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No description available.

No description available.

No description available.

Millions of children throughout the world suffer from some form of nutritional insufficiency resulting- in a retardation of their physical and mental development. Recently results of behavioural studies have suggested that inclusion of a programme of psycho-social stimulation in the management and treatment of such children might cause enhancements in their mental development. However, the morphological effects of a period of sensory stimulation on neural development in previously undernourished subjects have largely remained uninvestigated. Experiments described in this Thesis were designed to attempt such an investigation using the laboratory rat as the animal model. Rats were undernourished during their brain growth spurt period and then raised either in enriched or isolated environmental conditions. The enriched environmental condition consisted of a group of twelve male rats living together in a large cage containing a set of stimulus objects called "toys". The isolated environmental condition consisted of a single rat living in a small opaque cage which did not contain any toys. A parallel set of well-fed rats was raised in identical environmental conditions. The experiments were carried out on four separate occasions. At the end of the period of environmental modification various gross and microscopic characteristics of the brain were analyzed. These analyses included measurements of brain weights, forebrain dimensions and cortical depths. Stereo- logical procedures at the light microscopic level were used to estimate nuclear diameters and numerical densities of neurons and glial cells as well as neuronal perikarya.1 volumes in the visual cortex. At the electron microscopic level synaptic disc diameters, synaptic numerical densities and synapse-to- neuron ratios were estimated in visual cortical layers II and III. Results of these analyses suggested that environmental enrichment caused significant increases in forebrain weights and lengths as well as deficits in neuronal numerical densities particularly in the upper third of the visual cortex. It also produced significant increases in synaptic disc diameters and synapse-to-neuron ratios in cortical layers II and III. These changes were seen both in well-fed and previously undernourished rats Measurements of cortical depths and estimates of neuronal nuclear diameters, perikaryal volumes and glial cell numerical densities did not show consistent effects of environmental treatment. This latter finding is in contrast to several previously published results. Possible reasons for this are discussed. Results of the two-way analysis of variance tests on data combined from both nutritional groups indicated that the interaction between nutrition and environment was not significant for any of the measurements carried out. This suggested that the cerebral changes seen in both nutritional groups were similar in magnitude as well as direction. These results provide experimental evidence for the morphological basis of the rehabilitative potentials of sensory stimulation for previously undernourished subjects. This may have implications for designing a programme of therapy for children who have suffered an episode of earlylife malnutrition.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the most common heritable single gene cause of Autism Spectrum Disorder (ASD). The Fragile X (FMR1-KO) mouse model has been used to understand the pathophysiology of the disease. However, the majority of studies have been done in adult mice and early life outcomes have yet to be explored. Therefore, in order to contribute to the knowledge of the neurodevelopmental processes associated with brain disorders, this thesis examines postnatal outcomes in the Fragile X Mouse Model: early life behaviours, the developmental trajectory of a set of ASD risk genes, and neuroanatomical phenotype. The first study examined ultrasonic vocalizations in pups and showed a transient increase in calls in FMR1-KO mice. To understand the relationship between early life behaviours, the second study examined outcomes in the pre-pubertal period in these mice when challenged with lipopolysaccharide and maternal separation. The results showed genotype and treatment interactions affecting sexually dimorphic behavioural outcomes and developmental milestones. In the third study, possible underpinnings of behavioural differences were explored by examining mRNA expression of the neuroligins and neurexins. In FMR1-KO mice, changes were transient and sex-specific, suggesting these as molecular effectors in the disease. Lastly, using structural brain imaging, the fourth study examined regional volume differences that may be related to behavioural differences. Differences in regions affected in FXS patients were observed and genetic background was shown to affect the neuroanatomical phenotype. Overall, this thesis demonstrates that the FXS model recapitulates some outcomes in other ASD mouse models and shows that this single gene has multiple interactions with sex, strain, and postnatal challenge which manifests at specific ages at molecular, brain structure and behavioural levels. This work contributes to the efforts elucidating the neurobiology of ASD and reverse translation approaches to identify therapeutic targets for neurodevelopment disorders. / Dissertation / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) is a diagnosis based on observed behaviours: impaired communication and repetitive actions. However, there are genetic and other behavioural differences in ASD patients that are not shared among the group. It is important to tease apart this group since current treatments for ASD do not target the biological problems or the core impairments. This thesis focuses on Fragile X Syndrome, the leading genetic condition that results in ASD in order to understand the biological basis of ASD. Using a mouse model, compared to healthy mice, these studies report changes in behaviours, in the size of different brain regions, and in molecules involved in connecting brain cells during development. These findings shed light on the molecular story underlying ASD. By understanding the nature of influences on the developing brain, the type and timing of interventions can be designed to keep the brain on a healthy trajectory.

No description available.

Heparan sulphate proteoglycans (HSPGs) are a family of molecules that are found on the surface of cells or in the extracellular matrix, where they are involved in regulating key signalling events required for normal mammalian brain development. It is thought that specificity of HSPGs for particular signalling processes is encoded by their heparan sulphate (HS) sugar side chains, which can be modified post-translationally to yield huge variation in HS structure. Different sulphation patterns are generated by the action of the heparan sulphate sulfotransferases (HSTs) and sulfatase enzymes, which add or remove sulphate groups to specific positions on residues of the HS side chains. Depending on the expression of these enzymes and the resulting heparan sulphate ‘code’, it is proposed that cells are then able to regulate signals they receive and send in the ligand rich extracellular environment of the developing forebrain. Hs6st1 and Hs2st catalyse 6-O and 2-O HS sulphation, respectively. Following loss of either of these two HSTs, commissural tracts including the corpus callosum fail to develop normally during late mouse embryogenesis. The telencephalic midline environment is perturbed, with a striking mis-positioning of glial cell populations that normally act to guide axons towards the contralateral hemisphere. Too many radial glial cells at the glial wedge (GW) migrate towards the indusium griseum (IG) in mutant embryos. The running hypothesis to explain this phenotype is a change in critical signalling pathways required to set up the correct midline glia environment, such as Fgf8/ERK signalling which has already been identified as up-regulated at the Hs6st1-/- corticoseptal boundary (CSB). In order to further study what changes are occurring at the developing midline of HST-/- embryos compared to WT, we took a hypothesis free approach using RNA-sequencing analysis. RNA extracted from dissected midline regions of WT, Hs2st-/- and Hs6st1-/- mouse embryos at E16.5 was sent for sequencing, and a list of differentially expressed genes obtained. Overall we find few differentially expressed genes at the Hs6st1-/- midline compared to WT. At the Hs2st- /- midline there are a larger number of differentially expressed genes. Following validation studies, we find a significant and specific increase in Fgf17 protein distribution at the CSB of Hs2st-/- embryos compared to WT at E14.5. The results suggest the hypothesis that Hs2st’s normal role is to regulate Fgf17 protein distribution to limit exposure of GW radial glia cells to this translocation signal. When 2-O HS sulphation is lost then in Hs2st-/- embryos, ectopic Fgf17 signalling induces aberrant glia migration which ultimately prevents callosal axons from crossing the telencephalic midline to form the corpus callosum. To test this hypothesis, we used ex vivo slice culture experiments and showed ectopic Fgf17 protein expression is sufficient to trigger precocious translocation of midline glia in WT CSB, phenocopying the glia behaviour of Hs2st-/- embryos. Also consistent with the hypothesis, the Hs2st-/- glia phenotype can be rescued by addition of an FgfR1 inhibitor which reduces number of translocated glia cells. From these results we find for the first time that 2-O sulphated HS plays a remarkably specific role in regulating Fgf17-mediated translocation of midline glia cells at the developing mammalian telencephalic midline.

During fetal development, the hippocampal structures are folded forming the hippocampal sulcus which penetrates into the temporal lobe and then the entity rotates.  During this process, the hippocampal sulcus will be closed and the inverted hippocampus takes a rounded form. After complete inversion, the hippocampus has an oval form in a plane perpendicular to its long axis. If this process has not been completed the hippocampus remains the rounded form. That condition is called incomplete hippocampal inversion (IHI). The aims of this study was to evaluate the frequency of IHI in non-epileptic and epileptic children and adults and to explore the development of the hippocampal region by studying premature neonates and fetuses. Magnetic resonance (MR) images of 201 epilepsy patients and 150 non-epileptic subjects were evaluated without knowing clinical data. IHI was found in 19 % in seizure free controls (20 left-sided and 8 bilateral). 30% of the 201 epilepsy patients had IHI (40 left-sided, 4 right-sided, 16 bilateral). The difference was statistically significant (p<0.02). 25% of the temporal lobe epilepsy patients had IHI. The frequency was not significantly higher than in controls. There is no causality between temporal lobe epilepsy and IHI. 44% of the Rolandic epilepsy patients and 57% of the cryptogenic generalized epilepsy patients had IHI. IHI can be a sign of possible disturbed cerebral development in other parts of the brain. Cranial ultrasound examinations of 160 premature children were analyzed. The age at examination was 23-24 GW in 24 children, 25-28 GW in 72 children, and 29-36 GW in 64 children. IHI was found in 50%, 25% and 14%, respectively. The frequency difference between the children < 25 GW and > 25 GW was statistically significant (p< 0.001). From 25 GW onwards, the frequency and laterality of IHI is similar to that in the adult population. MRIs of 63 fetuses without intracranial pathology were reviewed independently by two radiologists. Three MRIs were performed post mortem at gestation week (GW) 17-18 and 60 in utero at GW 19-35. The hippocampal sulcus was open, bi- or unilaterally, in 35 fetuses at GW 17-32. The oldest of them was at GW 32.  The sulcus was closed at GW 21 at the earliest, unilaterally, and always from GW 33 onwards bilaterally. In 26/63 fetuses (41%), the hippocampal development was asymmetric and in 23 fetuses, the right side had developed faster.

The development of a child can be monitored by studying the changes in physical appearance or the development of capabilities e.g. walking and talking. But is it possible to find a quantitative measure for brain development? The aim of this thesis work is to investigate that possibility using quantitative magnetic resonance imaging (qMRI) images by answering the following questions: Can brain development be determined using qMRI? If so, what properties of the brain can be used? Can the age of a child be automatically detected with an algorithm? If so, how can this algorithm function? With what accuracy? Previous studies have shown that it is possible to detect properties in the brain changing with age, based on MRI images. These properties have e.g. been changes in T1 and T2 relaxation time, i.e. properties in water signal behavior that can be measured using multiple MR acquisitions. In the literature this was linked to a rapid myelination process that occurs after birth. Furthermore the organization and growth of the brain is a property that can be measured and monitored. This thesis have investigated several different properties in the brain based on qMRI images in order to identify those who have a strong correlation with age in the range 0-20 years. The properties that were found to have a high correlation were: Position of the first histogram peak in T1 weighted qMRI images, Fraction of white matter in the brain, Mean pixel value of PD weighted qMRI images, Volume of white matter in the brain, Curves on the form f(x) = ae^(-bx) +c are fitted to the data sets and confidence intervals are calculated to frame the statistical insecurity of the curve. The mean error in percent for the different properties can be seen in the list below: Property, Mean error [%] 0-20 years, Mean error [%] 0-3 years Peak position: 53.84, 98.17 Fraction of WM: 118.97, 71.67 Mean pixel value: 200.89, 126.28 Volume of WM: 241.72, 72.58 The conclusions drawn based on the presented results are that there are properties in the brain that correlates well to aging, but the error is too large for making a valid prediction of age over the entire range of 0-20 years. When decreasing the age range to 0-3 years the mean error becomes smaller, but it is still too large. More data is needed to evaluate and improve this result.