Brain cerebrospinal fluid (CSF) bulk flow is maintained thanks to a balance between CSF secretion from the choroid plexus and CSF absorption by arachnoid villi, where it drains into nearby blood vessels, thereby reaching the general blood circulation. Congenital hydrocephalus starts during the first trimester of pregnancy with impeded CSF flow, and consequent CSF build-up within the brain ventricles. This event is followed by CSF compositional changes, increased intracranial pressure, and, if untreated, brain damage and fetal death. Previous research has revealed a unique folate delivery system which serves the developing cerebral cortex. Abnormal folate provision due to impairment of this system was directly connected to a decrease in a CSF folate enzyme: 10-Formyl-Tetrahydrofolate dehydrogenase (FDH). In light of these findings, low FDH was linked with folate deficiency and the poor cortical development found in congenital hydrocephalus. In this context, investigations were carried out to ascertain whether folates in the presence and absence of the folate enzyme FDH are beneficial for fetal brain development. The current study also aims to investigate the FDH -folate delivery system in the fetal brain in order to understand its role in CNS development and its relationship to currently known folate transport mechanisms (FRα). Furthermore, we hypothesize that folates may prevent congenital hydrocephalus through a re-establishment of CSF drainage and flow circulation at the level of the arachnoid membrane/villi. This assumption implies that the leptomeninge arachnoid may also be dysfunctional in the hydrocephalic brain due to a variation in hydrocephalic CSF composition (folates). Finally, an overall metabolic pathway analysis of the constituents uniquely present in abnormal CSF, hence missing in normal CSF, and vice versa, was carried out to establish associations with suggested activated and inactivated biological processes during congenital hydrocephalus.

No description available.

Neuroimmune proteins are involved in a wide array of biological functions throughout brain development. Importantly, these molecular mechanisms regulate the activity-dependent sculpting of neural circuits during the critical period. Abnormal expression of these molecular mechanisms, especially in early development, is linked to the emergence of neurodevelopmental disorders. Despite having central roles in both normal and pathological conditions, very little is known about the lifespan expression of neuroimmune proteins in the human cortex. As studies exploring the relationship between inflammation and disease tend to rely on animal models, unpacking immune lifespan trajectories in the human brain will be essential for translational research. Furthermore, it will aid the development of timely and effective therapeutic interventions for neurodevelopmental disorders. In my thesis, I characterize the development of 72 neuroimmune proteins in 30 postmortem tissue samples of the human primary visual cortex. These samples cover the lifespan from 20 days to 79 years. I compare the developmental profiles of these immune markers to those of well-studied classic neural proteins including glutamatergic, GABAergic and other synaptic plasticity-related markers. Using a data-driven approach, I found that the 72 neuroimmune proteins share approximately eight developmental patterns, most of which undulate across the lifespan. Furthermore, I used unsupervised hierarchical clustering to show that the development of neuroimmune proteins in the human visual cortex varies from that of classic neural proteins. These findings facilitate a deeper understanding of human cortical development through two classes of proteins involved in brain development and plasticity. / Thesis / Master of Science (MSc) / The human brain develops across the lifespan. This ability of the brain to change and adapt to the environment is called plasticity and it is essential for normal brain functions, such as processing visual information. Immune proteins play important roles in the visual cortex- the brain region responsible for visual information processing. They help establish brain circuits in early development and regulate ongoing neural processes important to brain plasticity. In my thesis, I measure the expression of neuroimmune proteins to unpack their developmental patterns in the human visual cortex. I found that these proteins have fluctuating levels across development, with many displaying heightened expression levels in early childhood. Additionally, I found eight common trajectory patterns that were shared between the proteins. These findings enable a better understanding of how regulators of human brain development mature.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. Studies in humans and experimental animal models shows that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can lead to abnormal emotional behaviors in adulthood, with a majority of the studies focusing on male offspring behavior. In this dissertation, we assessed whether SSRI-induced neurobiological and behavior changes occur in both sexes and whether these changes emerge in the juvenile period. In addition, we observed gene expression changes in the hippocampus related to metabolism and synaptogenesis. Given that, we hypothesized that the behavioral impacts following SSRI exposure may be driven, in part, by these processes. Juvenile offspring exposed to SSRIs in early life, regardless of sex, displayed increased anxiety-like behavior and altered social play. In adulthood, perinatal SSRI-exposed male and female offspring displayed increased passive coping in the Forced Swim Test but showed no differences in anxiety-like behavior. In addition to emotional behaviors, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency. Alongside these behavioral changes, during infancy, we observed increased metabolic activity in the dentate gyrus of the hippocampus and decreased activity in the basolateral amygdala. During adulthood, the CA and dentate gyrus of the hippocampus in both sexes and the paraventricular nucleus of the hypothalamus in female offspring were more metabolically active in exposed offspring. We also observed differences in inter-correlations of limbic region COX activity in perinatal SSRI exposed and control offspring. Finally, a major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). As a G-protein coupled receptor (GPCR), it is an interesting potential therapeutic target, since most recently approved drugs in the central nervous system act on GPCRs. Data present here show that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together, these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms and metabolic changes that drive adverse effects of perinatal SSRI exposure and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia. Therefore, these data suggest that investigate the Bai3 network may be an exciting route as a potential therapeutic target for depression. / Doctor of Philosophy / Environmental factors during development play an important role in shaping the growth, structure, and function of the brain and as well behavior of an organism. Some of these factors that alter development which can negatively impact behavior include early life exposure to stress, toxins, or drugs. In this dissertation, we will discuss the impact of early life exposure to antidepressants. Many people take selective serotonin reuptake inhibitor (SSRI) antidepressants as a way to treat their depression during pregnancy. It is important to note that is it essential to treat depression during pregnancy, since depression can drastically impact the behavior of the offspring. However, while considering this, it is also critical to understand how exposure to SSRI antidepressants influences behavior of the offspring. SSRI antidepressants work by increasing the neurotransmitter serotonin in the brain and body. Previous work has demonstrated that early life exposure to SSRIs can alter the way the serotonin system develops in the brain and also increases the chance of children to develop emotional disorders (e.g., depression and anxiety). The same is true in rodents, a model organism in research, since we see an increase in depression-related behavior in our rats that are exposed to SSRI antidepressants in early life. Data shown in this dissertation support this claim, as we see altered behavior not only in adult but juvenile male and female rodent offspring. In adults, we found increased depression-related behavior and social deficits (e.g., maternal care). In the juvenile offspring, we saw alterations of social play behaviors and increase in anxiety-related behavior. Given this observation, we were interested in determining what occurs in the brain that alters these emotional and social behavior. To do this, we observed gene changes in the brain following early life SSRI exposure. We found changes in genes related to metabolic activity and communication between neurons (i.e., synaptogenesis). As a follow up to this study, we next wanted to characterize the metabolic and morphological (i.e., structural) changes that as a result of early life SSRI exposure. We found increased activity in several regions of the brain associated with emotion, including the hippocampus, amygdala, and hypothalamus. In addition, we did not find any morphological changes in the hippocampus, although ongoing studies will continue to analyze other brain regions. Lastly, when considering specific pathways whereby early life SSRI exposure can alter emotional and social behavior, we are interested in identifying potential therapeutic targets. One set of proteins (G-coupled protein receptors; GPCRs) are interesting targets to investigate, since most FDA approved medications in the central nervous system target these GPCRs. Interestingly, one GPCR stood out in our gene studies: Bai3. In this dissertation, we present data to show that the Bai3 network is altered in rodents exposed to SSRIs in early life. In addition, we show that manipulating Bai3 in early life can help to improve depression-related behavior. Lastly, to understand if Bai3 could play a role in depression, we assessed human postmortem samples to see if Bai3 alterations occur in the depressed human condition. In this study, we found increased Bai3 levels in human male sample relative to healthy patients. Overall, the work presented here shows that early life SSRI exposure negatively impacts emotional and social behaviors in rodents. Coinciding with these behavior changes, we find differences in gene expression and metabolic activity, thus providing us with a potential mechanism whereby early life SSRI exposure influences behavior. It is possible that by manipulating these aspects of brain function represent fruitful options for therapeutic targets for depression and other mood disorders.

Dicer endoribonuclease catalyzes the maturation of microRNAs (miRNAs) from double stranded precursors. Studies conditionally inactivating Dicer in the mouse embryonic forebrain continue to shed light on the spectrum of biological processes subject to miRNA regulation. This study looked at defects of brain development following a widespread ablation of Dicer in the early forebrain. The neuroepithelial stem cells failed to specify the radial glia appropriately around the time when the first postmitotic neurons begin to be generated in the neuroepithelium. Ablation of Dicer in only a subset of radial glia was not accompanied by the early apoptosis observed in all other models of Dicer ablation in the cortex. This allowed the study of the role of miRNAs in regulating cell numbers in the cortex. The study revealed that generation of cortical cells is increased during postnatal development. Finally, the study identified a miRNA which is able to negatively regulate the development of neuronal precursor cells of the developing cortex by targeting Tbox transcription factor 2. Together the results presented in this Thesis contribute to the understanding of the roles of endogenous RNA interference in the development of the brain.

During early development of the nervous system, gene expression patterns are known to vary widely depending on the specific developmental trajectories of different structures. Observable changes in gene expression profiles throughout development are determined by an underlying network of precise regulatory interactions between individual genes. Elucidating the organizing principles that shape this gene regulatory network is one of the central goals of developmental biology. Whether the developmental programme is the result of a dynamic driven by a fixed architecture of regulatory interactions, or alternatively, the result of waves of regulatory reorganization is not known. Here we contrast these two alternative models by examining existing expression data derived from the developing human brain in prenatal and postnatal stages. We reveal a sharp change in gene expression profiles at birth across brain areas. This sharp division between foetal and postnatal profiles is not the result of sudden changes in level of expression of existing gene networks. Instead we demonstrate that the perinatal transition is marked by the widespread regulatory rearrangement within and across existing gene clusters, leading to the emergence of new functional groups. This rearrangement is itself organized into discrete blocks of genes, each associated with a particular set of biological functions. Our results provide evidence of an acute modular reorganization of the regulatory architecture of the brain transcriptome occurring at birth, reflecting the reassembly of new functional associations required for the normal transition from prenatal to postnatal brain development.

Background An increasing body of research is suggesting that childhood trauma and adversity may be associated with various adverse mental health outcomes, including psychosis. Cognitive functioning is often compromised in psychosis, and research has shown that there may be a link between early trauma and cognitive impairment in people with psychosis. No systematic review of the literature of this link has been undertaken, and very few studies have examined samples of individuals at high clinical risk for psychosis, to assess whether the potential link between adversity and cognitive functioning exists, without the confounding factors of length of illness, antipsychotic medication and chronicity of symptoms. Method The systematic review of all relevant electronic databases investigates the research to date on the association between childhood adverse experiences and cognitive ability in psychosis, and the conclusions that can be drawn from the existing literature, taking into account relevant considerations regarding sample, methodology and statistical analysis. The subsequent empirical study utilizes a sample at clinical high risk of developing psychosis, and a healthy control group to investigate whether any putative association in specific domains of cognitive functioning, or global cognitive ability and childhood adversity exist in those at clinical high risk, compared to controls. Results The systematic review indicated that at present, the literature looking into childhood adversity and cognitive ability in relation to psychosis is heterogeneous, with some studies finding that this association only occurs in patients, whilst others suggest it only occurs in the control groups. Some studies found it to be specific to certain cognitive domains, whilst others suggest it was a more global impairment. Methodology, samples and analysis differed considerably across studies, and likely contribute to the heterogeneity of the literature. The empirical paper showed a significant interaction effect between group (high risk versus controls) in the high childhood adversity group, in relation to global cognitive ability. Interestingly, this was not related to psychotic symptom severity or distress. Conclusion Several limitations of the existing studies limit the conclusions that can be drawn from the existing evidence regarding the link between childhood adversity and cognitive ability, and future research in prodromal samples is essential. The empirical study showed that there is a link between childhood adversity and cognitive ability in those at clinical high risk of developing psychosis, before disorder onset, that is not present in controls. This suggests that this may form a vulnerability in those at high risk for psychosis, rather than a more general mechanism present in the typical population.

Myelin is an extensive cell membrane produced by oligodendrocytes to ensheath neuronal axons in the central nervous system with the primary goal of maximizing the efficiency of electrochemical impulse transmission. During brain development, oligodendrocytes differentiate into myelin forming cells in a tightly regulated process which makes them vulnerable to multiple insults. Previous results from the laboratory showed that the timing of oligodendrocyte differentiation and rat brain myelination were altered by perinatal exposure to buprenorphine and methadone, opioid analogues used for treating pregnant addicts. The mechanism by which these opioids exerted their effects involved two opioid receptors, the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOR). However, the role of these receptors and their endogenous ligands in controlling the timing of myelination under normal physiological conditions of brain development is not known. In this dissertation, we found that the endogenous MOR ligand endomorphin-1 (EM-1) acts as a strong promoter of rat pre-oligodendrocyte differentiation, but surprisingly, this effect is observed only in cells isolated from female pups. Interestingly, the stimulatory action of EM-1 was abolished upon co-incubation with the endogenous NOR ligand, nociceptin. Moreover, injections of NOR antagonist to 9-day-old female and male rat pups accelerated rat brain myelination in female rat pups with no significant changes in their male counterparts. Interestingly, the lack of major sex-dependent differences in developmental brain levels of EM-1 and nociceptin and the presence of the two receptors MOR and NOR in male and female oligodendrocytes suggested that the observed sex-specific responses may be highly dependent on critical intrinsic sex-dependent differences within these cells. Although nociceptin alone did not exert observable effects on pre-oligodendrocyte maturation, it increased the number of cells expressing Ki-67, a cell proliferation indicator, in oligodendrocyte progenitor cultures. These results suggest that nociceptin may be playing a stage specific role in oligodendrocyte development during brain maturation. The finding of critical functions of EM-1 and nociceptin in the developing female oligodendrocytes and brain myelination highlights the need for considering sexual dimorphism in the design of safer and more effective therapeutic approaches for treating opioid abuse, pain, and demyelinating disease as multiple sclerosis.

<p>Detta examensarbete handlar om hjärnans utveckling, inlärningen och våra inre inlärningsstilar. Det tar också upp kort om hur man kan utnyttja inlärningsstilar i skolan. Syftet har varit att ta reda på hur vi utvecklas och hur de utvecklingsstrukturer ser ut som vi föds med och utvecklar efterhand. </p><p>De frågeställningar jag haft under skrivandets gång har varit: </p><p>Vilka är "de sju olika intelligenserna"? </p><p>Hur utvecklas hjärnan? </p><p>Var och när börjar vi lära, och vad är det som ligger till grund för vår inlärning? </p><p>Hur kan man bearbeta olika inlärningsstilar i skolans högre stadier? </p><p>Den metod jag använt är en litteraturstudie med litteratur som behandlar inlärningen, hjärnans utveckling, hur vi tänker och lär mm. Jag har också besökt en högstadieskola som bedriver viss av sin undervisning med hjälp av olika inlärningsstilar. I projektbeskrivningen beskrivs kortfattat hur man kan använda inlärningsstilar i skolan.</p><p>I diskussionen har jag behandlat min frågeställning lite mer ingående om saker och ting jag anser mer eller mindre trovärdiga från litteraturen, jag har också dragit en mer eller mindre trovärdig parallell mellan vår utveckling och handlande till hur dagens samhälle ser ut. </p><p>Jag hoppas att du som läsare känner igen dig i vissa delar eller har lärt dig något av att läsa detta examensarbete, det har i alla fall jag gjort</p>

Lépilepsie myoclonique juvénile (EMJ) est un syndrome épileptique très répandu qui appartient aux épilepsies idiopathiques généralisées. Il se caractérise par des secousses myocloniques et des crises tonico-cloniques débutant pendant ladolescence, entre 12 et 18 ans. Son étiologie est génétique et impliquerait linteraction de plusieurs gènes. Des études de liaisons géniques ont permis lindentification, dans un gène localisé en 6p12, de cinq mutations faux-sens co-ségrégées avec le phénotype de EMJ. Ce gène code une nouvelle protéine, dénommée EFHC1, comportant un motif EF-hand, domaine potentiel de liaison au calcium et trois domaines DM10, de fonction inconnue. L'objectif de notre travail consiste à étudier les propriétés biochimiques et fonctionnelles d'EFHC1. Nous avons dabord étudié la localisation subcellulaire dEFHC1 dans différentes lignées cellulaires (HEK-293, HeLa et COS-7) au moyen de deux approches complèmentaires. Dune part nous avons surexprimé la protéine couplée à lEGFP, un marqueur fluorescent permettant se visualisation et dautre part, nous avons étudié la localisation de la protéine endogène au moyen dun anticorps spécifique. Dans les cellules en mitose, EFHC1 montre clairement une association avec le fuseau mitotique, spécialement au niveau des pôles et du corpuscule de Fleming pendant la cytokinèse. EFHC1 co-localise également avec le centrosome dans les cellules en interphase et en mitose. Dans le but de déterminer la région d'EFHC1 impliquée dans lassociation au fuseau mitotique, nous avons effectué des analyses au moyen de différentes formes tronquées de la protéine couplées à lEGFP. Les résultats indiquent que lextrémité N-terminale d'EFHC1, contenant les 45 premiers acides aminés de la protéine est cruciale pour ladressage au fuseau mitotique. Nous avons démontré, au moyen dexpériences dimmunoprécipitations et de co-sédimentation de microtubules, une association directe dEFHC1 avec lα-tubuline, composant des microtubules. Cette interaction est médiée par un nouveau domaine dassociation aux microtubules situé au niveau de lextrémité N-terminale de la protéine, entre les acides aminés 1 et 45. Dautre part, nous avons mis en évidence un rôle important dEFHC1 dans la régulation de la division cellulaire. En effet, la surexpression dune forme tronquée dEFHC1 ne contenant que les 45 premiers acides aminés de la protéine, agissant comme un dominant-négatif, ainsi que linhibition dexpression dEFHC1 par expression de shRNAs induit de façon significative des fuseaux mitotiques anormaux (fuseaux unipolaires, anomalies de condensation des chromosomes au niveau de la plaque équatoriale pendant la métaphase). De plus, nous avons observé que les cellules invalidées en EFHC1 présentaient un défaut de progression mitotique résultant du blocage des cellules en prométaphase anormale, conduisant à une augmentation significative de lindex mitotique (% de cellules en mitose) et à de lapoptose. Enfin, nous avons démontré un rôle dEFHC1 dans la corticogenèse cérébrale. En effet, linvalidation dEFHC1 (shRNAs et dominants-négatifs) dans le néocortex de rat en développement au moyen des techniques délectroporations ex vivo et in utero conduit à un défaut de migration neuronale radiaire. Nous avons montré que celui-ci résultait dune diminution de sortie de cycle cellulaire des cellules progénitrices neuronales conduisant à une accumulation de celles-ci, dune altération de larchitecture des prolongements de la glie radiaire, dune augmentation de la mort cellulaire par apoptose et dun défaut de locomotion des neurones post-mitotiques.