The present study investigated the brain-behavior relationships between cerebellar vermal volume, phonological processing, and verbal working memory in children with Reading Disability (RD) and Attention-Deficit/Hyperactivity Disorder (ADHD). It was hypothesized that there would be differences in inferior posterior vermal volume between those with and without ADHD. Individuals with and without RD were not expected to differ in posterior inferior vermal volume and an interaction in the RD/ADHD group was expected. Children with RD/ADHD were expected to have similar volumes to children who have ADHD. It also was hypothesized that inferior posterior vermal volumes would be correlated with verbal working and phonological short-term memory; anterior vermal volumes were hypothesized to be correlated with elision, and superior posterior vermal volumes were hypothesized to be correlated with rapid object and rapid letter naming. Results indicated that there were no group differences in posterior inferior vermal volume between children with and without RD as well as with and without ADHD. There were also no relationships between phonological processing and verbal working memory. The findings in this study were unexpected and suggest the need for further study between phonological processing, verbal working memory, and vermal volume in children with ADHD and RD.

No description available.

The deep cerebellar nuclei (DCN) function as output gates for a large majority of the Purkinje cells of the cerebellar cortex and thereby determine how the cerebellum influences the rest of the brain and body. In my PhD programme I have investigated how the DCN process two kinds of input patterns received from Purkinje cells: irregularity of spike intervals and pauses in Purkinje cell activity resulting from the recognition of patterns received at the synapses with the upstream parallel fibres (PFs). To that objective I have created a network system of biophysically realistic Purkinje cell and DCN neuron models that enables the exploration of a wide range of network structure and cell physiology parameters. With this system I have performed simulations that show how the DCN neuron changes the information modality of its input, consisting of varying regularity in Purkinje cell spike intervals, to varying spike rates in its output to the nervous system outside of the cerebellum. This was confirmed in simulations where I exchanged the artificial Purkinje cell trains for those received from experimental collaborators. In pattern recognition simulations I have found that the morphological arrangement present in the cerebellum, where multiple Purkinje cells connect to each DCN neuron, has the effect of amplifying pattern recognition already performed in the Purkinje cells. Using the metric of signal-to-noise ratio I show that PF patterns previously encountered and stored in PF - Purkinje cell synapses are most clearly distinguished from those novel to the system by a 10-20 ms shortened burst firing of the DCN neuron. This result suggests that the effect on downstream targets of these excitatory projection neurons is a decreased excitation when a stored as opposed to novel pattern is received. My work has contributed to a better understanding of information processing in the cerebellum, with implications for human motor control as well as the increasingly recognised non-motor functions of the cerebellum.

La souris scrambler (Dab1scm) est un mutant ataxique cérébelleux qui présente une mutation naturelle du gène mdab1, codant pour une protéine intracellulaire nécessaire à la voie de signalisation de la rééline. Cette protéine joue un rôle crucial dans la mise place et la plasticité des structures laminées telles que le cortex cérébral, l’hippocampe ou le cervelet. Notre objectif a été de caractériser le phénotype comportemental et neurochimique de la souris scrambler au cours du développement post-natal et à l’âge adulte. Les premiers signes de l’ataxie cérébelleuse sont observables dès 8 jours et sont majorés au cours des 2ème et 3ème semaines de vie post-natale. A l’âge adulte, la souris se caractérise par un trouble important de la coordination motrice et une hyperactivité locomotrice exacerbée et stéréotypée (comportement de rotation) lorsque l’animal est placé en milieu aquatique. Les tests du labyrinthe aquatique de Morris et de l’alternance spontanée mettent en évidence des déficiences possiblement causées par un trouble du guidage visuo-moteur et la désinhibition comportementale. Chez ces souris, l’activité métabolique régionale évaluée par le marquage de la cytochrome oxydase est relativement préservée dans le cervelet ; elle est en revanche altérée dans diverses régions du tronc cérébral qui lui sont associées ainsi que dans l’hippocampe et certaines régions corticales. Le comportement de rotation stéréotypé et l’hyperactivité causés possiblement par un déséquilibre neurochimique acétylcholine/dopamine a été évalué dans un rotamètre avec ou sans injection préalable d’un antagoniste des récepteurs D2. Parallèlement, l’innervation cholinergique du système nerveux central, révélée par l’activité de l’acétylcholinestérase était diminuée dans la substance noire pour laquelle nous avons observé une désorganisation et une perte partielle des neurones dopaminergiques. Bien que les atteintes multiples compliquent l’étude structuro- fonctionnelle de ce mutant, nos résultats ont permis de préciser le phénotype scrambler en le comparant aux autres mutants de la voie de la rééline. Ces mutants font l’objet aujourd’hui d’un intérêt croissant pour la modélisation non seulement de l’ataxie mais également de certaines maladies neurologiques et neuro-psychiatriques comme l’autisme et la schizophrénie / The Dab1scm scrambler mice is a cerebellar ataxic mutant spontaneously mutated for a gene encoding a protein of the reelin signaling pathway involved in the development and the plasticity of laminated structures such as the neocortex, the hippocampus, and the cerebellum. Our objective was to characterize the behavioral and neurochemical phenotype of the scrambler mice during postnatal developmental and adult stages. The first signs of cerebellar ataxia are observable as early as 8 days and increase during the 2nd and 3rd weeks of postnatal life. Adult mouse is characterized by a significant disturbance of motor coordination and a locomotor hyperactivity which increases ans becomes stereotyped (circling) when the animal was placed in water. Morris water maze and spontaneous alternation highlight deficiencies possibly caused by disorder of visuomotor control and disinhibitory processes. Brain regional metabolic activity measured by cytochrome oxidase is relatively preserved in the mutant cerebellum. However, it is impaired in various connected regions of the brainstem as well as in the hippocampus and some cortical regions. Circling behavior and hyperactivity, possibly caused by a neurochemical imbalance between acetylcholine and dopamine, were evaluated in a rotameter with or whithout prior injection of D2 receptor antagonist. In parallel, cholinergic innervation of the central nervous system measured by acetylcholinesterase activity is lower in the substantia nigra for which a partial disruption and loss of dopaminergic neurons is observed. Although the multiple alterations complicate the structuro-fonctional study of this mutant, results have clarified the scrambler phenotype by comparison with others mutants of the reelin pathway. This mutants are now subject to a growing interest in not only ataxia modeling but also some neurological and neuropsychiatric diseases

<p>The tumor suppressor protein p53, encoded by Tp53 gene, is a transcription factor that regulates cell cycle arrest and apoptosis following cellular stresses that compromise DNA integrity and normal cellular function. Tp53 is mutated in approximately 50% of human cancers, thereby allowing cancer cells to replicate uncontrollably. In cancers in which Tp53 is not mutated, p53 is frequently functionally inactivated through other mechanisms. For example, Mdm2, a proximal negative regulator p53 is often overexpressed in cancers in which p53 is wild-type. Mdm2 is E3 ubiquitin ligase that binds to and targets p53 for proteasomal degradation and as well as inhibits p53 transcriptional activity. Pharmacological disruption of the Mdm2-p53 interaction in cancer cells with wild-type p53 is currently being explored as a strategy to enhance p53-mediated cell death in response to conventional chemotherapeutics. Nutlin-3, an Mdm2 inhibitor, promotes cell death in cultured cells from human medulloblastoma (MB), a common cerebellar pediatric cancer, suggesting that Mdm2 is a promising target to treat this tumor type. Consistent with this idea, studies in a mouse model of MB have shown that loss of Mdm2 limits the development of preneoplastic lesion in the cerebellum. The developing nature of the cerebellum in the youngest of MB patients is a major contributing factor to the side-effects resulting from current MB therapies. Studies in adult rodents suggest that nutlin-3 is non-genotoxic in normal homeostatic tissues; however the effects of nutlin-3 have not been evaluated in developing tissues. To gain insight into the potential side effects of p53 activation on the developing cerebellum, the pharmacological effects of Mdm2 inhibition in Granule Neuron Precursor cells (GNPs) was mimicked genetically using a mouse model in which Mdm2 could be selectively deleted in postnatal GNPs. My studies revealed that deletion of Mdm2 in GNPs led to a reduction in cerebellum size but did not negatively impact gross motor coordination. These results suggest that Mdm2 inhibitors may promote the killing of MB tumor cells of pediatric patients without minimal side effects on normal cerebellum development</p> <p>In addition to cancer, p53 has an important role guarding proliferating cells during development. Activation of p53 has been implicated in the pathology of several human congenital syndromes, and mice lacking Mdm2 die in utero due to p53-mediated apoptosis. These studies highlight the need for p53 function to be tightly regulated as even modest decreases or increases in p53 function can promote cancer or disrupt normal development, respectively. During the course of my studies on Mdm2 inhibition in MB, it was serendipitously discovered that in the absence of a wild-type level of Mdm2, the phenotypic consequences of p53 activation on the developing mouse embryo were strongly influenced by the genetic background. On a 129S6/B6 F1 hybrid genetic background, mice expressing ~30% the wild-type level of Mdm2 were viable, while mice on an inbred C57BL/6 genetic background died at birth and exhibited an array of craniofacial abnormalities including coloboma, exencephaly, and cleft palate. This is the first demonstration of a role for Mdm2 in craniofacial development. The genotype-dependence, further, indicates the presence of additional genes affecting craniofacial dysmorphology. In human pleiotropic malformation syndromes, there is often clinical variability amongst individuals with an identical underlying mutation at the major effect locus. Currently, the modifier genes that influence craniofacial dysmorphology are unknown. The allelic variants encoded by the divergent genetic backgrounds that increase the penetrance and expressivity of craniofacial malformations in the Mdm2 hypomorphic mice identify the gene and protein networks governing craniofacial development. In the future, it will be important to determine the genes that are differentially expressed between mice that express low levels of Mdm2 in C57BL/6 and 129S6/B6 F1 genetic backgrounds. The results from this comparison are predicted to lead to the identification of candidate genes that influence craniofacial development through the modulation of p53 function.</p>

Medulloblastoma, the most common pediatric malignant brain tumor, is comprised of a heterogeneous group of tumors with distinct molecular subtypes and clinical outcomes. In particular, tumors with a cancer stem cell (CSC) population have been observed to be more resistant to conventional therapies, necessitating the elucidation of pathways important in this population. Work in our lab has shown that neurosphere culture-enriched cells from Ptch1LacZ/+;Trp53-/- mouse medulloblastomas exhibit properties of self-renewal, expression of neural stem cell (NSC) markers and potent tumor-initiation. The pathway dependencies and mechanisms of self-renewal in these medulloblastoma neurospheres (MBNS) have not yet been characterized.

Research suggests that the cerebellum is involved in cognition, but its exact role is unclear. The efficiency theory posits that the cerebellum supports processing speed. Other researchers argue that the cerebellum is functionally heterogeneous, and damage to lobes of the cerebellum causes selective loss of cognitive functions. This study sought to determine whether selective impairment in motor, verbal fluency, or processing speed occurred depending on the lobe of the cerebellum that was lesioned. Lesion mapping was used to measure lesion size and volumetric methods were used to measure atrophy in 25 adult survivors of cerebellar tumors. Participants had too a high degree of heterogeneous cerebellar lesions and accompanying atrophy to explore specialization. However, total cerebellar atrophy negatively impacted written and oral processing speed to a greater degree than total cerebellar lesion size. Younger ages at diagnosis and radiation therapy were associated with greater cerebellar atrophy.

Thesis (M.Sc. (Anatomy))--Mahidol University, 1982.

Thesis (Ph.D. (Physiology))--Mahidol University, 1978. / Financial support by the Rockefeller Foundation, the National Reasearch Counicl and the World Health Organization.

Diss. med. dent. Zürich. / Literaturverz.