Schizophrenia is a relatively poorly understood, debilitating psychiatric disorder affecting around 0.5% of the population worldwide. The main characteristics of the disease are hallucinations, delusions and cognitive impairment such as difficulty in learning. It has been recently suggested that Disrupted-in-Schizophrenia-1 (DISC1) might be one of the main genetic risk factors for this disease. Mouse Disc1 has been implicated in brain development, mainly in neurite outgrowth, integration of newborn neurons, neuronal precursor proliferation/differentiation and neuronal migration. Disc1 function in the cortical excitatory cells was studied in fair detail but there is little data on Disc1 role in cortical interneuron development. In this study I have investigated development of the cortical interneurons in 21 days old mice with ENU-induced point mutations in the mouse Disc1 sequence - L100P and Q31L; previously characterized as ‘schizophrenic-like’ and ‘depressive-like’ respectively. Bin analysis was performed on five brain regions: frontal and central primary somatosensory (fSSp and SSp respectively) cortices, ventral auditory (vAud) cortex, visual (Vis) cortex and medial prefrontal cortex (MPFC); for four major interneuronal markers: parvalbumin (PV), somatostatin (STT), calretitnin (CLR) and glutamate decarboxylase 67 (GAD67). A significant decrease in PV (protein and mRNA) expression was observed in a subclass of the cortical interneurons in the fSSp, SSp, vAud and Vis cortices of L100P homozyogous (L100P) and heterozygous (L100P +/-) mouse brains when compared to their wild-type (WT) littermates. No such difference in the PV positive cells was found in the MPFC in the L100P mouse brain. Other interneuronal markers expression was not different in the L100P and L100P +/- brain from that in the WT littermate controls. Furthermore, there was no significant difference in any of the interneuronal markers expression in the Q31L mouse brain cortex. A minor change in the relative distribution of the interneurons (GAD67 positive cells) was found in the L100P but not Q31L brain. With no difference in the number of the interneurons and the nature of PV expression regulation, the cell non-autonomous effect of L100P Disc1 on this subpopulation of intereneurons was investigated. Overexpression of the mouse Disc1-100P in utero in the radial glia cells born at E14.5 (future layer II/III and IV excitatory cells) resulted in a significant decrease in the PV positive cells in all of the electroporated regions (fSSp, SSp, vAud and Vis cortices) when compared to mouse WT Disc1 overexpression. Furthermore, a decrease in the PV cells on the contralateral side was observed in the SSp and Vis cortices. This study demonstrates that mouse Disc1 is involved in the generation of parvalbumin expressing interneurons within the cortex in a cell non-autonomous way. The L100P point mutation in Disc1 led to downregulation of parvalbumin, which in turn would result in abnormal inhibitory properties of this interneuron subtype.

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

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京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23334号 / 生博第452号 / 新制||生||60(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 永尾 雅哉, 教授 渡邊 直樹, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Cortical thickness and entheseal robusticity were used to measure the effects of activity and age in a group of 77 adult males from the site of Lisieux-Michelet in northern France. There was no known age at death for this population; age was determined using a series of osteological age estimation methods. Based on the currently available dates for this sample, the skeletal remains were primarily from the Late Roman Period (3rd-7th century AD).The adults were divided into three age categories based on these estimation results. Trends in cortical and entheseal development were measured within and between age categories. Results showed that entheses increased with age while cortical thickness decreased. However, low correlation between these two factors suggests that while entheseal robusticity responds to age, it is highly influenced by physical activity. Activity levels also affect cortical thickness which causes variation within age groups. A comparison of the Lisieux-Michelet entheseal and cortical measurements to both modern and archaeological populations indicated that these males engaged in physically demanding occupations. The degree of activity experienced by these individuals decreased during the middle adult years likely due to a shift to less physically demanding occupations. However, cortical and entheseal data suggest that the old adults from Lisieux-Michelet were not particularly frail and continued to be active even after the decrease in activity during the middle years. / Thesis / Master of Arts (MA)

In the absence of treatment following strokes, both humans and model organisms demonstrate partial improvements in motor function. Several endogenous mechanisms, such as cortical reorganization, are hypothesized to cause this spontaneous biological recovery. Reorganization of the motor cortex occurs within a time sensitive period and involves both proximal and distal sites of the intact brain. Despite these advancements, whether the same or different cells are used in the reorganized cortex after stroke remains unknown. In order to identify the motor networks involved in recovery, our lab has begun using the inducible Arc-CreERᵀ²:Rosa-YFPᶠᐟᶠ mice. In conjunction with the bimanual string-pulling task, this inducible model allows for the labelling of active cells throughout stroke recovery; either pre, 2 days post-stroke (dps) and 2 weeks post-stroke (wps). Behavioural deficits on the string-pull task were observed at 2 dps and accompanied by a decrease in active cells in the ipsilesional secondary motor (M2) cortex of stroke mice. By 2 wps, stroke mice had partial recovery of motor function with no differences in active cells in the ipsilesional M2. Interestingly, ~40% of cell in the motor cortex of sham and stroke mice were activated more than once while performing the string-pull task until 2 wps. Deeplabcut kinematic analysis of the string-pull task was also unable to identify differences in motor performance between stroke and sham mice. In addition, irrelevant of stroke injuries, only 60% of cells co-expressed the pan-neuronal marker NeuN after surgeries. Together these findings suggest that 40% of cells are reactivated up to 2 weeks post-stroke during the performance of a motor task, despite the acute decreases in active cells in the ipsilesional M2 of stroke mice. DeepLabCut kinematic results also highlight the need to redefine kinematic outcomes to better assess the full spectrum of stroke deficits.

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No description available.

Introduction: Anxiety is induced by a perceived threatening situation and can impair the decision-making ability and maintenance of attention on relevant stimuli. The pre-frontal cortex (PFC) has been implicated in anxiety through the multiple network theory however, the PFC’s role in anxiety is poorly understood. Implementing visual perturbations increases PFC activity due to increased attentional demands, which is observed in younger adults. Due to increased attentional processes produced from visual perturbations, cortical activity can be altered. Methods: Twenty healthy young adults performed three treadmill walking tasks, without visual cues, with visual cues and with perturbations. Cortical activity was recorded with a 22-channel, 18 optode fNIRS cap (Dual Brite MKII; Artinis Medical Systems, Netherlands). Anxiety measurements included the state-trait anxiety inventory (Spielberger et al., 1971) and heart rate variability (polar hear rate monitor). A Friedman rank sum test was performed to determine differences observed in heart rate variability RMSSD (HrvRMSSD) and mean oxyhemoglobin concentration change, among gait conditions. Mann-Whitney U tests were used to determine effects of trait anxiety on HrvRMSSD for gait conditions. Spearman rank correlations where ran between anxiety measures and PFC activity. Results: No significant condition effect on mean oxyhemoglobin concentration change (χ2 = 3.9, p = 0.14) was found. There was a significant condition effect for HrvRMSSD (χ2 = 17.2, p < 0.001). Post hoc analysis showed a significant decrease between baseline and stepping (p = 0.003, r = 0.17) and baseline and stepping varied (p = 0.02, r = 0.24). No significant trait anxiety effects found on HrvRMSSD during baseline (p = 0.15), stepping (p=0.20) and stepping varied (p=0.08), between low and moderate trait anxiety. No correlations were found between anxiety measures and PFC activity. Significance: The present experiment shows that PFC activity does not alter in young adults between a gait and visually perturbed gait. Further, we observed no significant change in PFC activity when anxiety, measured by HrvRMSSD, increased with gait condition difficulty. These results did not support our hypotheses, but the results will help inform protocol decisions of future investigations.

In this thesis, we look at evidence accumulated on the prefrontal cortical and hippocampal regions of the brain and review theories about the possible roles each structure has on human memory and behaviour. Aspects of these theories are tested via a self-reinforcing computational network model. We propose this model may simulate the underlying mechanisms or processes of the prefrontal-hippocampal interaction during performance of memory tasks that require intact prefrontal and hippocampal structures. / Thesis / Master of Science (MSc)