Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 26, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Ping Yu. Vita. Includes bibliographical references.

Thesis (M.S.)--University of Michigan, 1976.

Thesis (M.S.)--University of Michigan, 1971.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--Göteborg University, 2005. / Thesis statement inserted. Includes bibliographical references.

Schizophrenia is a complex mental disorder characterised by positive symptoms such as hallucinations and psychosis, negative symptoms such as avolition and anhedonia, and cognitive defects. Schizophrenia risk has a genetic component, and it is likely that this is caused by interaction between numerous genes with individually small effects. Environment also plays a role; factors associated with schizophrenia include drug use, prenatal stressors and living environment. Candidate genes linked to schizophrenia have been identified through recent GWAS of human populations with the disorder, including ANK3, TCF4 and CACNA1C. GWAS associations alone are not sufficient to identify these as definitive risk genes for the disease. In order to validate these findings, animal models (in particular the mouse) can be used to study the effect of mutations in these genes of interest. Knockouts of these genes in the mouse are lethal, so we have used the ENU mutagenesis DNA archive at MRC Harwell to screen for additional allelic variants expressing more subtle and varied behavioural phenotypes. Endophenotypes associated with schizophrenia and bipolar disorder, such as anxiety, cognitive deficits and sensorimotor gating deficits, can be characterised in these mutants and, together with molecular characterisation, this can validate these genes as risk factors. While mutations in Ank3 and Tcf4 proved to be non-functional, two mutations in Cacna1c have been associated with anxiety phenotypes and differences in EEG power spectra, as well as causing a cardiac phenotype.

La dépression est une maladie psychiatrique qui atteint environ 20% de la population. En 2006 notre équipe a montré l’implication du canal potassique TREK-1 dans cette pathologie, et, en 2010, elle a identifié un bloqueur de TREK-1, la spadine, ayant des propriétés antidépressives. La spadine a la même efficacité après quatre jours de traitement que les antidépresseurs classiques qui en nécessitent vingt-et-un. Lors de mon doctorat, nous avons démontré la spécificité de la spadine pour les canaux TREK-1 et l’absence d’effet secondaire notamment au niveau cardiaque et sur les fonctions où l’activation du canal TREK-1 a des effets bénéfiques (ischémie, épilepsie, douleur). Nous avons pour cela utilisé des techniques d’électrophysiologiques et différents tests comportementaux adaptés à ces différentes pathologies. J’ai également démontré les effets antidépressifs de la spadine sur deux modèles animaux, un modèle génétique, les souris Rouen, et un modèle induit par un traitement à la coticostérone. La dernière partie de ma thèse a porté sur l’identification d’analogues de la spadine ayant une meilleure affinité et une meilleure efficacité in vivo, et ne présentant pas d’effet secondaire. Deux peptides synthétisés par la technique de retro-inverso ont présenté ces propriétés. Parallèlement, nous avons également recherché, en collaboration avec la société MedinCell, une formulation de polymère permettant la libération constante et prolongée de l’analogue sélectionné. Cette formulation a pour but de résoudre les problèmes engendrés par le non-respect de la prise de médicaments par les patients en administrant en une seule injection le traitement pour trois voire quatre semaines. / Depression is a devastating psychiatric disorder which affects about 20% of the population. In 2006 our team demonstrated the involvement of TREK-1, a potassium channel, in this pathology, and that its inhibition has led to a depression’s resistant phenotype. The search of TREK-1 inhibitors, a potential antidepressant, has led to the discovery of spadin. Spadin has, after only a four day treatment, similar efficacy than classical antidepressants which require about three weeks of treatment to produce their therapeutic effects. My work was firstly focused on the potential side effects of spadin. Indeed, TREK- 1’s activation has beneficial effects in many pathophysiologies (ischemia, epilepsy, pain). Its inhibition by spadin could generate significant adverse effects. The use of animal models has allowed us to confirm that spadin has no side effects related to TREK-1 channel’s inhibition. The specificity of spadin has been demonstrated since it has no effect on other potassium channels belonging to the K2P family. My work was also to study the effects of spadin in two mice models of depression, a genetic model and an induced model. In both cases, spadin shows a specific antidepressant effect in different behavioral tests of depression. The last part of my work was focused on the development of spadin’s analogs in order to improve the affinity and in vivo efficiency. We also developed, in collaboration with the MedinCell society, a polymer formulation for the constant and prolonged release of the selected analog. This formulation will be administered as a single injection treatment for three to four weeks, solving the problems caused by non respected medication by patients.

Estudos prévios sugerem que a modificação da superfície de uma hidroxiapatita sinterizada, através do condicionamento ácido, favorece a interação deste biomaterial com o organismo. Este estudo avaliou o reparo de defeitos ósseos preenchidos por hidroxiapatita sinterizada modificada (HAM), taxa Ca/P = 1.5 e hidroxiapatita sinterizada pura (HA), taxa Ca/P = 1.67, em um modelo experimental in vivo. Foram utilizados 52 ratos, submetidos à confecção de defeitos ósseos que promoveram as exposições das raízes mesiais dos primeiros molares superiores, sendo utilizado implante de HAM no lado direito e, como controle, HA no lado esquerdo. Os animais foram distribuídos randomicamente em quatro tempos pós-operatórios (15, 30, 60 e 90 dias). Após a morte dos animais, as peças foram preparadas e avaliadas através de análise histológica, microscopia eletrônica de varredura (MEV) e microtomografia computadorizada (MicroCT). Os resultados mostraram maior neoformação óssea associada à HAM (p=0.009). Na análise longitudinal a HAM apresentou neoformação óssea superior no tempo experimental de 90 dias pós-operatório comparado aos tempos de 15 e 30 dias pós-operatórios (p=0.014 e p=0.018 respectivamente). Para os parâmetros atividade osteoclástica e processo inflamatório não foram observadas diferenças estatisticamente significativas entre HAM e HA (p=0.446 e p=0.411, respectivamente). As avaliações através da MicroCT demonstraram aumento da densidade óssea ao longo dos tempos experimentais para a HAM (p=0.0042), mas não para HA (p=0.356). A microscopia eletrônica de varredura permitiu a observação das microporosidades associadas à HAM e a incorporação dos biomateriais ao tecido ósseo. Nas condições experimentais desse estudo, a aplicação de HAM resulta em melhor reparo ósseo, quando comparada a HA. / Previous studies suggest that modifying the surface of a sintered hydroxyapatite (HA) through acid-etching favors the interaction between the biomaterial and organism. This study evaluated bone repair of defects filled with a modified sintered hydroxyapatite (HAM; Ca/P ratio = 1.5), and sintered hydroxyapatite (HA; Ca/P ratio = 1.67), in an experimental model in vivo. Bone defects were created to promote mesial roots exposure of superior first molars in 52 rats. HAM implant was put into the right side bone defect and HA was used on the left side, as control. Animals were randomized into four postoperative groups (15, 30, 60 and 90 days) and killed, respectively, in each time. Surgical pieces were prepared and essessed by histological analysis, scanning electron microscopy (SEM) and computed microtomography (MicroCT). The results showed increased bone formation associated with HAM (p = 0.009). Higher bone formation was related to HAM at 90 days postoperative compared to 15 and 30 days after surgery (p = 0.014 and p = 0.018, respectively). No statistically significant differences were found between HAM and HA for osteoclastic activity and inflammation (p = 0.446 and p = 0.411, respectively). MicroCT showed increased bone density throughout the experimental periods for the HAM (p = 0.0042), but not for HA (p = 0 356). Scanning electron microscopy allowed the observation of microporosities associated with HAM and the incorporation of biomaterials in bone tissue. Under the experimental conditions of this study, the application of HAM results in better bone healing compared to HA.

Substitutos ósseos são estudados com a finalidade de encontrar biomateriais que apresentem características semelhantes ao enxerto ósseo autógeno e que tenham facilidade para o seu uso. Em busca desses biomateriais, os vidros bioativos têm sido pesquisados demonstrando propriedades de osteoindução e osteocondução. Este estudo avalia o reparo ósseo associado ao emprego de vidros bioativos diferentes taxas de pentóxido de nióbio 3mol% e 10mol%, comparados ao enxerto ósseo autógeno. A amostra foi composta por 52 ratos aleatoriamente agrupados em quatro tempos experimentais (15, 30, 60, 90 dias pós-operatórios). Três cavidades cirúrgicas foram confeccionadas na diáfise femural direita, preenchidas randomicamente com o enxerto ósseo autógeno e as duas composições de vidros bioativos contendo pentóxido de nióbio. Avaliou-se através de análise histológica, microscopia eletrônica de varredura, microtomografia computadorizada e espectroscopia de micro-Raman. Os resultados mostraram reparo ósseo em estágio avançado pela análise histológica e diferenças significativas (P=0.0017) entre o volume ósseo para o grupo de vidro bioativo composto por 3mol% de nióbio, evidência de incorporação dos biomateriais ao tecido ósseo neoformado pela análise de superfície e alta concentração de fosfato verificada em período precoce nos grupos de vidros bioativos. Tais achados mostraram que os vidros bioativos avaliados apresentaram propriedades de osteocondução e osteoindução. / Bone substitutes are studied in order to find biomaterials that exhibit characteristics similar to autogenous bone graft and have easy to use. In pursuit of these biomaterials, bioactive glasses have been researched demonstrating osteoinductive and osteoconductive properties. This study evaluates bone healing associated with the use of bioactive glasses containing different rates of niobium pentoxide 3mol% and 10mol%, compared to autogenous bone graft. The sample consisted of 52 rats randomly grouped into four times (15, 30, 60, 90 postoperative days). Three surgical cavities were prepared in the right femoral shaft, randomly filled with autogenous bone graft and two compositions of bioactive glasses containing niobium pentoxide. It was evaluated by histological analysis, scanning electron microscopy, computed microtomography and micro-Raman spectroscopy. The results showed bone healing at an advanced stage by histological analysis and significant differences (P = 0.0017) between bone volume to the bioactive glass group of 3mol% niobium, evidence of incorporation of biomaterials to the newly formed bone tissue for surface analysis and High concentration checked phosphate at an earlier period in the groups of bioactive glasses. These findings showed that the evaluated bioactive glasses showed osteoconductive and osteoinductive property.

The motor symptoms of Parkinson's disease (PD) have been linked to the emergence of exaggerated oscillatory activity in the 13 - 35 Hz beta range in recordings of the basal ganglia (BG) thalamocortical circuit of PD patients and animal models. PD patients and animal models also express dopamine-dependent cognitive impairments, implying effects of dopamine loss on the function of the anterior cingulate cortex (ACC). This thesis examines the electrophysiological behavior of the BG thalamocortical circuit in PD and dopamine-normal states during cognitive and motor activity. In vivo recordings in the BG of PD and dystonic patients were used to study the influence of dopamine during a test of executive function. Normal executive function was also investigated in the dopamine-healthy ACC of chronic pain patients. Both the BG and ACC exhibited lateralized electrophysiological responses to feedback valence. The BG also exhibited dopamine-sensitive event-related behavior. In additional experiments, chronically implanted recording electrodes in awake, behaving hemiparkinsonian rats were used to examine the transmission of synchronized oscillatory activity from the BG, through the ventral medial (VM) thalamus, to the ACC. Modulation of subthalamic nucleus, VM thalamus, and ACC activity during a simple cognitive/movement task was also investigated in hemiparkinsonian rats. Findings in the rat model suggest that ACC-mediated executive function is dopamine-sensitive and is reflected in the region's electrophysiology. These results may provide further insight into the significance of excessive oscillatory activity in PD and its influence on cognitive systems.