in mood indicators, vocal signs and symptoms nor in vocal acoustic measures over the TPSS. Sequence and period effect were not evident for the reviewed measures. Separability criterion presented OT treatment correspondence of 29% for self-evaluation measurements and 23% for voice acoustic measures, which was estimated regardless of the carryover effect. In conclusion, OT had an anxiolytic effect, emphasizing an improvement in self-evaluation concerning performance with no adverse reaction in terms of voice signs and symptoms and vocal acoustic measures.

Ocitocina (OT) é um nonapeptídeo neurosecretório sintetizado nas células hipotalâmicas que se projetam para a neurohipófise e para locais extensamente distribuídos no sistema nervoso central. As microinjeções centrais de OT induzem uma variedade de comportamentos em animais no âmbito cognitivo, sexual, reprodutivo, de autolimpeza e afiliativo. O transtorno obsessivo-compulsivo (TOC) inclui uma escala dos sintomas cognitivos e comportamentais que tem alguma relação com dimensões de comportamento associadas com a OT. A administração de OT no núcleo central da amígdala (CeA) induz autolimpeza exacerbada, considerada um sintoma de TOC. Neste trabalho, nós estudamos os substratos neuroanatômicos e celulares deste comportamento. Nossos dados sugerem uma ligação entre o CeA e a “área hipotalâmica de grooming” (HGA). A HGA inclui parte do núcleo paraventricular do hipotálamo e a área hipotalâmica dorsal. Nossos dados mostrando co-localização de OT (imunohistoquímica para peptídeo), receptor para OT (ensaio de binding) e marcação de células retrogradamente depois da injeção de Fluoro-Gold no CeA sugerem que o CeA e conexões são substratos importantes nos circuitos subjacentes de comportamento normal e de quadro patológico tal como o TOC dependente de OT descrito neste trabalho. / Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells that project to the neurohypophysis as well as to widely distributed sites in the central nervous system. Central OT microinjections induce a variety of cognitive, sexual, reproductive, grooming and affiliative behaviors in animals. Obsessive-compulsive disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with OT. The administration of OT into central nucleus of amygdala (CeA) induces hypergrooming, considered a symptom of OCD. Here, we study the neuroanatomical and cellular substrates of this behavior. Our data suggest a link between the CeA and the “hypothalamic grooming area” (HGA). The HGA includes parts of the paraventricular hypothalamic nucleus and the dorsal hypothalamic area. Our data on co-localization of OT (immunohistochemistry for peptide), OT receptor (binding assay) and retrogradely labeled cells after Fluoro Gold injection in CeA suggest that CeA and connections are an important substrate of the circuit underlying this OCD-like OT-dependent behavior.

This dissertation research explored mechanisms of human milk (HM) expulsion by describing the effects of skin to skin contact (SSC) on maternal basal oxytocin (OT) secretion among 20 premature mothers with hospitalized premature infants. This one-group, repeated measures design consisted of: 1) daily SSC with covariant data via self-report diary and 2) maternal salivary OT with and without SSC at 4 time points were collected over a 7 day time frame. Results indicate that mean levels of basal OT increase over time (M 234 pg/ml, SD 108 pg/ml time point 1; M 257 pg/ml, SD 125 pg/ml time point 3). Through multilevel model data analysis basal OT was found to have a meaningful amount of dependence on SSC frequency (t(16) = 6.389, p = < 0.001) and SSC duration (t(17) = 6.867, p = < 0.001) with coefficient estimates that indicate that basal OT exposed to 75-85 minutes of SSC per day are 92 pg/ml higher. These findings provide preliminary data that suggest that lactating mothers with premature infants sustain positive effects of SSC that increase basal OT secretion over time.

Anxiety is the most commonly reported mental health problem among adolescents. Still, many adolescents in need of treatment are not detected and the clinical characteristics and etiological pathways of adolescent anxiety are under-researched topics. This thesis examined the clinical utility of the Swedish versions of the Spence Children’s Anxiety Scale (SCAS) and the clinical characteristics of multiple anxiety disorders among psychiatrically referred adolescents, and the influence of parenting and oxytocin gene (OXT) variants on anxiety among adolescents in the general population.  Studies employed cross-sectional and longitudinal designs and were based on questionnaire, interview, and genotype data. Support for the reliability and validity of both SCAS and SCAS-P was obtained. The overall ability to predict anxiety among referred adolescents ranged from fair to excellent for both scales.  Among adolescents psychiatrically referred for any reason, the prevalence of any anxiety disorder was 46%. Homotypic comorbidity was observed in 43%, and heterotypic comorbidity in 91%. Early adolescent anxiety influenced homotypic anxiety in late adolescence independent of parental rejection and control. The mediating role of parenting was small with indirect effect sizes no larger than one-tenth the size of direct effects, irrespective of the informant on parenting behavior. Significant interaction effects with positive and negative parenting were observed for OXT variants rs4813625 and rs2770378 in relation to social anxiety. The nature of the interactions was in line with the differential susceptibility framework for rs4813625, whereas for rs2770378, results indicated a diathesis–stress type of interaction. The findings suggest that psychiatrically referred adolescents with anxiety disorders are best characterized as a highly complex patient group and call attention to the necessity of structured assessment. For this purpose, this thesis provides evidence for the clinical utility of the SCAS; routine utilization of this questionnaire can improve detection of adolescents in need of anxiety treatment. Findings of this theses further suggest that the influence of positive and negative parenting behaviors on anxiety may be of greater importance among some adolescents than others, depending on individual differences in sensitivity to parenting. The etiology of anxiety among adolescents may therefore involve differential susceptibility effects of the interplay between genes and parenting behaviors.

Introdução: No Transtorno de Ansiedade Generalizada [TAG] observa-se prevalência de sintomas de ansiedade, perturbações do sono, irritabilidade, nervosismo persistente, tremores, tensão muscular, palpitações, tonturas e desconforto epigástrico, causando mal-estar e afetando negativamente a homeostase. Os mamíferos, inclusive os humanos, se acalmam ao receber cuidados maternos no início da vida, graças à ação regulatória conjunta do comportamento de apego e da liberação do neuropeptídeo ocitocina [OT]. Possivelmente por atenuar estados excitatórios, essa situação favorece o adormecer. Em seres humanos, a maternagem favorece, ainda, a criação de um forte e duradouro laço amoroso e estado de bem-estar e calma na díade mãe-bebê. Objetivos: Investigar possíveis relações entre OT, apego, e aspectos psicofisiológicos e homeostáticos de sono/insônia em pessoas com TAG. Desenho: Pesquisa translacional em neurociências, com N=27 participantes adultos do sexo masculino, diagnosticados com TAG, randomizados em grupo experimental [GE] e placebo [GP]. Hipótese: Após a intervenção, (administração de OT IN ou soro fisiológico) o GE deve apresentar, em relação ao GP, um estado de calma e bem-estar caracterizado pela diminuição nos níveis de cortisol salivar, no nível de ansiedade, e numa melhora dos afetos positivos e negativos [regulação ocitocinérgica], o que, por sua vez, deve favorecer o processo de adormecimento. Material e métodos: Entrevistas inicial e final; dados sociodemográficos; escalas sobre apego, ansiedade, afetos positivos e negativos, diário do sono. Após a randomização, GE e GP receberam respectivamente, de modo duplo-cego, spray com OT intranasal e soro fisiológico, duas vezes ao dia por quatro semanas, com avaliação de cortisol salivar, ansiedade e afetos antes e após a intervenção. Resultados: Os resultados finais, quando comparados com a linha de base, mostraram que o GE apresentou uma diminuição nos níveis de cortisol salivar e melhora na ansiedade e nos afetos, em relação ao GP. Ambos os grupos apresentaram redução na média de horas de sono, mas, qualitativamente, o GE teve desfecho melhor que o GP. Ambos os grupos apresentaram perfil de apego semelhante, com maiores índices de Superproteção do que de Cuidado, tanto materno quanto paterno, e prevalência do vínculo de tipo Controle Afetivo. Conclusões: Os resultados mostraram que as intervenções experimental e placebo estiveram associadas a índices mais altos de afetos positivos, e mais baixos de afetos negativos, ansiedade, e cortisol salivar nos dois grupos; no entanto, no GE esses resultados foram mais acentuados, e estiveram qualitativamente associados a melhora no humor, nas relações sociais e na qualidade do sono. Com relação ao apego, os resultados indicaram que os participantes receberam mais controle e superproteção do que cuidados amorosos de seu meio familiar / Introduction: In Generalized Anxiety Disorder [GAD] there is a prevalence of simptoms of anxiety, insomnia, irritability, persistent nervousness, trembling, muscle tension, palpitations, dizziness and epigastric discomfort, causing malaise and an imbalance in homeostasis. In humans and other mammals, babies and pups calm down upon receiving maternal care, as a result of the regulatory action of attachment behavior associated to the release of neuropeptide oxytocin [OT]. Falling asleep is probably eased as a consequence of attenuation of excitatory states. This associated action also favors the creation of a strong, long-lasting love bond, as well as states of well-being and calm in the mother-baby dyad. Objectives: To investigate eventual relations between OT, attachment and psychophysiological and homeostatic aspects of sleep-insomnia in patients with GAD. Hypothesis: After intervention (administration of IN OT or saline), GE should present, in relation to GP, a state of calm and well-being, characterized by a decrease in salivary cortisol levels, in anxiety, and improvement in positive and negative affects [oxytocinergic regulation], favoring, as a consequence, the process of falling asleep. Design: Translational Research in Neurosciences, with N = 27 male adults diagnosed with GAD, randomized in experimental [EG] and placebo group [PG]. Materials & Methods: Initial and final interviews; sociodemographic data, scales of attachment, anxiety and positive & negative affects; and sleep diary. After randomization, EG and PG were administered, in a double-blind way, respectively, intranasal OT spray and saline spray, twice a day, for four weeks, with assessment of salivary cortisol, anxiety and affects, before and after intervention. Results: When compared with baseline, final results showed a decrease in salivary cortisol levels, an improvement in anxiety as well as in affects in GE in relation to GP. Both groups presented a decrease in average sleep hours; however, GE had a qualitative improvement in sleep quality. Both groups presented a similar attachment profile, with higher levels of Overprotection when compared with Care, both maternal and paternal, and prevalence of the Affective Control-type bond. Conclusions: Results indicate that experimental and placebo interventions were associated with higher rates of positive affects, and lower rates of negative affects, anxiety, and salivary cortisol in both groups, however, in the EG these results were more accentuated, as well as qualitatively associated with improvement in mood, social relations, and sleep quality. As for attachment, results suggest that the participants probably received more control and overprotection than loving care from their parental environment

Beacon (BC) is a peptide of 73 amino acids, whose gene expression was first reported in the hypothalamus of Psammomys obesus (or Israeli sand rat). To appreciate better the functional role of BC in normal rats and sand rats, the distribution of BC immunoreactivity (irBC) and its subcellular localization were studied in the brain of Sprague-Dawley rats. In the hypothalamus, intense staining was present in neurons of the supraoptic (SO), paraventricular (PVH), and accessory neurosecretory nuclei and in cell processes of median eminence. Double labeling of the hypothalamic sections with mouse monoclonal oxytocin (OT) antibody and rabbit polyclonal BC antiserum revealed that nearly all OT-immunoreactive cells from SO, PVH, and accessory neurosecretory nuclei were irBC. Double labeling of the sections with guinea pig vasopressin (VP) antiserum and BC antiserum showed that a population of VP-immunoreactive neurons was irBC. By immunoelectron microscopy, immunoreactive product was associated with mitochondrial membranes or appeared as electron-dense bodies in many PVH and SO neurons. Most of the neurosecretory granules were unstained for BC. Taken together, our results indicate the presence of beacon in the OT-containing neurons and a population of VP-containing neurons, mostly associated with mithocondrial membrane. Insofar as the amino acids sequence of beacon is identical to that of ubiquitin-like 5, it is possible that the distribution of BC immunoreactivity noted in our study is that of ubiquitin-like 5 peptide in the rat hypothalamus.

Narcolepsy is a disorder of unstable wake and sleep states caused by the lack of orexin neurons which degenerate most likely as a consequence of an autoimmune process. The state instability of narcolepsy includes rapid eye movement (REM) sleep intruding into wake in the form of dream-like hallucinations and cataplexy, muscle paralysis (atonia) much like occurs in REM sleep. In mice lacking orexin peptides, cataplexy is also observed with similar presentation as in humans of muscle paralysis during wakefulness which is often triggered by positive emotions. Prior research showed that the activation of the central amygdala is sufficient to promote cataplexy in a mouse model of narcolepsy. The central amygdala (CeA) contains a variety of neuronal types, and we hypothesize that γ-aminobutyric acid (GABA)-ergic neurons expressing the oxytocin receptor (OTR) mediate cataplexy as these neurons project to a known REM sleep atonia-regulating region, the ventrolateral periaqueductal gray (vlPAG)/lateral pontine tegmentum (LPT), and, as oxytocin (OT) sensitive neurons in the amygdala, likely participate in emotional processing and social behavior. In this study, we used fiber photometry to investigate the behavior of these neurons in response to social and rewarding stimuli, during emotion-triggered cataplexy, and across arousal states in an effort to define their potential role in emotion-triggered cataplexy. Initial recordings were conducted at too low an excitation light power to stimulate the green fluorescent calcium indicator, GCaMP6s, but were useful in optimizing MATLAB analysis and behavioral tests later done at higher LED power. The second series of recordings with higher excitation light power and better signal to noise ratio, showed increased activity in response to social interaction and reward, prior to REM transitions, and decreased activity during cataplexy confirming patterns seen in initial recordings. In recordings with higher excitation light, these responses appear to occur before interaction with stimulus mice or reward stimulus. In the future, additional recordings with a higher signal to noise ratio will be needed to confirm these results. In conclusion, responses of CeA-OTR neurons to social and rewarding stimuli, cataplexy, and at REM transitions are in support of a possible role of these neurons in emotion-triggered cataplexy which can be tested using additional methods, such as optogenetics.

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