Insulin-like growth factor 1 (IGF-1) was considered as a factor potentially involved in arterial hypertension because of its effects on vascular tone. Several studies have suggested that IGF-1 might play an important role in the cardiovascular system for regulation of blood pressure. Previously, microinjection of insulin into the NTS of rats preceded prominent depressor and bradycardic and activates the PI3K downstream Akt. The aims of this study was to compare the cardiovascular responses induced by IGF-1 and to investigate the mechanisms of IGF-1induced signaling pathway in the nucleus tractus solitarius (NTS) between spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY) at 8/16 weeks old. The results indicate that microinjection of IGF-1 into the NTS of WKY and SHR produced dramatically depressor and bradycardic effects. The cardiovascular effects evoked by IGF-1 are less in SHR than WKY rats. The defect in IGF-1 vascular action is also present in young spontaneously hypertensive rats (age 8 weeks). Pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 significantly attenuated the responses evoked by microinjection of IGF-1 in both SHR and WKY at 8/16 weeks old. Moreover, mitogen-activated protein kinase kinase (p44/p42MAPK) inhibitor PD98059 administration attenuated the cardiovascular effects of IGF-1 in WKY at 8/16 weeks old but had no effect in SHR at age matched. In conclusion, both IGF-1/PI3K and p44/p42MAPK signal transduction pathways are involved in controlling central cardiovascular effects in WKY, whereas PI3K but not p44/p42MAPK signaling pathway is involved in SHR. This different condition suggests that such insensitive pathway may play a causative role in the development of hypertension.

No description available.

abstract: ADHD is a childhood neurobehavioral disorder characterized by inordinate levels of hyperactivity, inattention and impulsivity. The inability to withhold a reinforced response, or response inhibition capacity (RIC), is one aspect of impulsivity associated with ADHD. The first goal of this dissertation was to evaluate the fixed minimum interval (FMI) schedule as a method for assessing RIC. Chapter 2 showed that latencies were substantially more sensitive than FMI-derived estimates of RIC to the effects of pre-feeding and changes in rate and magnitude of reinforcement. Chapter 3 examined the ability of the FMI to discriminate between spontaneously hypertensive rats (SHR), an animal model of ADHD, and Wistar Kyoto (WKY) controls. Results from Chapter 3 showed that RIC was not substantially different between SHR and WKY rats. However, latencies were significantly shorter for SHRs than for WKYs suggesting incentive motivation differed between strains. The second goal of this dissertation was to examine the sensitivity of the SHR to nicotine. ADHD is a risk factor for tobacco dependence. The goal of Chapters 4 and 5 was to determine whether the SHR provided a model of ADHD-related tobacco sensitivity. Chapter 4 examined nicotine's locomotor and rewarding effects in adolescent SHRs using the conditioned place preference (CPP) procedure. SHRs developed CPP to the highest nicotine dose tested and were sensitive to nicotine's locomotor-enhancing properties. WKY controls did not develop CPP to any nicotine dose tested and were not sensitive to nicotine's locomotor properties. However, it is likely that nicotine effects were obscured by a pseudo-conditioning to saline in WKYs. Chapter 5 demonstrated that SHRs were more active than WKYs in the open-field but not in the Rotorat apparatus. Results also showed that SHRs and WKYs were both sensitive to nicotine's locomotor sensitizing effects. However, WKYs were more sensitive than SHRs to nicotine's locomotor suppressing effects. Collectively, results from Chapters 4 and 5 show that SHRs are sensitive to the rewarding and locomotor-enhancing properties of nicotine. However, more research is necessary to confirm that SHRs are a suitable model for studying ADHD-related tobacco use. / Dissertation/Thesis / Doctoral Dissertation Psychology 2015

O nervo vago (X nervo craniano) está formado por fibras motoras somáticas e viscerais e por fibras sensitivas e possui um trajeto e distribuição mais extensos do que qualquer outro nervo craniano. Nos seres humanos, o nervo vago tem sua origem craniana pelo forame jugular e possui dois gânglios no seu trajeto: o gânglio superior e o gânglio inferior. Em ratos, o nervo vago emerge pelo forame lacerado posterior, apresenta o gânglio nodoso e se estende posteriormente, em frente a coluna vertebral, por todo o pescoço, tórax até o abdome. Na literatura são escassos informações sobre as diferenças morfometricas e morfológicas dos nervos vagos em ratos normotensos (WKY) e ratos espontaneamente hipertensos (SHR). O objetivo do presente estudo foi comparar os aspectos morfológicos e morfométricos dos diferentes segmentos e lados do nervo vago de ratos das linhagens WKY e SHR, machos e fêmeas. Os animais (n =4 em cada grupo) foram pesados, anestesiados e sua pressão arterial aferida. Após o preparo com técnicas histológicas convencionais, secções transversais dos segmentos proximal e distal foram obtidas para análise de microscopia de luz e através de um sistema de imagem computacional. O peso corporal dos animais mais velhos acompanhou o crescimento, sendo maior nos machos do que nas fêmeas. Não foram observadas diferenças estatísticas na morfologia e morfometria entre os lados e segmentos tanto em fêmeas como machos. Quando comparados os animais entre as idades foi possível gerar alterações na área fascicular, número de fibras, diâmetro mínimo da fibra, área da bainha, área da fibra e diâmetro do axônio. / The vagus nerve (X cranial nerve) is formed by somatic and visceral motor fibers and by sensory fibers and has a more extensive path and distribution than any other cranial nerve. In humans, the vagus nerve has its cranial origin through the jugular foramen and has two ganglia in its path: the superior ganglion and the inferior ganglion. In rats, the vagus nerve emerges through the posterior lacerated foramen, presents the nodous ganglion and extends posteriorly, in front of the vertebral column, throughout the neck, thorax to the abdomen. In the literature, there is scarce information about the morphometric and morphological differences of the vagus nerves in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). The objective of the present study was to compare the morphological and morphometric aspects of the different segments and sides of the vagus nerve of rats of WKY and SHR, both male and female. The animals (n = 4 in each group) were weighed, anesthetized and their blood pressure measured. After preparation with conventional histological techniques, cross sections of the proximal and distal segments were obtained for light microscopy analysis and through a computer imaging system. The body weight of the older animals followed the growth, being higher in the males than in the females. No statistical differences were observed in morphology and morphometry between the sides and segments in both females and males. When comparing the animals between the ages it was possible to generate changes in the fascicular area, number of fibers, minimum diameter of the fiber, area of the sheath, area of the fiber and diameter of the axon.

Le choc septique est une pathologie fréquente associée à un taux de mortalité dépassant les 50%. Il s’agit de la première cause de mortalité en réanimation. Malgré les avancées des connaissances physiopathologiques sur le sepsis, le taux de mortalité reste très élevé. La majorité des recherches pré-cliniques sont réalisées sur des animaux jeunes et sains et sans antécédents cardiovasculaires, alors qu’il est bien établi que l’incidence et le taux de mortalité du sepsis augmente sévèrement avec l’âge. L’objectif de cette étude est la mise au point d’un modèle animal de sepsis ayant plusieurs antécédents cardiovasculaires, et l’évaluation des effets de la combinaison de deux maladies (hypertension et infarctus du myocarde (IDM)) chez des rats septiques sur la fonction cardiovasculaire et sur les voies de signalisation responsables de la réponse inflammatoire et apoptotique. L’étude a été réalisée sur des rats normotendus Wistar-Kyoto (WKY) et des rats Hypertendus Spontaneously Hypertensive (SHR) qui ont subi l’induction d’un IDM par ligature de l’artère coronaire gauche suivie ou non par l’induction d’un sepsis par ligature et perforation du caecum. Nous avons montré que les rats polypathologiques SHR, ayant subi un IDM préalable au choc septique, présentent une diminution drastique des paramètres cardiaques et hémodynamiques par rapport aux rats WKY ayant subi seulement un choc septique. En effet, le débit cardiaque, la pression artérielle moyenne et la fraction d’éjection sont diminuées respectivement de 70 %, 60 % et 67 % chez les rats SHR polypathologiques par rapport aux rats WKY ayant seulement un sepsis. On a observé également une hypo-réactivité vasculaire aux vasopresseurs plus importante chez les rats SHR-IDM-CLP comparée à celle des rats WKY-CLP. L’expression génique des récepteurs adrénergiques alpha-1 est fortement diminuée chez les rats SHR-IDM-CLP par rapport aux rats WKY-CLP. L’étude du taux d’expression des protéines impliquées dans l’apoptose révèle une surexpression des protéines caspase 3, caspase 8 et Pp38 chez les rats SHR polypathologiques des rats SHR-IDM-CLP par rapport aux rats WKY-CLP ayant seulement un sepsis. De plus, on remarque une forte diminution de l’expression des protéines eNOS et Akt chez les rats SHR-IDM-CLP comparés aux rats WKY-CLP. L’hypertension artérielle associée à l’insuffisance cardiaque a conduit à une plus grande sensibilité des rats au sepsis. Les rats SHR polypathologiques ont développé une insuffisance cardiaque aggravée par rapport aux rats WKY ayant seulement un sepsis. Le modèle de rats SHR ayant subi un IDM préalable au sepsis se rapproche d’avantage des situations cliniques observées quotidiennement dans les services de réanimation. Ce modèle pourrait servir de bon candidat pour les études pré-cliniques / Septic shock is considered as the most common cause of death among patients admitted in medical intensive care units. Mortality remains very high (50%) despite advances in physiopathological knowledge of this disease. In fact, most experimental studies are often conducted on young and healthy animals, whereas it is well established that the incidence and mortality rates dramatically increase with age. The goal of this study was to evaluate the effect of the combination of two diseases (hypertension and myocardial infarction) in a septic rat model, on cardiovascular function, cell survival and the inflammatory response. Therefore, we used normotensive Wistar-Kyoto rats (WKY) and Spontaneously Hypertensive Rats (SHR) in which myocardial infarction was induced by left coronary descending artery ligation, followed or not by cecal ligation and perforation-induced sepsis. Our results showed that the polypathological SHR rats in which a myocardial infarction and sepsis were induced, exhibited a significant decrease in cardiac and hemodynamic parameters compared to WKY rats that have sepsis (CLP) only. Indeed, cardiac output, mean arterial pressure and ejection fraction were reduced by 70%, 60% and 67% respectively in the polypathological SHR rats versus the WKY rats with sepsis. We observed also that the vascular hyporeactivity in the polypathological SHR rats was higher than for the WKY CLP rats. A mesure of gene expression level of alpha1 adrenergic receptor shows a relatively low expression level in the rats from SHR IDM CLP rats compared to WKY CLP that could explain the observed vasodilation. The protein level of caspase3 and 8, Pp38 and proteins involved in apoptosis, is upregulated in SHR IDM CLP rats compared to WKY CLP rats. However, the polypathological SHR rats show a significant decrease in the expression of eNOS and Akt protein compared to WKY CLP rats. The combination of hypertension with myocardial infarct is associated with higher sensitivity of the rats to sepsis. The polypathological SHR rats developed a severe heart failure compared to WKY rats having sepsis only. Our animal model, the polypathological SHR rats is very close to observed clinical situations in intensive care units. This model could serve as a good candidate for pre-clinical studies.

While women are diagnosed with depression at twice the rate of men, pre-clinical research on this topic has relied heavily on the responses of male animals. This thesis examined the behavioural and physiological effects of environmental manipulation in the female Wistar-Kyoto rat, a putative animal model of depression. At postnatal day 52, baseline behavioural measures were collected in 36 Wistar and 36 Wistar-Kyoto female rats using the following tests: the elevated plus maze to assess anxiety, the forced swim test for depression-like behaviour, and sucrose preference test to assess hedonic status. At postnatal day 62, the rats were randomly assigned to one of three environments for 30 days: 1) standard housing - 3 rats in one large cage 2) isolated housing - 1 rat per small cage, or 3) environmental enrichment - 6 animals in a multistory cage filled with novel objects and a running wheel. Following 30 days in their housing condition, the same behavioural measures were again collected. Large differences between strains were found with the Wistar-Kyoto females showing significantly less mobility and activity in both the forced swim test and elevated plus maze. Sucrose preference was significantly higher after enrichment in both strains. Post-environment immune cytokine and corticosterone levels were also assessed in these animals at baseline and after the forced swim test. No difference in corticosterone between strains was found at baseline. However, Wistar-Kyoto females had significantly higher corticosterone levels than their Wistar counterparts after the forced swim test. In contrast, Wistar-Kyoto females showed significantly lower serum levels of the pro-inflammatory cytokine IL-1β than Wistar females. In the hippocampus, astroglial staining intensity was significantly increased in the CA1 of Wistar females after environmental enrichment. Glucocorticoid receptor staining in the CA3 was also increased after environmental enrichment in both the Wistar-Kyoto and Wistar animals. Finally there was a trend towards higher levels of glucocorticoid receptors in the amygdala in Wistar-Kyoto animals who experienced environmental enrichment. Taken together, this thesis provides evidence for the effect of environment, specifically enrichment, on behaviour and physiological systems. These results suggest that incorporating social and physical enrichment as part of clinical intervention may benefit individuals with depression.

No description available.

Apesar de não alterar a pressão de normotensos, o treinamento físico (T) promove importantes ajustes periféricos e adapatações centrais do controle cardiovascular mediados pelo vago e simpático. Neste trabalho investigamos os efeitos do T (55% da capacidade máxima) sobre a inervação simpática vascular para os territórios muscular esquelético (locomotor e não locomotor) e renal e adrenais, através de imunohistoquimica e Western Blot para Tirosina-Hidroxilase (TH). T aumentou a capacidade física (+0,07±0,06 Km/h) e reduziu a FC (de 327±7 para 308±10 bpm), sem alterar a PA (126mmHg) e a estrutura de arteriolas dos diferentes territórios. T também determinou redução na imunoreatividade para TH nos músculos locomotores (-48%, p<0,05), sem alterações nos não locomotores e rins. A noradrenalina na artéria femoral (HPLC) encontrava-se reduzida após T. Nenhuma alteração foi detectada nas catecolaminas adrenais.Os dados indicam, que o T não altera as catecolaminas plasmáticas, mas reduz a atividade simpática vascular em normotensos, sendo este efeito tecido-específico. / Exercise training (T) does not reduce pressure in normotensive, but causes peripheral and central adjustments on cardiovascular system, mediated by autonomic nervous system. In this study we investigated whether T (55% maximal exercise capacity) is able to change vascular sympathetic drive to skeletal muscle (locomotor, non-locomotor), kidney and adrenals, using immunohistochemistry and western blot for tyrosine hydroxylase (TH). T improved performance (+0,07±0,06 Km/h) and reduced resting HR (from 327±7 to 308±10 bpm) without changing MAP (126mmHg) and arterioles wall/ lumen ratio in any tissue. T caused 48% decrease on TH-immunoreactivity of exercised muscles arterioles, without changes on non-exercised tissues. Norepinephrine concentration on femoral arteries was reduced after T. There was no change on adrenal. TH content. Decreased sympathetic drive to skeletal muscles arterioles (without changes on plasma cathecolamines) is a beneficial, tissue-specific effect in normotensive individuals.

Apesar de não alterar a pressão de normotensos, o treinamento físico (T) promove importantes ajustes periféricos e adapatações centrais do controle cardiovascular mediados pelo vago e simpático. Neste trabalho investigamos os efeitos do T (55% da capacidade máxima) sobre a inervação simpática vascular para os territórios muscular esquelético (locomotor e não locomotor) e renal e adrenais, através de imunohistoquimica e Western Blot para Tirosina-Hidroxilase (TH). T aumentou a capacidade física (+0,07±0,06 Km/h) e reduziu a FC (de 327±7 para 308±10 bpm), sem alterar a PA (126mmHg) e a estrutura de arteriolas dos diferentes territórios. T também determinou redução na imunoreatividade para TH nos músculos locomotores (-48%, p<0,05), sem alterações nos não locomotores e rins. A noradrenalina na artéria femoral (HPLC) encontrava-se reduzida após T. Nenhuma alteração foi detectada nas catecolaminas adrenais.Os dados indicam, que o T não altera as catecolaminas plasmáticas, mas reduz a atividade simpática vascular em normotensos, sendo este efeito tecido-específico. / Exercise training (T) does not reduce pressure in normotensive, but causes peripheral and central adjustments on cardiovascular system, mediated by autonomic nervous system. In this study we investigated whether T (55% maximal exercise capacity) is able to change vascular sympathetic drive to skeletal muscle (locomotor, non-locomotor), kidney and adrenals, using immunohistochemistry and western blot for tyrosine hydroxylase (TH). T improved performance (+0,07±0,06 Km/h) and reduced resting HR (from 327±7 to 308±10 bpm) without changing MAP (126mmHg) and arterioles wall/ lumen ratio in any tissue. T caused 48% decrease on TH-immunoreactivity of exercised muscles arterioles, without changes on non-exercised tissues. Norepinephrine concentration on femoral arteries was reduced after T. There was no change on adrenal. TH content. Decreased sympathetic drive to skeletal muscles arterioles (without changes on plasma cathecolamines) is a beneficial, tissue-specific effect in normotensive individuals.

A presença da hipertensão arterial pode comprometer a qualidade da reparação óssea, pois a doença é caracterizada por alterações fisiopatológicas vasculares e do metabolismo mineral. Com o objetivo de avaliar a neoformação e o remodelamento ósseo, este trabalho investigou o processo da reparação óssea em ratos geneticamente hipertensos (SHR) e de seus controles Wistar-Kyoto (WKY). Defeitos bicorticais de 2mm de diâmetro no lado direito e de 5mm no lado esquerdo, foram realizados com trefinas na região do ângulo de mandíbula. Os animais, divididos em grupos de cinco indivíduos cada, foram sacrificados após 2, 3, 5, 10, 15, 30, 60 e 90 dias pós-operatórios; as mandíbulas foram removidas, fixadas em formol a 10%, descalcificadas em ácido fórmico a 20%, incluídas em parafina e as secções histológicas, de 7m de espessura, coradas com hematoxilina e eosina. As imagens foram capturadas com aumento de 40x e a área do defeito mensurada pelo programa de histometria digital Image J versão 1.4. A análise estatística revelou que não houve diferença significante na comparação entre as linhagens WKY e SHR (p = 0,884), independente dos períodos ou lados avaliados; entre períodos, nas linhagens WKY (p = 0,101) e SHR (p = 0,479), independente dos lados avaliados; entre períodos por linhagens no lado direito; e entre linhagens por lados, esquerdo com p = 0,466 e direito com p = 0,689, independente do fator período. Houve diferença estatisticamente significante entre o lado esquerdo e o direito (p < 0,001), independente das linhagens e períodos avaliados; entre os lados por linhagens, WKY e SHR, ambas com p < 0,001; entre períodos por linhagens no lado esquerdo, no qual o grupo WKY de 15 dias apresentou área menor que o grupo WKY de 60 dias e o grupo SHR de 10 dias, e o grupo WKY de 60 dias apresentou área maior que o grupo SHR de 30 dias e SHR de 60 dias. Apesar das alterações encontradas no lado esquerdo, que podem ser atribuídas à remodelação funcional do osso da mandíbula, não houve diferenças significantes na reparação do defeito de 5mm e de 2mm entre ratos espontaneamente hipertensos e de seus controles Wistar-Kyoto. / Arterial hypertension may affect the quality of bone repair because this disease is characterized by physiopathological vascular and bone metabolism changes. With the objective of evaluating the bone neoformation and remodeling, this study investigated the process of bone repair in spontaneously hypertensive rats (SHR) and their match controls Wistar-Kyoto (WKY). Through-in-through defects were done with trephine burs in the mandibular angle area, of 2mm diameter on the right side and 5mm diameter on the left side. The animals were divided into groups of five individuals each one and killed after 2, 3, 5, 10, 15, 30, 60 and 90 postoperative days; the mandibles were removed, fixed in 10% formalin solution, decalcified with 20% formic acid, and embedded in paraffin; the histological sections of 7m thickness were stained with hematoxylin and eosin. The images were captured with 40x magnification and the defect area was measured by the image processing program Image J version 1.4. The statistical analysis showed that there is no significant difference in the comparison of WKY and SHR strains (p = 0,884), independent of periods or sides; among periods, in the WKY strain (p = 0,101) and SHR one (p = 0,479), independent of sides; among periods by strains on the right side; and among strains by sides, left side with p = 0,466 and right side with p = 0,689, independent of periods. There is a significant difference between left and right side (p < 0,001), independent of strains and periods; between sides by strains, WKY and SHR, both with p < 0,001; among periods by strains on the left side, which WKY 15 days group showed an area smaller than WKY 60 days and SHR 10 days groups, and WKY 60 days group showed an area bigger than SHR 30 days and SHR 60 days groups. Despite the changes founded on the left side that could be attributed to the functional remodeling of the mandibular bone, there were no differences in the bone repair of 5mm and 2mm diameter defects between spontaneously hypertensive rats and their match controls Wistar-Kyoto.