La maladie de Huntington (MH) est un trouble neurologique transmis selon un mode autosomique dominant qui conduit à l’apparition de symptômes moteurs, psychiatriques et cognitifs chez l’adulte. La MH est caractérisée par une neurodégénérescence massive des neurones striataux et corticaux. La MH est causée par une mutation de la séquence codante de la protéine Huntingtine (HTT) conduisant à la production d’une protéine mutée (mHTT). La mHTT gagne de nouvelles fonctions toxiques mais perd aussi certaines fonctions normales. L’étude de ces deux aspects (à la fois gain et perte de fonction) est donc indispensable à la compréhension du processus pathologique de la MH.La HTT et mHTT participent au développement des structures cérébrales. Notre hypothèse est donc que les défauts développementaux induits par la mHTT contribuent à la progression physiopathologique de la MH. Notre équipe s’intéresse tout particulièrement au développement du cortex cérébral, largement atteint dans la MH. Nos précédentes études ont démontré le rôle de la HTT et l’effet de sa mutation dans la prolifération des précurseurs neuronaux du cortex cérébral. Cependant, les fonctions de la HTT et de la mHTT lors des étapes plus avancées du développement cortical, restent à ce jour inconnues.Mon projet de thèse se décompose en deux axes principaux : (i) l’étude des fonctions de la HTT dans les neurones nouvellement produits dans le cortex en développement, notamment au cours de leur migration et de leur maturation dendritique et (ii), la caractérisation de la neurogenèse corticale dans un modèle génétique de la MH : zQ175. / Huntington disease (HD) is an autosomal dominant inherited neurological disorder conducting to the appearance of motors, psychiatrics and cognitives symptoms during mid-adulthood. HD is characterised by a massive neurodegenerescence of both striatal and cortical neurons. HD is caused by a mutation in coding region of the protein Huntingtin (HTT) leading to the production of a mutated form (mHTT). mHTT gain new toxic function but also loss some of normal function of HTT. Therefore, studying both gain and loss of function is mandatory to better understand the physiopathological progression of HD.HTT and mHTT both contribute to development of cerebral structures. Our hypothesis is that developmental defects induced by mHTT could contribute at least in part to the physiological progression of HD. Our work focuses on cerebral cortex development a structure which is largely impacted in HD. Our previous studies demonstrated roles of HTT and the effect of mHTT in neuronal precursor proliferation during neurogenesis. However, roles and functions of HTT and mHTT during later step of cortical neurogenesis remain elusive.My PhD project has focused on two main aspects: (i) study the function of HTT in newborn post-mitotic neurons in cerebral cortex, notably during their migration and maturation, and (ii), characterising cortical neurogenesis in genetically integrated mouse model of HD: zQ175.

Our perception of the world is limited by the senses we are endowed with. In the case of taste, its functional fidelity is so critical for our survival that we come into the world with innate preference for sweet and disgust for bitter. These stereotyped behaviors are hardwired at the lowest levels of taste processing and they support the view that taste serves as an arbiter of the chemical world, passing judgement before permitting ingestion. Yet our experience of foods is manifold. This complexity results from distinct contributions from the sights, sounds and smells of the foods we consume. Of these, odors are a co-equal component of flavor and the impairment of olfaction can disrupt enjoyment of eating and alter patterns of consumption. The goal of this thesis is to identify the neural basis of odor-taste perception and to characterize how neural activity is affected by odor-taste integration. In contrast to the discrete and innate categorization performed by the taste system, the sense of smell enables discrimination of thousands of unique odor percepts which have no innate value. At the level of olfactory cortex, odor representations are randomly distributed and have been shown to be conditioned through association with other stimuli. The act of eating produces near simultaneous taste and odor transduction originating from the same source. Yet despite ultimately projecting to neighboring cortical regions, taste and odor pathways are anatomically segregated prior to reaching the cortex. Using viral tracing strategies, we identified Agranular Insular cortex (AIc) as a putative site of odor-taste integration. We then used in vivo two-photon Ca2+ Imaging to characterize odor and taste responsive neurons and identify changes in population activity when these stimuli were simultaneously presented. We next asked whether specific flavor experiences altered activity in AIc compared to naive animals. Finally, we developed a behavioral task to test whether silencing AIc disrupted perception of a flavor compound.

The hippocampus appears to carry out spatial memory processing and navigation. As one of the inputs to the hippocampus originates in the perirhinal cortex and the spatial behaviour is affected by lesion of the perirhinal cortex, this structure may be critical for the functioning of hippocampal place cells. To investigate this hypothesis, the firing properties of hippocampal place cells were compared between control rats and rats with perirhinal cortex lesions. Rats were randomly assigned to control and lesion groups. Animals from both groups received recording electrode implantation and the lesion group rats received bilateral perirhinal cortex lesions. In experiment 1, the control and lesioned rats moved freely in an open field. In experiment 2, the control and lesion rats ran for reward in a linear track with either horizontal or vertical grating pattern stimulation along both sidewalls. These two experiments examined the spatial firing and movement-related firing properties of the control and lesion groups; and the theta-related firing properties of the two groups. In addition, experiment 2 investigated the influence of optic flow on these properties between the two groups. In experiment 3, the control and lesion rats were passively moved in the linear track with either a horizontal or vertical grating pattern on both sidewalls. This experiment examined the spatial firing and movement-related firing properties and also investigated the influences of optic flow, motor efferent and proprioceptive information on the firing properties of the control and lesion groups� place cells. The perirhinal cortex lesion affected the spatial firing properties of hippocampal place cells. The place field size in the lesion group was significantly reduced compared to the control group in both open field and linear track experiments. The lesion also altered the movement-related firing properties. The positive relationship between the animal�s movement speed and place cell�s firing rate was disrupted by the perirhinal cortex lesion whether the animals freely ran in the open field or in the linear track. In the open field study, the perirhinal cortex lesion altered the theta-related firing pattern, and the lesion disrupted phase precession in the linear track experiment. Phase precession is that when a rat passes through the place field, the firing of the cell advances progressively and systematically across the phase of the theta cycle from a late to an early phase of the cycle. The lesion also induced poorer theta "quality" of the EEG recorded at the hippocampal fissure. Optic flow affected the spatial firing of hippocampal place cells. The place field size was smaller in both the control and lesion group when the animals received vertical grating pattern stimulation compared to the horizontal grating condition. Change in the levels of optic flow stimulation did not, however, influence the relationship between the animal�s movement speed and place cell�s firing rate in the control group. When the animals were passively moved in a linear track, many of the place cells of both the groups stopped firing. The remaining cells from the control and lesion groups still displayed a place field. The cells in the control group lost the positive relationship between the animal�s movement speed and place cell�s firing rate. The perirhinal cortex lesion affected the spatial, movement- related and theta-related firing properties of hippocampal place cells. Change of optic flow had a subtle effect on the movement-related firing properties of the place cells. The PrhC lesion therefore disrupted motor efferent and proprioceptive input to the HPC rather than visual sensory information. Motor efferent / proprioceptive or vibrissae information may be conveyed from related cortex to the perirhinal cortex. This information may then project from the perirhinal cortex to the hippocampus directly or indirectly via the entorhinal cortex. Future studies could investigate the relationship between whisker stimulation and hippocampal place cell firing properties and further examine the possible role of motor efferent / proprioceptive signals in the firing of these cells.

Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, August 1999. / Includes bibliographical references. Also available on the Internet.

Over the past five years the role of epigenetic modifiers in brain development has become increasingly evident. In this regard, Snf2l, a homolog of the chromatin remodeling protein ISWI, was shown to have enriched expression in the brain and be important for neuronal differentiation. Mice lacking functional Snf2l have hypercellularity of the cerebral cortex due to increased cell cycle re-entry. In this thesis I demonstrate the effects of Snf2l-ablation on cortical progenitor cells including increased proliferation and cell cycle deregulation, the consequence of which is a delay in neuronal migration and altered numbers of mature cortical neurons. This phenotype arises from increased expression of Foxg1, a winged-helix repressor expressed in the forebrain and anterior optic vesicle. Moreover, genetically reducing its overexpression rescues the Snf2l-ablated phenotype. Snf2l is bound directly to a promoter region of Foxg1 suggesting that it acts as a repressive regulator in vivo and is an important factor in forebrain differentiation.

Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.

Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.

The cerebral cortex is gray matter tissue which covers cerebral hemispheres. In recent years, many studies reported that abnormal cortical thickness was found in several diseases of central neural system, such as multiple sclerosis, Alzheimer's diseases, and schizophrenia. Therefore, the whole-brain measurement of cortical thickness using the non-invasive magnetic resonance imaging becomes important. However, not many algorithms were reported in the past due to the extremely complex folding structure of human cortex. In this thesis, a voxel-based cortical thickness method proposed by Hutton et al was implemented using MATLAB to achieve automated measurement. Several crucial factors, including the definition of boundary condition, interpolation method, the step size of developing each streamline, and spatial resolution of imaging space, in the implementation were discussed. In addition, the analysis of stability, or precision, of our self-developed program was evaluated . Sixteen experiments of reproducibility were performed in two months on the same 24-year-old healthy volunteer repeatedly to obtain whole-brain 3D T1WI. Cortical thickness map was calculated independently and normalized to the same coordination. Mean, standard deviation, and normalized standard deviation of 16 measurements were calculated on every cortical voxel, along with whole-brain mean cortical thickness. Various sizes of 3D smoothing kernel were applied, and the results showed stronger smoothing might help higher precision by the cost of spatial resolution.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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