Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United States, and the fifth leading risk factor for premature death and disability, globally. There are currently very few treatment options for AUD and there is a need for effective preventive and treatment strategies for this condition. AUD risk has a significant hereditary component, with the contribution of genetic factors being estimated to be about 50%. The Davies-Bettinger laboratory uses C. elegans as a model organism to study the contribution of genetic factors in modulating neuronal responses to ethanol. In this project, we examined the role of mitochondrial beta-oxidation of fatty acids (FA) in altering ethanol responses using loss-of-function (lf) mutants and RNAi-mediated knockdown of specific genes in this pathway. We tested a total of 34 genes and found that lf in 13 genes significantly affected ethanol response phenotypes. We conclude that mitochondrial beta-oxidation of FA is essential for ethanol response behavior in C. elegans. Further experiments need to be conducted to dissect the specific contribution of various components of mitochondrial beta-oxidation in modifying the neuronal responses to ethanol.

Contusion spinal cord injury (SCI) results in devastating life-long debilitation in which there are currently no effective treatments. The primary injury site presents a complex environment marked by subsequent secondary pathophysiological cascades involving excessive reactive oxygen and nitrogen species (ROS/RNS) production, glutamate-induced excitotoxicity, calcium dysregulation, and delayed neuronal apoptosis. Many of these cascades involve mitochondrial dysfunction, thus a single mitochondrial-centric therapy that targets a variety of these factors could be far reaching in its potential benefits after SCI. As such, this dissertation examines whether transplantation of exogenous mitochondria after SCI can attenuate secondary injury cascades to decrease the spread and severity of the injury. Our first experiment tested the dose-dependent effects of mitochondrial transplantation on the ability to maintain acute overall bioenergetics after SCI. We compared transplantation of mitochondria originating from two different sources-cultured PC12 cells or rat soleus leg muscle. 24 hours after injury, State III oxygen consumption rates were maintained to over 80% of sham levels when 100ug of mitochondria was transplanted, regardless of the origin of the mitochondria. Complex I enzyme activity assays corroborated our findings that the 100ug dosage gave optimal benefits compared to vehicle injection. We also analyzed the rostral-caudal distribution and cell-type colocalization of transplanted transgenically-labeled tGFP mitochondria after SCI. There were greater volumes and rostral-caudal spread of tGFP mitochondria at the 24 hour time point compared to 7 days post injection. tGFP mitochondria had the greatest propensity to colocalize with macrophages and pericytes. Colocalization was evident in endothelial cells, oligodendrocytes and astrocytes, though no such colabeling was present in neurons. Further, colocalization of tGFP was always greater at the 24 hour time compared to 48 hour or 7days post injection time points. These data indicate that there is a cell-type difference in incorporation potential of exogenous mitochondria which changes over time. Finally, we tested the effects of mitochondrial transplantation on long term functional recovery. Animals were injected with either vehicle, 100ug cell-derived mitochondria, or 100ug muscle-derived mitochondria immediately after contusion SCI. Functional analyses including BBB overground locomotor scale and von Frey mechanical sensitivity tests did not show any differences between treatment groups. Likewise, there were no differences in tissue sparing when mitochondria were transplanted compared to vehicle injections, though there were higher neuronal cell counts in tGFP mitochondria injected groups caudal of the injury site. These studies present the potential of mitochondrial transplantation for therapeutic intervention after SCI. While our acute measures do not correspond into long term recovery, we show that at 24 hours transplanted mitochondria do have an effect on bioenergetics and that they are taken into host cells. We believe that further investigation into caveats and technical refinement is necessary at this time to translate the evident acute bioenergetic recovery into long term functional recovery.

The present thesis explores how personality traits are connected to academic achievement. First, a theoretical discussion on the neurobiological basis of different personality traits is presented, where variance in brain- activity, volume and chemistry describes possible differences in personality. Traits previously linked to academic achievement is also described in terms of neurobiology. This is followed by an empirical investigation of the connection between personality traits and academic achievement. Previous research suggest the Big Five (Costa & McCrae, 1992a) personality traits of conscientiousness, order and self-discipline to be positively associated with academic achievement. Also, similar suggestions have been put forward concerning the Values in Action (VIA-IS; Peterson & Seligman, 2004) character strengths of love of learning, self-regulation and persistence and academic achievement. 90 students in a medium sized Swedish senior high school completed the two personality inventories and their grades were collected. Positive correlations were found for the personality traits conscientiousness, order, and self-discipline and for the character strengths persistence, love of learning, perspective and open-mindedness. The results partly supported the hypotheses as well as extended the knowledge about what factors contribute to academic achievement. Discussion of the results and suggestions for further research concludes the thesis. Keywords: personality trait, character strength, neurobiology, academic achievement, BFI, VIA-IS

L’étude des inositols hautement phosphorylés est un domaine en pleine expansion. Leurs essors ne datent que d’une dizaine d’années, mais de nombreuses fonctions y sont déjà associées bien qu’ils en restent sans doute encore à découvrir. Les inositols phosphates (incluant les inositols hautement phosphorylés) s’inscrivent dans un cycle dont le représentant le plus connu est inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). De ce fait, chaque inositol phosphate influence directement ou indirectement les autres membres de ce cycle.<p>Au cours de la thèse, nous avons pu éclaircir une controverse de la littérature sur la voie de synthèse des inositols hautement phosphorylés. Grâce à un modèle de cellules MEF (mouse embryonic fibroblast) n’exprimant aucune des trois isoformes de l’inositol 1,4,5-trisphosphate 3-kinase (ITPK) et à l’aide des cellules souches déficientes pour l’inositol polyphosphate multikinase (IPMK), nous avons pu révéler le rôle majeur de cette dernière dans la génération de l’InsP5 et l’InsP6.<p>Dans un second temps, nous avons comparé la neurogenèse de ces cellules souches IPMK+/+ et IPMK-/- mises dans un milieu de différenciation par défaut (DDM). Les cellules dépourvues de l’IPMK entrent en apoptose et se différencient très difficilement en progéniteurs neuronaux et en neurones. Afin de comprendre le mécanisme sous-jacent pouvant expliquer ce phénomène, nous avons réalisé des PCRs quantitatives qui ont montré une sous expression des gènes du neuroectoderme ainsi qu’une augmentation de l’expression de gènes du mésoderme dans les cellules IPMK-/- par rapport aux cellules IPMK+/+. De plus, nous avons découvert que le phénomène d’apoptose observé au cours de la différenciation en DDM était spécifique à ce milieu. En effet, nous n’avons pas pu mettre en évidence un tel phénomène au cours de la différenciation en corps embryoïdes.<p>Durant la thèse, nous avons également développé des anticorps dirigés contre l’isoforme B de l’inositol 1,4,5-trisphosphate 3-kinase et contre la forme native de l’IPMK. Ceci nous a permis de mener à bien nos expériences et d’ouvrir de futures perspectives de recherche.<p>En conclusion, nous avons démontré le rôle majeur de l’IPMK dans la voie de synthèse des inositols hautement phosphorylés. Nous avons également découvert que l’IPMK est très importante pour la survie de ces cellules souches en cours de différenciation et nous avons également introduit une nouvelle fonction pour l’IPMK dans la neurogenèse.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

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Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. An unstable CAG expansion within the gene normally encoding for the Huntingtin protein is responsible. The expanded mutant form of Huntingtin and the putative protein co-factor Rhes interact and cause cell death within the striatum. We hypothesized chronic treatment with simvastatin, a cholesterol lowering drug, would disrupt the biosynthetical pathway which gives both Rhes and its target cells binding sites and render Rhes inactive. Healthy and HD mice were treated with simvastatin or a vehicle. Animals’ motor behavior was assessed with three separate tests over the first four months of life. No significant differences were found between the HD groups; however, the HD treated animals’ performance on the rotarod test, at month 4, was intermediate between healthy mice and HD vehicle treated mice. The results hint at simvastatin’s therapeutic potential, but are interpreted cautiously.

Human histidyl-tRNA synthetase (HARS) is an aminoacyl-tRNA synthetase (AARS) that catalyzes the attachment of the amino acid histidine to histidyl-tRNA (tRNAHis) in a two-step reaction that is essential for protein translation. Currently, two human diseases, Usher Syndrome IIIB (USH3B) and an inherited peripheral neuropathy, Charcot Marie Tooth Syndrome (CMT), have been linked genetically to single point mutations in the HARS gene. The recessive HARS USH3B mutation encodes an Y454S substitution localized at the interface between the anticodon-binding domain and the catalytic domain of the opposing subunit. Patients with Usher Syndrome IIIB lose their sight and hearing during their second decade of life, and clinicians have observed that the onset of deafness and blindness may be episodic and correlate with febrile illness. Furthermore, some young USH3B patients present with a fatal form of acute respiratory distress. In addition to the single HARS mutation linked to Usher Syndrome, eight other mutations in the HARS gene are associated with CMT, an inherited peripheral neuropathy. Peripheral neuropathies are associated with progressive and length-dependent damage of the motor and sensory neurons that transmit information to the spinal cord. The age of onset and phenotypic severity of CMT linked to HARS is highly variable. When expressed in a yeast model system, the HARS variants are dominantly lethal, and confer defects in axonal guidance and locomotor deficiencies when expressed in C.elegans. Here, the biochemical characterization of the HARS USH3B and three peripheral neuropathy variants are described. The approaches included enzyme kinetic analysis with purified HARS enzymes to monitor catalytic deficiencies, differential scanning fluorimetry (DSF) to evaluate structural instability, and cellular models to detect physiological effects of axonal outgrowth by CMT variants. The results suggest that Usher Syndrome IIIB is unlikely to be a consequence of a simple loss of aminoacylation function, while HARS-linked peripheral neuropathy variants all share common catalytic defects in aminoacylation. The HARS system represents a notable example in which two different complex human diseases arise from distinct mutations in the same parent gene. By understanding the biochemical basis of these inherited mutations and their link to Usher Syndrome and CMT, it may be possible to develop mechanism-based therapies to improve the quality of life of patients afflicted with them.

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings.

Uganda´s well-being ranks among the worst in the world, while Sweden´s well-being ranks among the best. This thesis investigates if there is a difference in well-being and dispositional optimism in Uganda and Sweden. The neurobiology underlying well-being and optimism is also examined. The neural correlations of well-being and optimism are connected to areas in the limbic system and cerebral cortex. Prefrontal cortex and anterior cingulate cortex are two curial regions involved in both well-being and optimism. Amygdala, parahippocampal gyrus, and thalamus are central areas for hedonic well-being, dispositional optimism, and optimism bias. In this thesis 284 Ugandans and 256 Swedes completed a questionnaire based survey. Greater hedonic well-being was found among Swedes, whereas greater eudiamonic well-being was found among Ugandans. Swedes reported greater global life satisfaction than Ugandans, but Ugandans expressed higher satisfaction with their current lives compared with Swedes. In relation to dispositional optimism, Ugandans were found to be both more optimistic and more pessimistic than Swedes. This unexpected dispositional optimism pattern is discussed and future research directions are proposed.

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