O presente trabalho é uma avaliação do efeito da administração de ocitocina nasal sobre o perfil de ativação do sistema nervoso autônomo e níveis salivares de cortisol, buscando compreender a relação entre esses vetores dentro da perspectiva da teoria polivagal e da concepção da ocitocina como um peptídeo de ação pró-social. A hipótese testada foi se o sistema pró-social, mediado pela ocitocina, exerce um efeito de ativação no ramo parassimpático, diminuindo o nível salivar de cortisol, comprovando o efeito anti-stress dessa molécula, ao desligar o sistema de alarme, reação filogenética para a preparação fisiológica para a interação social (relaxamento e tranquilidade). Para tanto, utilizou-se do Trial Social Stress Test, cuja tarefa é falar em público, situação em que parâmetros autonômicos foram medidos em sujeitos humanos, assim como o nível de cortisol salivar avaliado, em dois grupos: um experimental (com administração de ocitocina) e um controle (com administração de placebo) e em dois momentos (pré e pós stress social), relacionando-os a dados de personalidade (teste Bateria Fatorial da Personalidade). Os achados foram indicativos que a ocitocina exerce um efeito inibitório notável sobre os níveis de cortisol, não encontrando dados conclusivos sobre o vinculo ou não da atividade parassimpática relacionada com a presença da ocitocina e baixo nível de cortisol, embora se tenha encontrado forte influência da presença da ocitocina na atividade cardíaca (mediada pelo sistema nervoso autônomo). O fator de personalidade se mostrou bastante relevante nos resultados de cortisol e efeitos de ocitocina, correlacionados com o índice de Neuroticismo e se encontrou indicativos de que outros fatores de personalidade podem também ser importantes / The present work is an evaluation of nasal administration effect of oxytocin over the activation profile of the autonomic nervous system and salivary levels of cortisol, seeking to understand the relationship between these vectors within the perspective of the polyvagal theory and the conception of oxytocin as a pro social peptide. The hypothesis tested was whether the pro-social system, mediated by oxytocin, exerted an activation effect over the parasympathetic branch, reducing the salivary level of cortisol, proving the anti-stress effect of this molecule, when the alarm system was turned off, phylogenetic reaction to the physiological preparation for social interaction (relaxation and tranquillity). For this purpose, the Trial Social Stress Test was used, whose task is to speak in public, in which its autonomic parameters were measured, as well as the level of salivary cortisol evaluated, in two groups: one experimental (with oxytocin administration) and one control (with placebo administration) and at two moments (pre and post social stress), relating these results with personality data (Personality Factor Battery test). The findings were indicative that oxytocin exerts a remarkable inhibitory effect on cortisol levels, and we did not find conclusive data about the relationship or not of the parasympathetic activity related to the presence of oxytocin and low cortisol level, although strong oxytocin influence was found over the cardiac activity (mediated by the autonomic nervous system). The personality factor was shown to be very relevant in the cortisol and oxytocin effects correlated with the Neuroticism Index and it was found that other personality factors may also be important

Utilizando Análise Espectral (FFT) para quantificar a variabilidade autonômica no animal intacto, analisamos pressão arterial, intervalo de pulso (IP) e fluxo sangüíneo no repouso e no exercício, em ratos normotensos (WKY) e hipertensos (SHR), sedentários (S) ou treinados (T), após pré-tratamento do NTS/DMV com veículo e antagonista de ocitocina (OTant). As principais alterações foram relacionadas à freqüência cardíaca (FC) e ao IP: bradicardia de repouso em WKYT e SHRT; aumento na resposta taquicárdica do exercício após OTant apenas nos WKYT. No repouso, os SHR apresentaram queda da variância do IP com diminuição dos componentes de baixa (LF-simpático) e alta (HF-vago) freqüências, corrigidas pelo T. No exercício houve queda dos componentes espetrais do IP nos grupos experimentais, exceto o HF que não diminuiu nos WKYT. OTant no NTS/DMV reduziu o HF dos SHRT no repouso e exercício; a ausência da queda do HF nos WKYT foi abolida. Resultados indicam a importância da ocitocina agindo sobre o vago na modulação da FC basal e da taquicardia do exercício apenas em T. / Using Spectral Analysis (FFT) to quantify the autonomic variability in intact animal, we analyzed blood pressure, pulse interval (PI) and blood flow at rest and during exercise, in normotensive (WKY) and hypertensive (SHR) rats, sedentary (S) or trained (T), after solitary vagal complex (NTS/DMV) pre-treatment with vehicle and oxytocin antagonist (OTant). The main changes were related to heart rate (HR) and PI: rest bradycardia in WKYT and SHRT; increased exercise tachycardia after OTant only in WKYT. At rest, SHR presented a fall of in PI variance with decreased low (LF-simpathetic) and high (HF-vagal) frequencies components that were normalized by T. During exercise, the spectral components decreased in the experimental groups, except HF unchanged in WKYT. OTant into the NTS/DMV reduced the HF of the SHRT at rest and exercise; the absence of the fall in HF of WKYT was abolished. Results indicate the importance of oxytocin acting on vagus in the modulation of basal HR and exercise tachycardia only in T rats.

Submitted by Liliane Ferreira (ljuvencia30@gmail.com) on 2018-03-01T12:16:05Z No. of bitstreams: 2 Tese - Nathalia Oda Amaral - 2018.pdf: 7340078 bytes, checksum: dd36d7fb333869ee8d969019a9f88b63 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-03-01T13:16:17Z (GMT) No. of bitstreams: 2 Tese - Nathalia Oda Amaral - 2018.pdf: 7340078 bytes, checksum: dd36d7fb333869ee8d969019a9f88b63 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-01T13:16:18Z (GMT). No. of bitstreams: 2 Tese - Nathalia Oda Amaral - 2018.pdf: 7340078 bytes, checksum: dd36d7fb333869ee8d969019a9f88b63 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-02-02 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Hypertension is the most common pathologies which affect population. Of the factors that can promote hypertension, food behavior is highlighted in relation to unhealthy eating habits present in western diet. Thus, present study sought to evaluate some aspects of this pathology in several situations, and themes were discussed separately in two chapters. In the first moment, effect of maternal hyperlipidic diet on metabolic and autonomic parameters in offspring was evaluated. It is known which obesity induced by maternal diet can modify central regulatory pathways of the fetus, mainly long-term regulation of appetite, but no work sought to evaluate the influence of the maternal hyperlipidic diet (HD) on cardiovascular and autonomic parameters in the offspring . Female Holtzman rats (280-300 g) were divided into two groups. One group received standard diet (SD) and other HD. The animals had free access to SD or HD for 6 weeks prior and during gestation and lactation period. All pups were weaned after 21 days of life and had free access to SD. After one week some offspring and mothers were submitted to glycemic test and later euthanized for removal of adipose tissue and blood. Other offspring were submitted to in situ preparation. DH increased adipose tissue in all females, but was able to change only metabolic triacylglycerols concentration. Offspring of HFD dams (OffHFD) showed an increase in adipose tissue and total cholesterol and HDL levels. Offspring of SD dams (OffSD) showed decrease in sympathetic activity after pre-colicular transection. This effect was not observed in males offspring of mothers with HFD (OffHFD). KCN infusion caused similar increases in abdominal activity (ABD), in phrenic nerve frequency (PNA f) and sympathetic activity (SNA), but in OffHFD this increase in SNA was smaller. KCN caused increase in phrenic nerve amplitude (PNA) and was higher in OffHFD. Hypercapnia resulted in increase in SNA, ABD and PNA and decrease in PNA f in both groups. The decrease in PNA f was more pronounced in OffHFD and increased PNA was higher in OffHFD. Phenylephrine caused in both groups decrease in SNA, ABD and PNA, and generated an increase in PNA f. The reduction of SNA was higher in OffHFD. These results suggest that maternal HFD during fetal development alters central connections in offspring. In second moment oxytocin effects on vascular reactivity and its role in hypernatremia-induced responses were evaluated. Changes in volume and/or extracellular compartments composition are known to evoke various autonomic, cardiovascular and hormonal responses that to modulate renal excretion of water and sodium. The main vegetative adjustments are: renal vasodilation and oxytocin secretion. Regulation of osmolarity and volume is critical for survival. Despite knowledge, no study evaluated interaction between renal sympathetic activity and oxytocin secretion on renal and cardiovascular responses induced by sodium overload. Male Wistar rats (280–350 g) were anesthetized with sodium thiopental (40 mg/kg, i.v.). Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 μg/kg, i.v.) induced renal vasodilation. Ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OTR) reduced these responses to OT, indicating a direct effect of this peptide on OTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml/kg b.wt., i.v.) was infused over 60 s. In sham rats (n=6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; n=7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. Atosiban with renal denervation (RX+AT; n=7) completely abolished renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 42% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia. The understanding of regulatory mechanisms activated both during obesity and during hyperosmolarity allows greater possibility development new therapeutic tools for hypertension prevention and treatment. / A hipertensão arterial é uma das patologias mais comuns que afetam a população. Dentre os fatores que podem propiciar a hipertensão o comportamento alimentar ganha destaque no que se referem aos hábitos alimentares não saudáveis presentes na dieta ocidental. Sendo assim, o presente trabalho procurou avaliar alguns aspectos dessa patologia em diversas situações, e os temas foram discutidos de forma separada em dois capítulos. No primeiro momento avaliou-se o efeito da dieta hiperlipídica materna sobre os parâmetros metabólicos e autonômicos na prole. Sabe-se que a obesidade induzida pela dieta materna pode modificar os caminhos regulatórios centrais do feto, principalmente a regulação em longo prazo do apetite, porém nenhum trabalho procurou avaliar a influência da dieta hiperlipídica (DH) materna sobre os parâmetros cardiovasculares e autonômicos na prole. Ratas Holtzman adultas (280 - 300 g) foram divididas em dois grupos. Um grupo recebeu dieta padrão (DP) e o outro grupo DH. Os animais tiveram acesso livre a DP ou DH durante 6 semanas prévias (período de pré-gestação) e durante período de gestação e lactação. Todos os filhotes foram desmamados após 21 dias de vida e tiveram livre acesso a DP. Após uma semana alguns filhotes e as mães foram submetidos ao teste glicêmico e posteriormente eutanasiadas para retirada de tecido adiposo e sangue. Os outros filhotes foram submetidos à preparação coração-bulbo-hipotálamo (in situ). A DH aumentou o tecido adiposo nas ratas, mas foi capaz de alterar apenas as concentrações metabólicas de triacilgliceróis nesses animais. Filhotes machos de mães com DH (FMDH) apresentaram aumento no tecido adiposo, aumento nos níveis de colesterol total e nos níveis de HDL. Filhotes machos de mães com DP (FMDP) apresentaram redução da atividade simpática após transecção pré-colicular. Esse efeito não foi observado nos FMDH. A infusão de KCN provocou aumentos similares entre FMDP e FMDH quanto à atividade abdominal (ABD), na frequência do nervo frênico (f PNA) e na atividade simpática torácica (SNA), porém, no grupo FMDH esse aumento na SNA foi menor. O KCN provocou um aumento na amplitude do nervo frênico (PNA) sendo maior em FMDH. A hipercapnia provocou nos filhotes um aumento na SNA, na ABD e na PNA e gerou uma diminuição na f PNA em ambos os grupos. A diminuição na f PNA foi mais acentuada em FMDH e o aumento da PNA foi maior em FMDH. A fenilefrina provocou nos dois grupos uma diminuição na SNA, na ABD e na PNA, e gerou um aumento na f PNA. A simpatoinibição foi maior em FMDH. Esses resultados sugerem que a DH materna durante desenvolvimento fetal provavelmente altera as conexões centrais na prole. No segundo momento avaliou-se os efeitos da ocitocina sobre a reatividade vascular e seu papel nas respostas induzidas pela hipernatremia. Sabe-se que alterações no volume e/ou na composição dos compartimentos extracelulares evocam várias respostas autonômicas, cardiovasculares e hormonais que atuam em conjunto para modular a excreção renal de água e sódio. Os principais ajustes vegetativos são: vasodilatação renal e secreção de ocitocina. A regulação da osmolaridade e do volume é fundamental para sobrevivência. Apesar do vasto conhecimento na área nenhum estudo avaliou a interação entre a atividade simpática renal e a secreção de ocitocina sobre as respostas renais e cardiovasculares induzidas pela sobrecarga de sódio. Ratos Wistar machos (280-350 g) foram anestesiados e instrumentalizados para implantação de cateteres na bexiga, na veia e na artéria femoral e também para medição da pressão arterial média (PAM) e fluxo sanguíneo renal (FSR). Em ratos anestesiados (n = 6), a infusão de OT (0,03 μg/kg, i.v.) induziu vasodilatação renal. Em experimentações ex vivo a OT causou relaxamento da artéria renal. O bloqueio dos receptores de OT (OTR) reduziu essas respostas à OT, indicando um efeito direto desse peptídeo em seu receptor nesta artéria. O bloqueio dos receptores de ocitocina e a desnervação renal reduziu a vasodilatação renal e natriurese induzida pela sobrecarga de sódio aguda e a combinação do antagonista de receptores de ocitocina e a desnervação renal aboliram completamente a vasodilatação renal e reduziram ainda mais a natriurese induzida pela hipernatremia. Estes resultados sugerem que a OT e os nervos renais estão envolvidos na vasodilatação renal e natriurese induzida por hipernatremia aguda. O amplo conhecimento na área e a compreensão dos mecanismos regulatórios ativados tanto durante a obesidade quanto durante hiperosmolaridade permite uma maior possibilidade de desenvolvimento de novas ferramentas terapêuticas para a prevenção e tratamento da hipertensão.

A ocitocina tem sido usada como parâmetro para medir os laços sociais em animais. Recentemente foi demonstrado que a concentração de ocitocina aumenta em cães e donos quando interagem positivamente e, possivelmente, que na interação com crianças e adultos, cães fêmeas são mais afetivas do que os cães machos. Objetivo: determinar se existe diferença nos níveis séricos de ocitocina e no comportamento afetivo de cães machos e fêmeas, quando interagem com crianças e adultos. Método: foi realizado um estudo experimental, com 6 machos e 6 fêmeas da raça Beagle, pertencentes ao Laboratório de Ensino de Zootecnia (LEZO) da Faculdade de Agronomia, Universidade Federal do Rio Grande do Sul (UFRGS). Antes da interação foi colhido sangue para determinação da ocitocina basal dos cães. O teste foi filmado durante 3 minutos para posterior análise dos comportamentos caninos, enquanto os animais estiveram em contato com uma menina, fechados em uma sala, um após o outro, intercalando machos e fêmeas, sucessivamente. Retirados do local, voltaram as suas baias, e após 10 minutos foi feita nova coleta de sangue. Para determinação dos valores de ocitocina séricos será utilizado o Oxytocin ELISA kit ADI-900-153A-0001 da Assay Designs. As dosagens séricas de ocitocina serão testadas para normalidade e igualdade de variância e, se de distribuição normal, avaliadas pelo teste t de Student. As interações entre cachorros e participantes foram registradas ao longo de180 segundos por uma câmera de vídeo colocada no centro do teto da sala de teste. A partir de um etograma previamente determinado foi feita uma análise das gravações. Latência, frequência e duração total dos comportamentos foram medidas, utilizando um sistema de medição baseado no tempo. Resultados: após análise, entre os 15 comportamentos, apenas a latência para intenção de contato e comportamento de fuga foram significativamente diferentes entre machos e fêmeas, p de 0,03 e 0,003, respectivamente. Todos os demais não demonstraram diferenças estatísticas significativas. Segundo a análise subjetiva dos pesquisadores, fêmeas se mostraram mais dóceis com crianças do que machos. Os ensaios para ocitocina sérica não puderam ser realizados. Conclusão: Análise do comportamento demonstrou que em dois parâmetros as fêmeas tiveram interação mais prazerosa com a criança. Após a dosagem da ocitocina, esta conclusão poderá ser corroborada. / Oxytocin has been used to measure social bonds in animals. Recently it has been shown that oxytocin concentration increases in dogs and owners when interacting positively. It is expected that during interaction with children and adults, female dogs are more affective than male dogs, resulting and the augmentation of serum oxytocin levels. Objective: To determine if there is a difference in serum oxytocin levels and affiliative behavior in male and female dogs when interacting with children and adults. Methods: an experimental study was done, with 12 Beagles, 6 males and 6 females, belonging to the Laboratory of Animal Education (LEZO) of the Faculty of Agronomy, Federal University of Rio Grande do Sul (UFRGS). Prior to the interaction, blood was collected for determination of basal oxytocin in dogs. The test was filmed for 3 minutes for further analysis of canine behavior, while the animals were in contact with a girl, closed in a room, one after the other, intercalating males and females, successively. After this period, they returned their stalls, and 10 minutes later, the blood was drawned again. For determination of serum oxytocin values the Oxytocin ELISA kit ADI-900- 153A-0001 from Assay Designs will be used. Serum oxytocin dosages will be tested for normality and equality of variance and, if normal distributed, evaluated by the Student t test. Interactions between dogs and participants were recorded over 180 seconds by a video camera placed in the center of the test room ceiling. From an ethogram previously determined by the researchers, an analysis of the recordings was made. Latency, frequency and total duration of behaviors were measured using a timebased measurement system. Results: after 15 behaviors analyses, only latency for intention of contact (p=0.03) and escape behavior (p=0.003) were significantly different between males and females. Other behaviors did not show significant statistical differences. According to the researchers' subjective analysis, females were more docile with children than males. Serum oxytocin assays could not be performed. Conclusion: Behavioral analysis showed that in two parameters females had a more pleasant interaction with the child. After the dosage of oxytocin, this conclusion can be corroborated.

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2018-05-03T21:06:02Z No. of bitstreams: 1 2014 - Leandro Mendes Mascarenhas.pdf: 2602264 bytes, checksum: 2ecbf1ab9ebc2505d6ab0ed4cbcfc5d4 (MD5) / Made available in DSpace on 2018-05-03T21:06:02Z (GMT). No. of bitstreams: 1 2014 - Leandro Mendes Mascarenhas.pdf: 2602264 bytes, checksum: 2ecbf1ab9ebc2505d6ab0ed4cbcfc5d4 (MD5) Previous issue date: 2014-02-26 / In cows, the "critical time" of the estrous cycle determined by the physiological state that must be defined to maintain the corpus luteum (CL) and pregnancy or luteolysis and a new estrus occurs 15 to 19 days after ovulation. The mechanisms involved in premature luteolysis and regression of the CL are not yet understood complements. It is probable that the early CL regression is related to PGF2a release mediated by the endometrium lower concentrations of P4 receptors, higher concentrations of OT receptors, or both, in the endometrium. Thus, uterine receptors for P4 and OT may influence the secretion of PGF2a from the 10th day of the cycle, during which the CL is more sensitive to the luteolytic action of PGF2a. This study aimed to evaluate the effect of exogenous OT, postpartum crossbred cows on reproductive efficiency, with emphasis on the period of maternal recognition of pregnancy. The experiment was conducted in Bom Jesus do Itabapoana, Northwest Region Fluminense between September 2013 and January 2014. Twenty- four cows were entered into a TAI program (D0 - progestin releasing intravaginal device + estradiol benzoate (EB - 2 mg, im); D8 - intravaginal device removal and application of PGF2a (0.526 mg, im); D9 - BE (1 mg, im); D10 - IA). After ovulation, cows were divided randomly into two groups: GO (n=12): oxytocin (25 IU, iv, milking morning and afternoon), GC (n=12): without OT. Sonographic evaluations were performed on days 10, 15, 18, 28 and 42. The diameter of CL was calculated as the average of the two major axes and volumes (vol) using the formula for volume of a sphere (V = 4/3p ? (D / 2) 3) where D is the average diameter (DM) of CL. On day 28 of pregnancy diagnosis, confirmed at 45 and 60 days was carried out. We observed an increase in GC DM CL between the 10th and 18th. In GO DM CL decreased among 10th and 15th and most cows expressed estrus before day 18 (9/12 - 75%), six (50%) with return to estrus between the 15th and 18th. The vol. CL was higher in cows GC at all times with a significant difference (p<0.05) compared to GO on the 15th. Cows in the CG had vol. CL higher at all times and had a higher pregnancy rate (41.7%) compared to GO (25 %). The rates of fertilization and maintenance of pregnancy until day 42 demonstrates the low reproductive efficiency in GO compared to the CG (p=0.0022). With successive inseminations at 90 days one seven cows were empty in CG (8.33%) and GO (58.3%), respectively. The pattern of development and regression of the CL confirms the involvement of OT in the reproductive activity of lactating cows. The low reproductive efficiency in GO is probably due to the action of OT, confirming the hypothesis that exogenous OT can inhibit the maternal recognition of pregnancy. / Em vacas, o ?per?odo cr?tico? do ciclo estral determinado pelo estado fisiol?gico em que deve ser definida a manuten??o do corpo l?teo (CL) e da prenhez ou a lute?lise e um novo estro ocorre 15 a 19 dias ap?s a ovula??o. Os mecanismos envolvidos com a lute?lise prematura e regress?o do CL ainda n?o est?o complemente compreendidos. ? prov?vel que a regress?o precoce do CL esteja relacionada ? libera??o de PGF2a pelo endom?trio mediada por concentra??es mais baixas de receptores de P4, maiores concentra??es de receptores de OT, ou ambos, no endom?trio. Assim, receptores uterinos para a P4 e OT podem influenciar a secre??o de PGF2a a partir do 10? dia do ciclo, per?odo em que o CL ? mais sens?vel ? a??o luteol?tica da PGF2a. Objetivou-se avaliar o efeito da OT ex?gena, no p?s-parto de vacas mesti?as sobre a efici?ncia reprodutiva, com ?nfase no per?odo do reconhecimento materno da gesta??o. O experimento foi conduzido em Bom Jesus do Itabapoana, Regi?o Noroeste Fluminense entre setembro de 2013 e janeiro de 2014. Vinte e quatro vacas foram inseridas em um programa de IATF (D0 - dispositivo intravaginal liberador de progest?geno + benzoato de estradiol (BE - 2 mg, i.m.); D8 - remo??o do dispositivo intravaginal e aplica??o de PGF2a (0,526 mg, i.m.); D9 - BE (1 mg, i.m.); D10 ? IA). Ap?s a ovula??o, as vacas foram distribu?das aleatoriamente em dois grupos: GO (n=12): 25 UI ocitocina, i.v., na ordenha da manh? e da tarde; GC (n=12): sem OT. Avalia??es ultrassonogr?ficas foram realizadas nos dias 10, 15, 18, 28 e 42. O di?metro do CL foi calculado pela m?dia dos maiores eixos e os volumes (vol.) por meio da f?rmula para volume de uma esfera (V= 4/3p x (D/2)3), em que D ? o di?metro m?dio (DM) do CL. No dia 28 foi realizado o diagn?stico da gesta??o, confirmada aos 45 e 60 dias. Observou-se no GC um aumento do DM do CL entre os dias 10 e 18. No GO o DM do CL diminuiu entre os dias 10 e 15 e a maioria das vacas manifestaram cio antes do dia 18 (9/12 ? 75%), sendo seis (50%) com retorno ao cio entre os dias 15 e 18. O vol. do CL foi maior nas vacas do GC em todos os momentos com diferen?a significativa (p<0,05) em rela??o ao GO no dia 15. As vacas do GC tiveram o vol. do CL maior em todos os momentos e obtiveram uma maior taxa de prenhez (41,7%) comparativamente ao GO (25%). As taxas de fecunda??o e manuten??o da gesta??o at? o 42o dias evidencia a baixa efici?ncia reprodutiva no GO em rela??o ao GC (p=0,0022). Com sucessivas insemina??es aos 90 dias uma e sete vacas estavam vazias no GC (8,33%) e GO (58,3%), respectivamente. O padr?o de desenvolvimento e regress?o do CL confirma o envolvimento da OT na atividade reprodutiva de vacas em lacta??o. A baixa efici?ncia reprodutiva no GO deve-se provavelmente ? a??o da OT, confirmando a hip?tese de que a OT ex?gena pode inibir o reconhecimento materno da gesta??o.

The process of protein and RNA folding has been understood in general terms through the principle of minimal frustration, and is usually thought of as being guided by a folding funnel on the energy landscape, which is based around the native structure. However, more recently, various biomolecules have been associated with multifunnel energy landscapes, where each funnel exhibits a distinct structural ensemble and function. This work explores how the principle of minimal frustration may be extended to multifunnel energy landscapes that are associated with multifunctional biomolecules. To achieve this aim, the computational potential energy landscape framework is employed to analyse four example systems. Additionally, this study analyses mutants for all four systems, where the mutations are chosen to change properties of the systems without destabilising the native sequence ensemble entirely. The first system considered is a two-state coiled-coil. It is shown how mutations fundamentally change the energy landscape from the minimal frustrated organisation necessary to fulfil biological function. These changes can introduce alternative pathways for folding, as well as new structural ensembles. Similar effects are observed for ubiquitin. In addition, the landscape exploration allows us to calculate a number of experimentally determined properties for this protein, which exhibit excellent agreement, and we characterise folding at an atomistic level of detail. Next we consider the hormones oxytocin and vasopressin, which are themselves mutants of each other, along with a number of other mutants for both molecules. Again, the frustration in the landscape increases due to mutations, and a greater variety in the resulting structural ensembles is observed, leading to changes in binding affinities. Finally, the HP1 loop of RNA 7SK is analysed, revealing that the principles established for the energy landscapes of proteins extend to nucleic acids. Overall, the results indicate that sequences have evolved to exhibit the minimum number of funnels on the energy landscape to support multiple functions, extending the principle of minimal frustration to multifunnel energy landscapes.

Traditionnellement associée à la reproduction féminine, l'ocytocine (OT), une hormone peptidique synthétisée par les noyaux paraventriculaire et supraoptique de l'hypothalamus et sécrétée par l'hypophyse postérieure (neurohypophyse), a été récemment revue et a été démontrée avoir plusieurs nouveaux rôles dans le système cardio-vasculaire. En effet, notre laboratoire a montré que l’OT peut induire la différenciation des cellules souches embryonnaires (CSE) en cardiomyocytes (CM) fonctionnels. À l’aide du modèle cellulaire embryonnaire carcinomateux de souris P19, il a été démontré que ce processus survenait suite à la libération de la guanosine monophosphate cyclique (GMPc) dépendante du monoxyde d’azote. De même, il est connu que le peptide natriurétique auriculaire (ANP), un peptide produit, stocké et sécrété par les myocytes cardiaques, peut aussi induire la production du GMPc. De nombreuses études ont démontré que le cœur ayant subi un infarctus pouvait être régénéré à partir d’une population isolée de cellules souches et progénitrices transplantées. Une de ces populations de cellules, fréquemment isolées à partir d'organes provenant d'animaux aux stades de développement embryonnaire et adulte, appelée « Side Population » (SP), sont identifiées par cytométrie en flux (FACS) comme une population de cellules non marquées par le colorant fluorescent Hoechst 33342 (Ho). Les cellules SP expriment des protéines de transport spécifiques, de la famille ATP-binding cassette, qui ont pour rôle de transporter activement le colorant fluorescent Ho de leur cytoplasme. La sous-population de cellules SP isolée du cœur affiche un potentiel de différenciation cardiaque amélioré en réponse à un traitement avec l’OT. Récemment, l'hétérogénéité phénotypique et fonctionnelle des CSE a été mise en évidence, et cela a été corrélé avec la présence de sous-populations cellulaires ressemblant beaucoup aux cellules SP issues du cœur. Puisque l’ANP peut induire la production du GMPc et qu’il a été démontré que la différenciation cardiaque était médiée par la production du GMPc, alors nous émettons l'hypothèse selon laquelle l’ANP pourrait induire la différenciation cardiaque. Étant donné que les CSE sont composés d’un mélange de différents types cellulaires alors nous émettons aussi l’hypothèse selon laquelle l’utilisation d’une sous-population de CSE plus homogène renforcerait le potentiel de différenciation de l'ANP. Méthodes : Les SP ont été isolées des cellules P19 par FACS en utilisant la méthode d’exclusion du colorant fluorescent Ho. Puis, leur phénotype a été caractérisé par immunofluorescence (IF) pour les marqueurs de l’état indifférencié, d’auto-renouvellement et de pluripotence octamer-binding transcription factor 4 (OCT4) et stage-specific embryonic antigen-1 (SSEA1). Ensuite, la dose pharmacologique optimale d’ANP a été déterminée via des tests de cytotoxicité sur des cellules P19 (MTT assay). Pour induire la différenciation en cardiomyocytes, des cellules à l’état de sphéroïdes ont été formées à l’aide de la technique du « Hanging-Drop » sous la stimulation de l’ANP pendant 5 jours. Puis, des cryosections ont été faites dans les sphéroïdes afin de mettre en évidence la présence de marqueurs de cellules cardiaques progénitrices tels que GATA4, Nkx2.5 et un marqueur mitochondrial spécifique Tom22. Ensuite, les cellules SP P19 ont été stimulées dans les sphéroïdes cellulaires par le traitement avec de l'ANP (10-7 M) ou de l’OT (10-7 M), de l’antagoniste spécifique du guanylate cyclase particulé (GCp) A71915 (10-6 M), ainsi que la combinaison des inducteurs OT+ANP, OT+A71915, ANP+A71915. Après la mise en culture, la différenciation en cardiomyocytes a été identifié par l’apparition de colonies de cellules battantes caractéristiques des cellules cardiaques, par la détermination du phénotype cellulaire par IF, et enfin par l’extraction d'ARN et de protéines qui ont été utilisés pour le dosage du GMPc par RIA, l’expression des ARNm par RT-PCR et l’expression des protéines par immunobuvardage de type western. Résultats : Les sphéroïdes obtenus à l’aide de la technique du « Hanging-Drop » ont montré une hausse modeste de l’expression des ARNm suivants : OTR, ANP et GATA4 comparativement aux cellules cultivées en monocouches. Les sphéroïdes induits par l’ANP ont présenté une augmentation significative des facteurs de transcription cardiaque GATA4 et Nkx2.5 ainsi qu’un plus grand nombre de mitochondries caractérisé par une plus grande présence de Tom22. De plus, L’ANP a induit l’apparition de colonies de cellules battantes du jour 7 (stade précoce) au jour 14 (stade mature) de façon presque similaire à l’OT. Cependant, la combinaison de l’ANP avec l’OT n’a pas induit de colonies de cellules battantes suggérant un effet opposé à celui de l’OT. Par IF, nous avons quantifié (nombre de cellules positives) et caractérisé, du jour 6 au jour 14 de différenciation, le phénotype cardiaque de nos cellules en utilisant les marqueurs suivants : Troponine T Cardiaque, ANP, Connexines 40 et 43, l’isoforme ventriculaire de la chaîne légère de myosine (MLC-2v), OTR. Les SP différenciées sous la stimulation de l’ANP ont montré une augmentation significative du GMPc intracellulaire comparé aux cellules non différenciées. À notre grande surprise, l’antagoniste A71915 a induit une plus grande apparition de colonies de cellules battantes comparativement à l’OT et l’ANP à un jour précoce de différenciation cardiaque et l’ajout de l’OT ou de l’ANP a potentialisé ses effets, augmentant encore plus la proportion de colonies de cellules battantes. De plus, la taille des colonies de cellules battantes était encore plus importante que sous la simple stimulation de l’OT ou de l’ANP. Les analyses radioimmunologiques dans les cellules SP P19 stimulés avec l’ANP, A71915 et la combinaison des deux pendant 15min, 30min et 60min a montré que l’ANP stimule significativement la production du GMPc, cependant A71915 n’abolit pas les effets de l’ANP et celui-ci au contraire stimule la production du GMPc via des effets agonistes partiels. Conclusion : Nos résultats démontrent d’une part que l’ANP induit la différenciation des cellules SP P19 en CM fonctionnels. D’autre part, il semblerait que la voie de signalisation NPRA-B/GCp/GMPc soit impliquée dans le mécanisme de différenciation cardiaque puisque l’abolition du GMPc médiée par le GCp potentialise la différenciation cardiaque et il semblerait que cette voie de signalisation soit additive de la voie de signalisation induite par l’OT, NO/GCs/GMPc, puisque l’ajout de l’OT à l’antagoniste A71915 stimule plus fortement la différenciation cardiaque que l’OT ou l’A71915 seuls. Cela suggère que l’effet thérapeutique des peptides natriurétiques observé dans la défaillance cardiaque ainsi que les propriétés vasodilatatrices de certains antagonistes des récepteurs peptidiques natriurétiques inclus la stimulation de la différenciation des cellules souches en cardiomyocytes. Cela laisse donc à penser que les peptides natriurétiques ou les antagonistes des récepteurs peptidiques natriurétiques pourraient être une alternative très intéressante dans la thérapie cellulaire visant à induire la régénération cardiovasculaire. / Traditionally associated with female reproduction, oxytocin (OT), a peptidic hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus and secreted by the posterior pituitary (neurohypophysis), was revisited recently and was revealed to have several new roles in the cardiovascular system. Indeed, our laboratory has shown that OT can induce the differentiation of embryonic stem cells (ESC) into functional cardiomyocytes (CM). On the model of embryonal carcinoma cell line P19, it has been shown that this process occurs following the release of cyclic guanosine monophosphate (cGMP)-dependent nitric oxide. Similarly, it is known that atrial natriuretic peptide (ANP), a peptide produced, stored and secreted by cardiac myocytes, can also induce the release of cGMP. However, the cellular mechanisms involved in cardiac differentiation are still poorly understood. Numerous studies have shown that the injured heart can be regenerated from an isolated population of transplanted stem and progenitor cells. One of these cell populations, frequently isolated from embryonic and adult animal organs, called "Side Population" (SP), is characterized by active efflux of the fluorescent dye Hoechst 33342 (Ho). SP cells express specific ATP-binding cassette transporter proteins which actively transport Ho out of their cytoplasm. The SP cell subpopulation isolated from the heart display enhanced differentiation potential into cardiac phenotype in response to OT treatment. Recently, the phenotypic and functional heterogeneity of embryonic stem cells has been demonstrated, and this was correlated with the presence of cell subpopulations much like the SP cells from the heart and these cells can be identified by flow cytometry (FACS) as a population of unmarked cells by the Ho and which exhibit sensitivity to the inhibitor of the family of ATP-binding cassette ABC, verapamil. Thus, the SP from ESC could be a good candidate to induce cell differentiation more effectively to the cardiac phenotype. Since ANP can induce the release of cGMP and it has been shown that cardiac differentiation was mediated by the release of cGMP through the nitric oxide (NO), then we therefore formulate the hypothesis that ANP could also induce cardiac differentiation. Since ESC are composed of a mixture of different cell types so as we emit the hypothesis that the use of a subpopulation of more homogeneous ESC strengthen the differentiation potential of ANP. Methods: SP were isolated from P19 cells by FACS using the method of exclusion of fluorescent dye Hoechst and their phenotype was characterized by immunofluorescence (IF) for markers of the undifferentiated state, self-renewal and pluripotency OCT4 and SSEA1. Then, the optimal pharmacological dose of ANP was determined via cytotoxicity tests in P19 cells (MTT assay). For cardiac differentiation, cells in the form of spheroids were formed using the technique of "Hanging Drop" under the stimulation of ANP for 5 days. Then cuts were made in the spheroids via cryosection to highlight the presence of cardiac progenitor cell markers such as GATA4, Nkx2.5 and a specific mitochondrial marker Tom22. Next, the P19-SP cells were stimulated in cell spheroids by the treatment with ANP (10-7 M) or OT (10-7 M), the specific antagonist of particulate guanylate cyclase A71915 (10-6 M), and the combination of the inducers OT + ANP, OT + A71915, A71915 + ANP. After cell plating, the differentiation into cardiomyocytes has been identified by the appearance of beating cell colonies characteristics of contractile cardiac cells, by determining the cellular phenotype by IF, and finally by the extraction of RNA and proteins that were used for the determination of cGMP by RIA, the mRNA expression by RT-PCR and protein expression by western blotting. Results: The spheroids induced by ANP showed a significant increase in the presence of cardiac transcription factors GATA4 and Nkx2.5 as well as a greater number of mitochondria characterized by a greater presence of Tom22 compared with no induced cells suggesting a cardiomyogenic effect of ANP. In addition, ANP induced the appearance of beating cell colonies from day 7 (early stage) to day 14 (mature stage) similarly to OT. However, the combination of ANP with OT did not induce beating cell colonies suggesting a negative additive effect on cardiomyogenesis. The spheroids, obtained using the technique of "Hanging Drop", have shown a modest increase in mRNA expression as follows: OTR, ANP and GATA4 compared to cells grown in monolayers. By IF, we quantified (number of positive cells) and characterized, from day 6 to day 14 of differentiation, the cardiac phenotype of our cells using the following markers: Cardiac Troponin T, ANP, Connexines 40 and 43, Myosin Light Chain-2V, OTR. The SP differentiated under the stimulation of ANP showed a significant increase in intracellular cGMP compared with undifferentiated cells. Surprisingly, the antagonist A71915 induced a greater appearance of beating cell colonies compared to OT and ANP in early day of cardiac differentiation and the addition of OT or ANP potentiated its effects, further increasing the proportion of beating cells colonies. In addition, the size of beating cell colonies was even greater than under the simple stimulation of OT or ANP. Radioimmunoassay analysis in SP P19 cells stimulated with ANP, A71915 and the combination of both during 15min, 30min and 60min showed that ANP significantly stimulates the release of cGMP, however, A71915 does not abolish the effects of ANP and it rather stimulates the release of cGMP through partial agonist effects. Conclusion: Our results demonstrate firstly that ANP induces the differentiation of P19-SP cells into functional CM. Moreover, it appears that the signaling pathway NPRA-B/pGC/cGMP seems to be involved in the mechanism of cardiac differentiation since the abolition of cGMP mediated by the pGC potentiates cardiac differentiation and it appears that this signaling pathway is additive to the signaling pathway induced by OT, NO/sGC/cGMP, since the addition of OT to the antagonist A71915 stimulates cardiac differentiation more strongly than OT or A71915 alone. This suggests that the therapeutic effect of natriuretic peptides observed in heart failure and vasodilatory properties of certain natriuretic peptide receptor antagonists included the stimulation of stem cell differentiation into cardiomyocytes. This would therefore suggest that the natriuretic peptides or natriuretic peptide receptor antagonists could be an attractive alternative to cell therapy to induce heart regeneration.

Introduction: L’ocytocine (OT) était connue pour ses effets lors de la parturition et de la lactation. Depuis quelques années, d’autres rôles de l’OT ont été proposés. Ainsi, la découverte de l’OT et de son récepteur (OTR) dans le cœur a suggéré le rôle fonctionnel de cette hormone dans cet organe. Aujourd’hui, il existe une controverse concernant l’implication de l’OT dans la régulation de la pression artérielle (PA). Des études additionnelles sont donc requises pour préciser le rôle de l’OT dans le contrôle de la PA. C’est dans ce cadre que se situe la présente étude. Méthodes: Deux types d’expériences ont été faites: Une pour l’étude des paramètres métaboliques et l’autre pour les paramètres cardiovasculaires. Pour la première, l’OT (0.04 mg/kg) a été testée pour son effet métabolique. Les rats SD sont injectés avec l’OT et immédiatement placés dans des cages métaboliques individuelles et adaptées pour recueillir les urines. Les urines recueillies sur 3 heures nous ont permis de mesurer la diurèse, la natriurèse et la kaliurèse chez les rats. Pour le 2ème type, des rats spontanément hypertendus (SHR) et des Sprague-Dawley (SD) ont subi une chirurgie pour l’implantation de la sonde de télémétrie. Après 10 jours de récupération, nous avons commencé l’expérience qui s’est déroulée en 2 séries: la série des injections intraveineuses (i.v.) (0.04, 0.08, 0.1, 0.2 et 0.4 mg/kg en une seule injection) et la série des injections sous-cutanées (s.c.) (0.5 et 1 mg/kg/jour pendant 5 jours d’injection). La pression artérielle (PA), la fréquence cardiaque (FC) et de l’activité des rats ont été mesurées continuellement pendant toute l’expérience. Résultats: En i.v. la plus petite dose d’OT (0.04 mg/kg/0.3 ml) utilisée pour les effets rénaux a amené une diurèse significative, montre une tendance de natriurèse et de diminution de kaliurèse. Cette dose et celle d’OT (0.08 mg⁄kg⁄0.3 ml) sont sans effets sur la PA mais diminuent la FC des SHR et des SD (seulement les nuits). Pour les doses élevées en i.v. (0.1, 0.2 et 0.4 mg/kg d’OT), à l’exception de l’effet vasopresseur transitoire observé avec OT 0.4 mg/kg chez SD, l’OT 0.1 et 0.2 mg/kg ont diminué la PA. Les doses (0.2 et 0.4 mg/kg) d’OT ont diminué la PA chez les SHR. Elles ont augmenté la FC en journée aussi bien chez les SD que chez les SHR pendant que 0.1 mg/kg l’a diminuée. Pendant les nuits, c’est seulement la dose de 0.4 mg/kg qui a un effet sur la FC qu’elle diminue aussi bien chez les SD que les SHR. Les doses de 0.5 et 1 mg/kg injectées en s.c. ont diminué significativement la PA chez les SHR. Mais, chez les SD c’est l’OT à la dose de 1 mg/kg qui a amené une baisse de PA. À l’exception de OT 0.5 mg/kg/jour qui a augmenté la FC et l’activité chez les SHR en journée et ce au cours des injections, l’OT en s.c. a également entraîné une diminution de la FC et de l’activité. Conclusion: Ces résultats démontrent que l’OT intervient dans la régulation de la PA et la FC et les effets de l’OT dépendent de la souche de rats, de la dose, de la voie d’administration et du moment d’enregistrement des paramètres cardiovasculaires (jour ou nuit). Parlant de dépendance des résultats en fonction des voies d’administration, force est de signaler qu’avec les injections s.c. l’effet hypotenseur de l’OT est puissant et sans équivoque. Cela serait dû au fait que la duré de vie de l’OT est très courte (5 à 10 minutes) quand elle entre dans le sang. Ainsi, contrairement à la voie i.v., l’efficacité de l’OT en s.c. résulterait de sa libération lente dans le sang et donc toute la quantité administrée en s.c. ne se dégrade pas d’un seul coup. / Introduction: Oxytocin (OT) is known for its effects during parturition and lactation. In recent years, new roles of OT have been brought to light. Thus, the discovery of OT and its receptors (OTR) in the heart suggest a functional role in the body. Nowadays, the involvement of OT in blood pressure (BP) regulation is still controversial. Additional studies are therefore required to accurately determine the role of OT in the control of BP. Methods: Two types of experiments were carried out: Diuretic effect: conscious male, Sprague-Dawley rats were administered OT intravenously (0.04 mg/kg) and immediately placed in metabolic and individual cage; urine was collected and measured every hour for 3 hours. Urine measurement allowed diuresis, natriuresis and kaliuresis to be determined Telemetry: telemetry implants and catheters were inserted into the abdominal aorta of spontaneously hypertensive (SHR) and Sprague-Dawley (SD) rats. After 10 days (of necessary recovery), heart rate (HR), BP and animal locomotor activities were measured continuously. The same experiment was done on two batches of rats. Different doses of OT: 0.04; 0.08; 0.1, 0.2 or 0.4 mg/kg were injected once by intravenous (i.v) route. After each injection, we waited for the normalization of BP and HR before the next dose. Further more, 5 consecutive injections of OT were made (0.5 and 1 mg/kg) subcutaneously (s.c.). Results: The dose of 0.04 mg/kg of OT administrated for renal effects led to significant diuresis, a tendancy in natriuresis and kaliuresis decreased with no effect on BP. That dose as well as 0.08 mg/kg decreased HR in SHR and SD rats (only in the night). Whereas the highest doses in i.v. (0.1, 0.2 et 0.4 mg/kg d’OT), except a transient vasopressor effect observed with the OT 0.4 mg/kg in SD rats, OT 0.1 and 0.2 mg/kg decreased BP. OT 0.2 and 0.4 mg/kg decreased BP in SHR but increased HR during the days in both strains. The dose of 0.4 mg/kg led to a decrease of HR in SHR and in SD rats. The s.c. injections (0.5 and 1 mg/kg) of OT led to a significant decrease in BP in SHR, whereas in SD rats the lowering was only significant with a dose OT 1 mg/kg. HR significantly decreased in both strain with 1 mg/kg, whereas with 0.5 mg/kg, HR increased in SHR only and during the day. Conclusion: These results demonstrate that oxytocin acts on blood pressure and heart rate depending on strain, dose and route of administration. It’s important to point out that with s.c. injections the hypotensive effect of OT is powerful and unequivocal. This is probably because OT administered s.c. is slowly released into the bloodstream. Therefore the entire amount administered s.c. does not degrade at once and leads to the effectiveness of s.c. results. / réalisé avec la codirection de Marek Jankowski

As duas primeiras semanas de vida em ratos são críticas para o desenvolvimento, pois os animais são suscetíveis a influências ambientais. Diversos parâmetros neuroendócrinos e comportamentais podem ser influenciados, a curto e a longo prazo, pelas interações com a mãe, assim como por estressores. Entre esses estressores, um ambiente precoce socialmente aversivo pode alterar os comportamentos sociais, a ansiedade e as respostas neuroendócrinas ao estresse em adultos. O foco deste trabalho foi investigar o impacto do paradigma de provocação social na díade mãe-filhote sobre os comportamentos sociais e as respostas hormonais da prole em três idades. A provocação social foi realizada nos dias pós-natais (PP) 2 e 5. O comportamento maternal das lactantes foi registrado em PP3, 4, e 6. Os filhotes foram submetidos ao teste de preferência olfatória em PP7, o comportamento de brincadeira em juvenis foi registrado em PP30 e os ratos adultos (a partir de PP80) foram submetidos aos testes de campo aberto, labirinto em cruz elevado e interação social. Os adultos também foram expostos ao estresse por contenção (PP90). Os resultados mostraram que a intervenção aumentou a presença das mães no ninho. A intervenção reduziu o tempo gasto pelos filhotes no lado da maravalha do ninho, reduziu os níveis plasmáticos de ocitocina e prolactina, porém, aumentou os níveis de arginina-vasopressina. Nos juvenis, a intervenção reduziu a brincadeira de luta e os níveis plasmáticos de arginina-vasopressina. Nos adultos, a intervenção não levou a alterações na ansiedade e nas respostas hormonais ao estresse, porém, reduziu a latência para os comportamentos agressivos e os níveis plasmáticos basais de ocitocina. Conforme observado nas lactantes e nos neonatos, a provocação social levou a uma alteração da relação mãe-filhote, afetando, também, hormônios relacionados ao comportamento afiliativo em neonatos. Da mesma forma, a redução da brincadeira de luta em juvenis expostos à intervenção neonatal pode ter ocorrido devido à alteração da argininavasopressina, hormônio envolvido nesse comportamento. Apesar da intervenção não ter alterado a ansiedade e as respostas hormonais ao estresse em adultos, afetou de maneira específica o comportamento agressivo, reduzindo a sua latência. Este achado pode ser relacionado à ocitocina diminuída, conhecida por ter efeitos antiagressivos. Logo, sugerimos que a provocação social altere, tanto de forma precoce quanto duradoura, os comportamentos sociais, assim como os hormônios responsáveis pela modulação desses parâmetros. / The first two weeks of life in rats are critical for development because the animals are susceptible to environmental influences. A variety of neuroendocrine and behavioral parameters may be influenced in a short or long lasting way by the interactions with the mother as well as by stressors. Among these stressors, a socially aversive environment may alter social behaviors, anxiety and neuroendocrine responses to stress in adult subjects. The focus of this work was to investigate the impact of the social instigation paradigm on motherlitter dyad over social behaviors and hormonal responses in rats at 3 ages. Social instigation was carried out at postpartum days (PP) 2 and 5. Maternal behavior from lactating rats was registered at PP3, 4 and 6. Pups were submitted to the nest odor preference test at PP7, play behavior was registered in juveniles at PP30, and adult rats (starting at PP80) were submitted to the open field, elevated plus maze and social interaction tests. Adult rats were also submitted to restraint stress. Results show that the intervention increased presence in nest of lactating rats. The intervention reduced time spent on nest bedding side in pups, decreased oxytocin and prolactin plasma levels, however, increased arginine-vasopressin levels. Juveniles submitted to the neonatal intervention had reduced play-fighting frequencies and arginine-vasopressin levels. In adults, the intervention has not altered anxiety and hormonal responses to stress, however, it decreased the latency for aggressive behaviors, as well as oxytocin basal levels. According to the outcomes observed in lactating rats and pups, social instigation altered mother-infant relationship, as well as levels of hormones involved in affiliative behavior in neonatal rats. Similarly, the reduced play-fighting in juveniles exposed to the intervention may be related to the decreased arginine-vasopressin levels, which is a hormone involved in such behavior. In spite of the intervention having not altered the anxiety and hormonal responses to stress in adult rats, it altered in a specific manner the aggressive behavior, reducing its latency. This finding may be related to the decreased oxytocin levels, which is a hormone known to have antiaggressive effects. Thus, we suggest that social instigation impairs early to late social behaviors, as well as the hormones responsible for the modulation of such parameters.

Contexte : L’ocytocine (OT) et la vasopressine (VP) modulent les comportements sociaux. Leurs rôles ont été étudiés indépendamment l’un de l’autre mais des effets combinatoires de ces deux peptides sont à envisager puisqu’ils sont tous les deux libérés au cours des comportements sociaux. Dans le septum latéral (SL), une structure cérébrale intégrant des informations sociales, l’ocytocine et la vasopressine sont libérées au cours des interactions sociales et modulent la reconnaissance ainsi que la discrimination sociale.Objectif : Comprendre la fonction duale de l’ocytocine et de la vasopressine mise en jeu lors des interactions sociales dans un cadre physiologique et pathologique. Méthode : Chez la souris mâle, nous avons utilisé l’activité électroencéphalographique (EEG) comme marqueur et avons caractérisé des traces EEG dépendantes de l’OT et de la VP. Nous avons manipulé le système OT et le système VP au sein du septum au cours d’un protocole de reconnaissance/discrimination sociale en utilisant des outils pharmacologiques ou optogénétiques. Des expériences d’électrophysiologie sur tranche ont permis de caractériser la réponse électrophysiologique des neurones du septum latéral à l’application de chacun de ces peptides.Résultats : L’étude de l’activité EEG nous a permis de discriminer des effets induits par l’action septale de l’OT et la VP dans la bande de fréquence theta. Ces résultats suggèrent que la VP serait libérée dans le septum au cours de la première rencontre avec un juvénile alors que l’OT serait libérée au cours du processus d’habituation. La modulation de l’action de l’OT et de la VP sur le SL démontre que l’activation des récepteurs V1a au cours de la première rencontre est essentielle à la discrimination sociale tandis que l’activation des récepteurs à l’OT au cours du processus d’habituation permet de regain d’intérêt lorsqu’un nouveau juvénile sera présenté. Nous montrons aussi que l’OT et la VP modulent l’activité électrique de la quasi-totalité des neurones septaux. La nature de ces modulations définit 3 catégories de neurones qui communiquent entre eux via des signaux GABAergiques. Chez la souris Magel2KO, un modèle murin de troubles des comportements sociaux, la balance des effets septaux de l’OT et de la VP est altérée. Ceci suggère que cette régulation pourrait être impliquée dans certaines conditions pathologiques.Conclusion : Ces résultats mettent en évidence qu’il est essentiel, lorsque l’on étudie l’ocytocine, d’étudier le système vasopressinergique. Avec cette approche, nous avons montré que l’activation séquentielle du SL par l’OT et la VP est importante pour la régulation des interactions sociales. De plus, cette séquence d’évènements est altérée dans un modèle animal présentant des troubles sociaux. / Context : Oxytocin (OT) and vasopressin (VP) modulate social behaviors. The roles of OT and VP have been interrogated so far in isolation whereas combinatorial effects are anticipated as both hormones are secreted during social behavior. In the lateral septum (LS), a brain area processing behavioral social cues, OT and VP are released during social interaction and modulate social recognition or discrimination. Aim : To understand the dual function of OT and VP during social behavior in physiological and pathological conditions. Methods : In male mice, we used electroencephalographic (EEG) activity as a readout to characterize OT and VP dependent electrophysiological signatures and their sequence. We manipulated OT and VP systems to LS during social recognition/discrimination paradigm using pharmacology and optogenetic tools. Using slice electrophysiology, we characterized electrophysiological responses of LS neurons to both of these hormons.Results : Measurement of EEG theta activity allowed us to discriminate between OT and VP dependent LS modulation and indicated that VP would be released in the LS during 1st encounter with a juvenile while OT would be released during the habituation process. Modulation of OT and VP actions on the LS demonstrate that V1a activation during 1st encounter is essential for social discrimination and OT receptor activation during the habituation process allows the regain of interest for a new juvenile. We also demonstrated that OT and VP modulate electrical activity of almost all LS neurons. The nature of this modulation define 3 neuronal categories that communicate with each other through GABAergic signalling. Magel2KO mouse, which features social deficits, presents an altered balance of LS regulation by OT and VP. It suggests that this regulation could be involved in some pathological symptomatology.Conclusions : These results shed a light on the necessity to study vasopressin along with oxytocin. Doing this, we showed that vasopressinergic and oxytocinergic activation of the LS are sequentially important during the social recognition paradigm. Futhermore, this sequence of events is impaired in a mouse model featuring deficits of OT and social disabilities.