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Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

This study examined whether cortical changes underlying treatment for children with aggressive behaviour problems are related to changes in executive function (EF) performance. Fifty-five 8- to 12-year-old clinically-referred children were tested before and after a 14-week treatment intervention. Performance on four EF tasks varying in affective relevance was assessed at each session. EEG was also used to record peak amplitudes for the “inhibitory” N2, an event-related potential, while the children completed an emotion-induction Go/Nogo task. Results showed that changes in N2 amplitudes significantly predicted changes in performance only for the Iowa Gambling Task (IGT) – an affectively relevant task. Subsequent analysis revealed that only children who improved with treatment displayed significant decreases in N2 amplitudes and significant improvement in IGT performance from pre- to post-treatment. These findings suggest that cortical changes underlying successful treatment for children’s aggressive behaviour problems tap improvement in executive functions recruited for emotionally demanding events.

This study examined whether cortical changes underlying treatment for children with aggressive behaviour problems are related to changes in executive function (EF) performance. Fifty-five 8- to 12-year-old clinically-referred children were tested before and after a 14-week treatment intervention. Performance on four EF tasks varying in affective relevance was assessed at each session. EEG was also used to record peak amplitudes for the “inhibitory” N2, an event-related potential, while the children completed an emotion-induction Go/Nogo task. Results showed that changes in N2 amplitudes significantly predicted changes in performance only for the Iowa Gambling Task (IGT) – an affectively relevant task. Subsequent analysis revealed that only children who improved with treatment displayed significant decreases in N2 amplitudes and significant improvement in IGT performance from pre- to post-treatment. These findings suggest that cortical changes underlying successful treatment for children’s aggressive behaviour problems tap improvement in executive functions recruited for emotionally demanding events.

Sensory biology of animals is studied throughout the world for the insight it provides to understanding ecosystems and improving how we manage species. In this research, I designed experiments to investigate the sensory biology and behaviour of two Australian species of freshwater crayfish from the genus Cherax, the yabby (Cherax destructor) and redclaw crayfish (Cherax quadricarinatus). Experimental apparatus were constructed and tailored to test specific questions on physiology, tactile (touch) sensitivity, observation techniques, aggressive behaviour and responses to electrical fields. The outcomes were: / • abdominal muscle mass was positively correlated to the size of the electrical fields produced by swimming crayfish, / • behaviour changed in response to contact with different structures and textures of wall surfaces, / • computer analysis of underwater behaviour was similar to that scored by a human observer, / • the level of aggression in groups of crayfish changed as group size increased, and / • two species of crayfish responded to electrical fields in the water by decreasing their locomotory movement. / These results reveal a way in which physiology relates to behaviour, how crayfish and other crustaceans may sense the invisible and behave in aquaculture ponds, as well as documenting methodology to further investigate these areas in the future.

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Violence in the workplace is a serious and growing problem both in Sweden and internationally (Menckel & Viitasara, 2002). Especially in the caring professions where users or clients is in a dependent position, and deprived of their liberty in some way, threats and violence proved to be particularly prevalent (Hallberg, 2011). In Sweden, according to Menckel & Viitasara (2002), six in ten reports regarding threats and violence in the workplace come from people working in the care sector, but despite extensive searches in the area it seems to be difficult to find specific studies on precisely how threats and violence affect staff within the LVM- care (compulsory treatment for addicts). The purpose of this study is to increase knowledge and understanding of what the work situation might look like for people who work with people sentenced to LVM-compulsory treatment and their perceptions of how threats, harassment and violence in the workplace affect them. This by answering the following questions: How can the treatment staff experience threats and violence in the workplace, How can the treatment staff experience regulations and guidelines regarding threats and violence at the workplace and What strategies are taken at the workplace for the purpose of securing the safety and health of the staff?   The study is based on semi-structured interviews, based on 31 predefined questions, with five employees who work in a business where they care for both women and men, sentenced to compulsory care under the law of LVM.   The results show that the majority of the participants have been exposed to threats or veiled threats and some form of violence in their work place, either personally or by watching a co-worker be exposed, which the participants also experience as stressful and a cause for worry and alertness. The respondents states that they feel they have adequate control over their worksituation but that they often are understaffed or overcrowded. They handle aggressive behavior by keeping a closely knitted workteam through careful communication between colleagues and by support from co-workers and leadership.

Obesity is a growing public health issue with few effective treatments. Many of the human genes involved in weight regulation have homologues in other species. In Drosophila melanogaster, 11-cis-vaccenyl acetate (cVA) is a pheromone shown to affect both aggression and feeding behaviour. The aim of this study was to investigate the effect of cVA exposure on gene expression in wild type flies and to confirm crosses with genetic knockouts in the cVA pathway. The genes studied in the wild type flies were Akh (homologue of glucagon), Dilp2,-3 and -5 (homologues of insulin), Dsk (homologue of cholecystokinin), sNPF (homologue of neuropeptide Y) and TβH. The knockout genes studied were Or65a, Or67d and TβH. RNA was extracted from whole heads, cDNA synthesis was performed and the cDNA was then used in SYBR Green RT-qPCR. The knockout genes were not confirmed, due to methodological problems. The expression of Dilp3, Dilp5 and Dsk were significantly lower in the experimental flies, the expression of the other genes where not affected. The results indicate that exposure to cVA affects the expression of some of the neuropeptides involved in weight regulation. Due to the methodological problems experienced, a recommendation is to confirm the data using different reagents.