名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成5年5月14日 雄山博文氏の博士論文として提出された

Thesis (M.Sc.)--Memorial University of Newfoundland, 2000. / Restricted until November 2001. Bibliography: leaves 51-55.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2009. / Härtill 4 uppsatser.

Increasing evidence illustrates an involvement of stress in a large variety of physical and mental illness. Together with the evolutionary development of the social behavior in humans, the traditional interpretations of the attachment theory and the social support theory underscores the importance of affection, belonging and appreciation for human well-being. Not only can an imbalanced stress system be the cause of severe pathological consequences, insufficient social contact can also hamper recovery. Frequent usage of animals in various settings steadily illustrates both physiological and psychological benefits on both the young and the old, the healthy and the ill. Through the study of neurobiological factors, with oxytocin as a central mediator of social behavior and its  impact in turn on the stress- and cortisol system, this paper examines the possibility of animals to function as social support. The potential of animals to reduce the suffering in patients with stress related psychiatric disorders, such as the highly frequent exhaustion disorder, human-animal interactions might offer a non-invasive complementary tool to current treatment methods.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2004. / Härtill 5 uppsatser.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The aim of the present study was to examine the role of oxytocin (OT) on the control of oocyte meiotic resumption in the events that involves progesterone (P4) and prostaglandins (PGs). Oocytes were co-cultured with follicular hemisections for 15 h to determine the effect of different doses of OT or atosiban (ATO; oxytocin receptor antagonist) on the oocyte meiotic resumption. In another experiment, we examine the effect of P4, OT and PGs interaction on the regulatory cascade of the induction of oocyte meiotic resumption. Oxytocin in the concentration of 1 μM was effective in inducing the resumption of meiosis of oocytes co-cultured with follicular cells (84.0%), not differing statistically from the positive control group (74.4%). Similarly, atosiban inhibited the positive effect of OT on meiotic resumption in a dose-dependent manner, in which the metaphase I (MI) rate was only 27.6% in the presence of 10 μM ATO, not differing from the negative control group (25.5%). The possible toxic effect of ATO was tested in a 15 or 24 h-cumulus-oocyte complex culture system. In the third experiment, we demonstrated that P4 was able to induce the oocyte meiotic resumption, which was inhibited by ATO. However, the positive effect of OT was not blocked by mifepristone (P4 antagonist) but was inhibited by indometacine (a non-selective PTGS2 inhibitor). Collectively, these results evidenced that P4 is upstream to OT and PGs are required for the positive effect of OT to induce oocyte meiotic resumption. In conclusion, our results evince that together with Ang II, already proved by our group as involved in oocyte meiotic resumption, P4, OT and PGs are sequential steps in the hormonal cascade that culminates with resumption of meiosis in cattle. / O objetivo do presente estudo foi examinar o papel da ocitocina (OT) no controle da retomada meiótica de oócitos bovinos, além da interação desse peptídeo com a progesterona (P4) e prostaglandinas (PGs) neste evento fisiológico. Nesse estudo, verificamos a interação da P4, OT e PGs na cascata de indução de retomada meiótica do oócito. Oócitos foram co-cultivados com metades foliculares por 15 h para determinar o efeito de diferentes doses de OT ou atosiban (ATO; antagonista do receptor de ocitocina) no reinício da maturação meiótica A OT na concentração de 1 μM foi eficaz em induzir a retomada da meiose de oócitos co-cultivados com células foliculares (84,0%), não diferindo estatisticamente do grupo controle positivo (74,4%). O ATO inibiu o efeito positivo da OT sobre o reinício da meiose de uma forma dose-dependente onde a porcentagem de oócitos que atingiu o estádio de metáfase I (MI), foi apenas 27,6% na presença de 10 μM de ATO, não diferindo do grupo controle negativo (25,5%). Para confirmar que este efeito não era resultante de toxicidade ocasionada pelo ATO, foi realizado um experimento onde o efeito tóxico do ATO foi testado em um cultivo durante 15 e 24 horas, e foi possível observar que ele não apresenta efeitos tóxicos aos oócitos em cultivo, permitindo a retomada da meiose. Foi demonstrado também que a P4 foi capaz de induzir a retomada da meiose do oócito bovino ao qual foi inibida pelo ATO. No entanto, o efeito positivo da OT não foi bloqueado pela mifepristona (antagonista P4), mas foi inibida por indometacina (inibidor não-seletivo de PTGS2). Coletivamente, estes resultados evidenciam que P4 requer OT e esta requer PGs para que oócitos bovinos reiniciem a meiose. Em conclusão, nossos resultados demonstram que, P4, OT e PGs são passos seqüenciais da cascata hormonal que culmina com a retomada da meiose em bovinos.

L’arthrose est une pathologie fréquente et responsable d’une morbidité majeure. En France, cette pathologie est devenue une priorité de santé publique et jusqu’à récemment il n’existait aucune donnée épidémiologique en population générale. Mon travail a permis d’apporter les premiers chiffres de prévalence en population générale et a constitué une étape préliminaire essentielle à la réalisation d’une étude de prévalence nationale et à la constitution d’une cohorte de cas prévalents d’arthrose symptomatique des membres inférieurs. Ces travaux m’ont amené à m’intéresser à l’apport diagnostique des clichés en Schuss et ainsi mettre en évidence que ces clichés seuls sont aussi contributifs que l’association clichés en extension et clichés en Schuss classiquement réalisés pour le diagnostic de gonarthrose. L'ocytocine est une hormone exprimée dans un grand nombre de cellules dont les ostéoblastes et les adipocytes. Son rôle dans l'ostéoporose a été démontré. A ce jour aucune donnée sur son éventuel rôle dans l’arthrose n’a été publiée. J’ai donc recherché un éventuel rôle direct et/ou indirect de l'ocytocine. Pour cela, nous avons utilisé un modèle cellulaire: ’’Multipotent Adipose-Derived Stem’’ (hMADS) développé dans notre laboratoire de recherche. Nous avons, dans un premier temps, montré les capacités chondrogéniques de ces cellules ainsi que leur intérêt comme potentiel outil de tests pharmacologiques dans l’arthrose. La deuxième étape a consisté à démontrer un rôle de l’ocytocine dans la chondrogenèse. Nous avons montré que l’ocytocine a une action bénéfique sur l’expression des gènes chondrocytaire. De plus, le traitement des cellules par l'ocytocine atténue l'effet négatif de l'IL-1β sur ADAMTS-4 qui est responsable de la dégradation de l'aggrécane. L’ensemble de ces résultats indique que l'ocytocine représente un modulateur positif de la formation des chondrocytes et prometteur comme traitement potentiel pour l'arthrose. / Osteoarthritis is the most frequent cause of rheumatic complaints in Rheumatology. Osteoarthritis is responsible of major morbidity. Increase of life span is accompanied by an increase of aging diseases such as osteoporosis and osteoarthritis. In France, the disease became a public health priority, and until recently, there was no osteoarthritis epidemiologic data in the general population concerning lower limbs. My clinical studies enabled me to bring the first prevalence study in the general population. It was an essential preliminary step for a national prevalence study, and the constitution of a prevalent symptomatic cases cohort of lower limbs osteoarthritis. These observations let me to analyze the diagnostic contribution of Schuss X rays and to show that Schuss X-rays alone do not provide less information’s for the diagnosis of knee osteoarthritis, than the usual association standard extension X rays -Schuss X rays. Oxytocin is a hormone expressed by a large number of cells including osteoblasts and adipocytes. Recently, its role in osteoporosis has been shown. So far, no data about its potential role in osteoarthritis are available. I thus searched for a possible direct and / or indirect role of oxytocin on chondrogenesis. For that, I used a cellular model developed in our research laboratory: the “Multipotent Adipose-Derived Stem’’ (hMADS) cells. A first step, I show that hMADS cells are endowed with a chondrogenic capacity, and they represent a powerful tool for therapeutic test in osteoarthritis. The second step was to analyze the role of oxytocin in chondrogenesis. We shown that oxytocin has a benefic effect especially on the aggrecan (increase), probably via a negative effect on ADAMTS4, and also several other major chondrogenesis genes such as COMP and Sox9. Taken together, these results indicate that oxytocin represents a positive modulator of chondrocyte formation and holds promise as a potential therapy for osteoarthritis.

A complex system exists to monitor the body’s energy status and regulate food intake and energy expenditure to maintain a constant body weight. However, this homeostatic system is not the sole system regulating appetite. The hedonic system comprised of the mesolimbic reward pathway influences motivation to eat and acts alongside the homeostatic system to control feeding behaviours. It is often assumed that the hedonic system promotes the consumption of palatable, energy-dense foods and this can disrupt homeostatic mechanisms regulating food intake, resulting in energy overconsumption and weight gain in the long term. Yet, it is unclear to what extent the homeostatic system can defend body weight in an environment rich in palatable, energy-dense foods. I hypothesised that the homeostatic system compensates for the energy in palatable foods by reducing subsequent energy consumption, defined as homeostatic caloric compensation. I investigated homeostatic caloric compensation in a rat model of restricted palatable, high-sugar food access. Rats were schedule-fed moderate amounts of sweetened condensed milk (SCM) daily in addition to ad lib bland diet access. Both male and female rats calorically compensated for the energy consumed from moderate amounts of SCM through a robust and accurate reduction in energy consumed from bland diet, resulting in no short-term changes in body weight gain. However, homeostatic responses were limited as male rats were unable to fully calorically compensate for the scheduled-feeding of large amounts of SCM, an apparent loss of homeostatic control. It was not investigated whether female rats are also unable to fully calorically compensate for large amounts of SCM. It is possible that male rats consume these large amounts of SCM due to hedonic drive but continue to eat bland diet to acquire nutrients that are not present in SCM. To determine whether male rats defend bland diet consumption due to nutrient requirements, rats were schedule-fed large amounts of SCM enriched with protein or fibre. However, male rats did not fully calorically compensate for the energy in large amounts of SCM when enriched with protein or fibre. Overall, these findings demonstrate that the homeostatic system is able to respond to the hedonic consumption of palatable food through caloric compensatory mechanisms to defend body weight. However, it appears that the homeostatic system is unable to effectively respond to excessive hedonic palatable food consumption through caloric compensation alone. To shed light on what homeostatic mechanisms may underlie this compensatory behaviour, I used expression of the immediate early gene c-Fos to investigate neuronal activity following the scheduled-feeding of moderate amounts of SCM in male rats. c-Fos expression was increased in the ventral tegmental area of the mesolimbic reward pathway and in the lateral hypothalamus. The lateral hypothalamus has been proposed to act as an interface between homeostatic and hedonic systems. Therefore, in response to the hedonic consumption of palatable food, the homeostatic system and reward pathway may interact. Additionally, c-Fos expression was increased in satiety mediating brain regions of the homeostatic system, including the nucleus of the solitary tract and dorsomedial hypothalamus. This suggests that the homeostatic system may compensate for the energy in the palatable food by reducing subsequent food intake through inducing satiety. Furthermore, following the consumption of SCM, c-Fos expression was increased in magnocellular oxytocin neurons of the hypothalamic supraoptic and paraventricular nucleus. I demonstrated that the oxytocin system was activated by gut-brain signalling potentially involving the nucleus of the solitary tract. Therefore, the oxytocin system may be involved in homeostatic compensatory mechanisms triggered in response to the hedonic consumption of SCM, as part of a pathway mediating satiety. Moreover, I showed that c-Fos expression was also increased in the hypothalamic supramammillary nucleus (SuM) following the consumption of SCM. It has been previously shown that the SuM is involved in reward-related motivated behaviours and was recently implicated in the motivation to acquire and consume palatable food rewards. I also demonstrated that c-Fos expression in the SuM might be specific to the motivated consumption of palatable food, consistent with the SuM being involved in reward-related motivated behaviours. Furthermore, there is additional evidence from these studies that the SuM may functionally communicate with brain regions in the homeostatic and hedonic systems, including the lateral hypothalamus, dorsomedial hypothalamus and ventral tegmental area. Finally, I explored whether the gut-secreted orexigenic hormone ghrelin activates the SuM, as ghrelin may act at the SuM to influence feeding motivation. However, systemic ghrelin administration did not influence SuM c-Fos expression. As the SuM is activated following the consumption of SCM and may act as an interface between the homeostatic and hedonic systems, it is possible that the SuM could be a key component in the regulation of hedonic feeding. Using a rat model, I have shown that homeostatic compensatory mechanisms are triggered in response to the hedonic consumption of palatable, high-sugar food to regulate energy intake. This response is likely to involve homeostatic satiety mechanisms and interactions between multiple brain regions involved in the homeostatic and hedonic control of food intake. Overall, these findings shed light on how the homeostatic system responds to hedonic energy consumption and highlights specific brain regions that may be involved in hedonic feeding or homeostatic compensatory responses.

Recent research has indicated a causal link between oxytocin and spirituality. The present experiment sought to examine the effects of intranasal oxytocin (IN-OT) and absorption on mysticism and spirituality in a sensory deprivation setting. The results failed to find any main effects of IN-OT on mysticism, or on spirituality. Interaction effects were discovered however, where IN-OT interacted with absorption both on mysticism and spirituality. More specifically IN-OT undermined the association between absorption and outcomes that were observed in the placebo control condition. The results contradict the findings from the only previous experiment conducted on IN-OT and spirituality. The interaction effects align with previous research on IN-OT, suggesting an increase in suggestibility among low absorption scorers. These results motivate further research on the relation between oxytocin, absorption and spirituality, keeping the idea of suggestibility in mind.