published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

published_or_final_version / Anatomy / Master / Master of Philosophy

<p>Supratherapeutic doses of anabolic androgenic steroids (AASs) are administered, not only as performance-enhancing drugs in the world of sports, but also in order to modify behaviour. AAS abusers are at risk of developing serious physical and psychological side effects such as dependence and aggressive behaviour. The aim of this thesis was to investigate the impact of supratherapeutic doses of nandrolone decanoate after subchronic administration on dopamine and serotonin pathways involved in drug dependence and aggression, in the male rat brain.</p><p>Adult male Sprague-Dawley rats received intramuscular injections of nandrolone decanoate (3 or 15 mg/kg) or vehicle once daily for 14 days. Nandrolone decanoate pre-exposure abolished the effect of amphetamine on the 3,4-dihydroxyphenylacetic acid (DOPAC) tissue level in the hypothalamus and on the DOPAC/dopamine ratio in the hypothalamus and the hippocampus. A significant decrease of the basal extracellular DOPAC and homovanillic acid (HVA) levels could be detected in the nucleus accumbens, which remained low during the first hour following the amphetamine challenge. Nandrolone decanoate significantly reduced the activity of both monoamine oxidase A and B (MAO-A and -B) in the caudate putamen and amygdala. The gene transcript levels of MAO-B, and the dopamine D1 and D4 receptors were altered in limbic regions. No changes in transcriptional levels could be detected among the serotonin receptor genes examined. However, the density of the serotonin transporter protein was elevated in a range of aggression-related brain regions.</p><p>Taken together, subchronic administration of nandrolone decanoate causes dopaminergic and serotonergic dysregulations in distinct brain regions. These areas of the brain are involved in the development of drug dependence and expression of impulsive and aggressive behaviours. These results may contribute to explain some of the behavioural changes often reported in AAS abusers, such as polydrug use and impaired impulse control.</p>

Arthropods are the most species-rich group of animals, and as such they exhibit an amazing diversity of morphological, behavioral, and ecological adaptations. Because of this diversity, the evolutionary history of this group has been, and still is notoriously difficult to determine because considerations of different traits invariably support alternative evolutionary relationships. Their nervous systems provide an invaluable set of characters for systematic inferences about the origins and evolutionary trajectories of Arthropoda. This is because nervous systems are ubiquitous and contain a wealth of structures from which to infer shared ancestry. Considerations of ancestral arthropod relationships have further provided insights into how arthropod nervous systems have maintained some traits through evolutionary time and how others have been modified or acquired as novelties. This dissertation explores the evolution of arthropod brains within an interdisciplinary framework, utilizing comparative neuroanatomical, neural cladistic, and molecular phylogenetic analyses to support novel hypotheses of nervous system evolution in arthropods. The field of neurophylogenetics relies on the characterization of shared derived neural traits to infer ancestry amongst taxa. The first portion of this work describes highly conserved neural elements from the lamina, or first optic neuropil, of several crustaceans. This study is followed by a neural cladistic study that infers evolutionary relationships amongst major arthropod groups based solely on neural traits. The results of this study are then compared to those from a large-scale molecular phylogenomic analysis of hundreds of conserved orthologous genes. Results from neural cladistic and molecular phylogenetics suggest several species whose neuroanatomical characterization would provide support for novel evolutionary hypotheses. The last portion of this dissertation details a comparative neuroanatomical study on one such diagnostic taxa, the copepod Tigriopus californicus. Two principles of arthropod nervous system organization and evolution are repeatedly supported with this approach: 1) many complex neural structures shared amongst arthropod groups have been inherited from ancient common ancestors, suggesting that the neural arrangements seen today have been carried over from antiquity; and 2) these same complex attributes are absent in numerous late-diverging lineages, supporting the hypothesis that secondary simplification of nervous systems is a common property of arthropods.

Capacity to perform prolonged exercise is reduced in high ambient temperatures, but this premature fatigue is not adequately explained by peripheral mechanisms. The aim of this thesis was to examine some possible underlying mechanisms of central fatigue operating during prolonged exercise in a warm environment. The first series of experiments investigated the effect of nutritional manipulation of central serotonergic activity through alterations to the plasma concentration ratio of free-tryptophan to branched-chain amino acids (f-TRP:BCAA). In contrast to previous reports, acute BCAA supplementation failed to alter perceived exertion and delay the onset of fatigue (Chapter 3). This response was similar when exercise was preceded by an exercise and diet regimen designed to reduce glycogen availability (Chapter 4). The ingestion of meals containing added carbohydrate and fat did not alter f-TRP:BCAA at rest (Chapter 5). Acute dopaminergic / noradrenergic reuptake inhibition with bupropion increased exercise perfonnance by 9 % in warm conditions (30C), but this effect was not apparent at 18C (Chapter 6). This response was accompanied by attainment of a higher core temperature and heart rate towards the end of the bupropion trial in the heat despite no detectable difference in perceived exertion and thermal stress. These data suggested that maintenance of catecholaminergic activity may dampen inhibitory signals from the CNS due to the attainment of a high core temperature, allowing power output to be maintained. The blood-brain barrier (BBB) regulates the exchange of substances between the cerebral interstitial fluid and the blood to maintain a stable environment for the CNS. If the BBB is compromised this may adversely influence nonnal brain function. Serum S1OOb, a proposed peripheral marker of BBB penneability, was increased following exercise in a warm environment (Chapter 7). These data indicate that exposure to combined exercise and heat stress may result in a loss of BBB integrity.

Introduction: Pulmonary Surfactant reduces surface tension in the terminal airways thus facilitating breathing and contributes to host's innate immunity. Surfactant Proteins (SP) A, B, C and D were recently identified as inherent proteins of the CNS. Aim of the study was to investigate cerebrospinal fluid (CSF) SP levels in hydrocephalus patients compared to normal subjects. Patients and methods: CSF SP A-D levels were quantified using commercially available ELISA kits in 126 patients (0±84 years, mean 39 years). 60 patients without CNS pathologies served as a control group. Hydrocephalus patients were separated in aqueductal stenosis (AQS, n = 24), acute hydrocephalus without aqueductal stenosis (acute HC w/o AQS, n = 16) and idiopathic normal pressure hydrocephalus (NPH, n = 20). Furthermore, six patients with pseudotumor cerebri were investigated. Results: SP AÐD are present under physiological conditions in human CSF. SP-A is elevated in diseases accompanied by ventricular enlargement (AQS, acute HC w/o AQS) in a significant manner (0.67, 1.21 vs 0.38 ng/ml in control, p<0.001). SP-C is also elevated in hydrocephalic conditions (AQS, acute HC w/o AQS; 0.87, 1.71 vs. 0.48 ng/ml in controls, p<0.001) and in Pseudotumor cerebri (1.26 vs. 0.48 ng/ml in controls, p<0.01). SP-B and SP-D did not show significant alterations. Conclusion: The present study confirms the presence of SPs in human CSF. There are significant changes of SP-A and SP-C levels in diseases affecting brain water circulation and elevation of intracranial pressure. Cause of the alterations, underlying regulatory mechanisms, as well as diagnostic and therapeutic consequences of cerebral SP's requires further thorough investigations.

No description available.

Introduction: Aging, comorbid conditions, and use of medications render older adults more susceptible to alcohol-disease or alcohol-drug interactions that may lead to harmful outcomes. In this dissertation project the risk profile of alcohol and medications use among older adults was investigated. Considering the rise in CNS-acting medication use and the adverse effect profile linked to CNS-acting medications, it was also of interest to find if older adults were at risk of falling due to interactions between alcohol and CNS-acting medication. Objectives: The objectives were as follows: 1) to determine the prevalence, pattern and factors associated with at-risk drinking, 2) to determine the prevalence and pattern of potential concurrent use of CNS-acting medication and alcohol, and to identify factors associated with alcohol use among CNS-acting medication users, 3) to assess the effects of potential concurrent use of CNS-acting medications and alcohol on the risk for falls in older adults. Methods: The study population comprised a nationally representative sample of community-dwelling older adults aged 65 years or older. The 2009 Medicare Current Beneficiary Survey (MCBS) data (n=7163) were employed to determine at-risk drinking based on the Comorbidity Alcohol Risk Evaluation Tool (CARET) and to assess the effects of potential concurrent use of CNS-acting medication and alcohol on the risk for falls. The National Health and Nutrition Examination Survey (NHANES) 2005-2010 data (n=3220) were employed to determine potential concurrent use of alcohol and CNS-acting medications. The effect of combined use of alcohol and CNS-acting medications on risk of falls was assessed using logistic regression modeling and adjusting for confounders. Alcohol consumption was measured by the quantity-frequency method and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommended drinking limits were utilized in all analyses. Results: In the MCBS study, 5.6% of the older adults were identified as at-risk drinkers. Adults aged between 65-74 years, being male, non-married, former or current smoker, and having no comorbid conditions were factors associated with at-risk drinking. In the NHANES study, 8.9% reported potential concurrent use of alcohol and CNS-acting medication. Use of at least one CNS-acting medication and drinking excessive alcohol, or binge drinking, was significantly associated with odds of falling. Conclusion: Hazardous alcohol use is common among older adults. A substantial proportion of older adults may concomitantly consume alcohol and CNS-acting medications. Odds of falling are greater in the presence of high alcohol intake and CNS-acting medication use. It is important for health care professionals to warn patients against excessive alcohol consumption. Increasing awareness of this issue among older adults and caregivers may help prevent falls. Contributions from healthcare professionals in the form of screening for potentially harmful alcohol use, prescription monitoring, and initiating counseling may help to reduce older adults’ risk for falls or other adverse effects.

L'obésité est depuis quelques années reconnue comme un des fléaux du XXIe siècle en affectant environ 10% de la population adulte mondiale. Le passage de l'obésité au stade de pandémie est le résultat de multiples facteurs dont une mauvaise hygiène alimentaire et une sédentarité croissante. La découverte récente de l'existence d'un état inflammatoire chronique au cours de l'obésité pouvant intervenir dans la physiopathologie de la maladie et de ses nombreuses complications fait aujourd'hui l'objet d'intenses investigations. Or, le tissu adipeux (TA) qui, parallèlement à son activité métabolique, possède également une activité sécrétoire intense, est un acteur majeur de ce syndrome inflammatoire. L'autotaxine (ATX), l'adiponectine et la résistine sont les médiateurs de l'inflammation sécrétés par le TA. Si le rôle de ces facteurs dans la régulation du métabolisme est bien établi, leurs effets sur d'autres organes ne sont pas toujours connus. Il est notamment intéressant d'étudier leurs effets dans le système nerveux central (SNC), les récepteurs de certains y étant présent. Dans ce contexte, nous avons dans un premier temps étudié l'effet de l'ATX sur le stress oxydant généré par le H2O2 (peroxyde d'hydrogène) et sur l'inflammation induit par le lipopolysaccharide (LPS) ou le trimethylétain (TMT) dans les cellules microgliales murines, cellules immunitaires résidentes du SNC. Nos résultats montrent pour la première fois, l'effet anti-oxydant et anti-inflammatoire de l'ATX sur les cellules microgliales. Chez la souris, le TMT affecte la région hippocampique du SNC et nous avons montré qu'il induit la production d'ATX après 5 jours d'une injection i.p. de TMT. Ce qui suggère un rôle important de l'ATX dans la régulation de l'homéostasie des microglies et du SNC ainsi que dans la neuroinflammation. L'effet du TMT sur l'inflammation produite par le TA a également été étudié et les résultats montrent que le TMT induit une réponse inflammatoire dans deux types cellulaires du TA : adipocytes et macrophages ainsi que dans le TA de souris obèse ob/ob. Ensuite, nous avons sous-cloné les ADNc de l'adiponectine et de la résistine dans des vecteurs d'expression eucaryote afin d'étudier leurs effets sur les cellules microgliales dans des conditions normales ou inflammatoires. Cette étude devrait permettre une meilleure compréhension de l'influence du TA sur le SNC et donc la relation entre l'obésité les maladies neurodégénérative afin de proposer de nouvelles approches thérapeutiques. / In the last years, Obesity has been considered a major health issue with around 10% of the world population affected. The causes of this pandemy are multiple, but include bad alimentary habits and an increasing settle way of life. The recent discovery that chronic inflammation during obesity was associated with this disease physiopathology and others complications is the center of many investigations. Adipose tissue (AT), in addition to its metabolic activity, has an intense secretory activity and is a main player in this inflammatory syndrome. Autotaxin (ATX), adiponectin and resistin are such mediators secreted by AT. These factors functions in metabolism regulation are well described, but their effects on others organs are not always known. As it has been shown that some of these factors receptors are present in the central nervous system (CNS), it is interesting to study their effects in this organ. In this context, we initially studied the effect of ATX on the oxidative stress generated by H2O2 (hydrogen peroxide) and inflammation induced by lipopolysaccharide (LPS) or trimethyltin (TMT) in murine microglial cells, resident immune cells of the CNS. Our results show for the first time, the anti-oxidant and anti-inflammatory effects of ATX in microglial cells. In mice, TMT affects hippocampal region of CNS and we showed that ATX RNA is up regulated in the hippocampus 5 days post TMT treatment. Our results suggest that ATX could be involved in the regulation of microglia homeostasis and in neuroinflammation. The effect of TMT on the inflammation produced by the AT has also been studied and the results show that TMT induces an inflammatory response in two cell types of AT: adipocytes and macrophages and in fat tissue from ob/ob mice.We then subcloned the cDNA of adiponectin and resistin in eukaryotic expression vectors to study their effects on microglial cells under normal or inflammatory conditions. This study should lead to better understanding of adipose tissue influence on the CNS and therefore the relationship between obesity and neurodegenerative diseases to develop new therapeutic approaches.