Groucho/transducin-like Enhancer of split (Gro/TLE) family proteins are corepressors found as part of multiple transcriptional complexes that play significant roles during many developmental processes, including neurogenesis. This thesis sought to characterize the molecular mechanisms underlying the biological activity of Gro/TLE1. More specifically, the aim was to clarify the contribution of different transcriptional cofactors, as well as phosphorylation events induced by cofactor binding, to Gro/TLE1 ability to inhibit neuronal differentiation from proliferating neural progenitor cells. / By characterizing specific point mutations within the C-terminal domain of Gro/TLE1, we were able to selectively impair binding of Gro/TLE1 to different classes of DNA-binding proteins and then assess the effect of those mutations on Gro/TLE1 anti-neurogenic function. These studies showed that the inhibition of cerebral cortex (cortical) neuron differentiation by Gro/TLE1 requires interaction with transcription factors that use short tetrapeptide sequences, WRP(W/Y), to recruit Gro/TLE1. In contrast, interactions with proteins that either interact with the C-terminal domain of Gro/TLE1 using a different type of binding sequence, termed engrailed homology 1 (Eh1) motif, or bind to the N-terminal part of the protein, are not required for Gro/TLE1 anti-neurogenic function. / Using a similar strategy based on mutation analysis, we characterized point mutations that block the hyperphosphorylation of Gro/TLE1 induced by transcription cofactor binding ("cofactor-activated phosphorylation") without impairing cofactor binding and transcriptional corepression ability. These mutations map at phosphorylatable serine residues, Ser-286, Ser-289, and Ser298. Mutation of those residues to alanine blocks/reduces both cofactor-activated phosphorylation and anti-neurogenic activity of Gro/TLE1, demonstrating that cofactor-activated phosphorylation is required for that function. Tandem mass spectroscopy analysis showed further that Ser-286 is phosphorylated. Taken together, these findings characterize the role of cofactor-activated phosphorylation and identify residues important for this mechanism. / Our studies also showed that homeodomain-interacting protein kinase 2 (HIPK2) mediates phosphorylation of Gro/TLE1 when the latter is complexed with transcriptional partners of the WRP(W/Y) motif family. However, HIPK2 is not involved in Gro/TLE1 cofactor-activated phosphorylation. Rather, HIPK2--mediated phosphorylation is antagonistic to the latter and decreases the ability of Gro/TLE1 to interact and repress transcription with WRP(W/Y) motif proteins. / Taken together, these results improve significantly our understanding of the mechanisms underlying the anti-neurogenic function of Gro/TLE1. This information provides new insight into the regulation of mammalian neuronal development and, possibly, other developmental processes controlled by Gro/TLE proteins.

The biological mechanisms proposed to underlie primary mood disorder do not usually include a neuropathological component. Over recent years, a significant imaging literature attests to structural abnormalities in various brain regions in mood disorder, and has encouraged neuropathological investigations. Although the neuropathological understanding of mood disorder is still rudimentary, structural correlates have begun to emerge. The studies described in this thesis investigate the neuropathology of the anterior cingulate cortex in mood disorder. The anterior cingulate cortex is extremely diverse and complex, particularly in respect to its cytoarchitecture and functional organisation. These details are important when considering the precise localisation and clinical correlates of the neuropathological changes of this region in disease. Accordingly, I performed a detailed analysis of the cytoarchitecture of the human anterior cingulate cortex, as a prelude to investigations of this region in mood disorder. I measured several morphometric parameters within different anatomical levels and both hemispheres of the anterior cingulate cortex. Overall I found a clear distinction in the cellular composition of the supragenual and subgenual regions of the anterior cingulate cortex. The subgenual region demonstrated a lower glial density and smaller neurons in comparison to the supragenual region. A modest difference in neuronal density was also observed, with a higher density in the deep layers of the subgenual cortex compared to the deep layers of the supragenual cortex. Total cortical depth was also thinner in the subgenual region. This work may have important implications for the interpretation of imaging and pathological data in mood disorder. To assess the cytoarchitecture of this brain region in mood disorder, I examined several morphometric indices in addition to various parameters of gene expression in post mortem brains. I found a range of cytoarchitectural abnormalities in the supragenual anterior cingulate cortex in mood disorder. The most prominent change included a reduction in glial density, which was evident in all layers of the cortex. Glial fibrillary acidic protein was also reduced, providing some evidence for astrocyte involvement. Various neuronal changes were also observed in the mood disorder group. These included layer-specific reductions in pyramidal neuron density and a modest change in the density of cairetinin-immunoreactive neurons. I did not find any evidence supporting synaptic pathology in the anterior cingulate cortex in mood disorder. These findings extend previous evidence of cytoarchitectural alterations in the anterior cingulate cortex in mood disorder and in particular emphasise the prominent involvement of glial cells in the neuropathology of this disease. The origins of the glial (and neuronal) deficits in mood disorder remain to be established, but they are likely to have pathophysiological consequences.

In den letzten Jahren ist zunehmend deutlich geworden, dass die Multiple Sklerose (MS) nicht nur eine Erkrankung der weißen Substanz des zentralen Nervensystems ist, sondern auch häufig und beträchtlich die graue Substanz in allen klinischen Verlaufsformen betrifft. Besonders die kortikale Pathologie mit entmarkten Läsionen wurde durch verbesserte immunhistochemische Färbetechniken und neuen magnetresonanztomographischen Verfahren ausführlicher untersucht. MS-Patienten leiden klinisch oft an körperlichen Beeinträchtigungen und neuropsychologischen Defiziten, welche die Lebensqualität beeinflussen. Diese Symptome wurden mit Läsionen in der grauen Substanz assoziiert. Mechanismen, die zu dieser Pathologie führen, müssen daher aufgeklärt werden um vorbeugende oder akute Behandlungen entwickeln zu können. Zur pathologischen Untersuchung der grauen Substanz werden angemessene Tiermodelle benötigt, welche die humane kortikale Pathologie wiederspiegeln. Das am häufigsten verwendete Tiermodell in MS-Studien ist die Experimentelle Autoimmune Enzephalomyelitis (EAE), die in ihrem ‘konventionellen’ Immunisierungsprotokoll nur selten den zerebralen Kortex betrifft. Ein EAE-Modell mit Einbezug des Kortex, das MS-Läsionen nachahmt, wurde in Ratten beschrieben. Hierzu wurden proinflammatorische Zytokine in eine vorbestimmte kortikale Region injiziert. Da spezifisch genveränderte Rattenstämme fehlen um die Mechanismen der Pathologie in der grauen Substanz zu untersuchen ist es notwendig das Tiermodell in Mäusen zu entwickelen. Das Ziel dieses Projekts war die Entwicklung eines kortikalen EAE-Mausmodells sowie dessen histopathologische Charakterisierung. Desweiteren wurde kortikales Gehirnmaterial von MS-Patienten im späten Krankheitsstadium auf dendritische Patholgie untersucht. Die kortikale EAE wurde in Myelin Oligodendrozyten Glykoprotein (MOG)-immunisierten BiozziABH (hohe Antikörper) und F1 Nachkommen, die aus BiozziABH und Mäusen mit einem C57BL6/J-Hintergrund generiert worden sind, durch die intrakortikale Injektion von TNF-α und IFN-γ induziert. Histologische Untersuchungen zeigten eine ausgedehnte subpiale Entmarkung und Entzündung im Kortex drei Tage nach der Zytokininjektion in der betroffenen Hirnhälfte. Die Entzündung ging innerhalb von drei Wochen fast vollständig zurück und entmarkte Regionen wiesen teilweise eine Remyelinisierung auf. Axone blieben in läsionalen Regionen erhalten und neuronaler Verlust wurde im Kortex nicht beobachtet. Desweiteren wurde eine Methode etabliert, die es erlaubt detailliert dendritische Pathologien in der Maus zu untersuchen. Kortex-enthaltenes Autopsiematerial von progressiven MS-Patienten mit langandauerndem Krankheitsverlauf zeigte einen Verlust von dendritischen Dornfortsätzen (Spines) in Neurone, die in den unteren korikalen Layern sowohl in chronisch entmarkten Läsionen als auch im umliegenden normal erscheinendem Gewebe der grauen Substanz lokalisiert waren. Im vorliegenden Projekt wurde ein kortikales EAE-Mausmodell entwickelt, das die humane MS-Pathologie der grauen Substanz in frühen Krankheitsstadien wiederspiegelt. Dieses Modell ist für Untersuchungen früher Mechanismen im entmarkten Kortex und für die Erprobung therapeutischer Behandlungen wie die Erhöhung der Remyelinisierung nützlich. Darüberhinaus wurde ein ausgedehnter Verlust dendritischer Dornfortsätze im zerebralen Kortex in chronischen MS-Patienten gezeigt, der auf oft beobachtete neuropsychologische Defizite zurückgeführt werden könnte.

The experiments reported in the present dissertation investigated the contribution of the pyriform cortex and of the basolateral amygdala to three classes of affective behavior: conditioned aversions, conditioned preferences, and neophobia. It was demonstrated that lesions of the pyriform cortex cause an impairment in the acquisition of aversions to olfactory, but not gustatory, stimuli and that this impairment is not secondary to alterations in primary olfactory function. The acquisition of a preference for a particular odor paired with reward was also shown to be impaired by such lesions. These results are discussed in terms of the rich innervation of the pyriform cortex by olfactory fibers, and of its projections to sub-cortical structures. Ibotenic-acid lesions of the basolateral amygdala caused a significant deficit in conditioned taste aversion, whereas these same lesions did not affect conditioned odor aversion. This dissociation was examined in light of the differences in anatomical projections from the olfactory and gustatory cortical areas to the basolateral region. The performance of animals with electrolytic lesions of the basolateral amygdala on a conditioned taste- and a conditioned odor-preference task raised some important questions concerning the contribution of this neural structure to stimulus-reward associations. The last two experiments demonstrated that the pyriform cortex plays an important role in neophobia, a role that is not limited to olfactory stimuli. This suggests that the analysis and subsequent transmission of olfactory information is critical to the expression of the neophobic response.

Les malalties del cervell representen avui en dia un dels problemes de salut més importants del món desenvolupat, tant pel que fa a malalties neurològiques d’ampli abast, com la malaltia d’Alzheimer, com pel que fa a malalties psiquiàtriques greus, com l’esquizofrènia i la depressió. Els costos socioeconòmics directes (tractaments) i indirectes (baixes laborals, incidència familiar, atenció al malalt, etc.) de les malalties del cervell a la UE dels 25 pugen fins als 286.000 milions de € anuals, dels quals gairebé 240.000 milions són deguts a malalties mentals (Andlin-Sobocki et al., 2005). Dins d’aquestes, depressió i esquizofrènia. La prevenció i correcte tractament d’aquestes dues malalties representen avui en dia un dels reptes més importants de la Neurociència.

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 Sydney, 2002. / Title from title screen (viewed Apr. 28, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Psychological Medicine, Faculty of Medicine. Includes bibliography. Also available in print form.

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references (leaves 216-223). Also available via the Internet.

Thesis (Ph.D.)--Marshall University, 2009. / Title from document title page. Includes abstract. Document formatted into pages: contains xi, 116 p. Includes bibliographical references p. 104-116.

Thesis (M.C.S.)--Carleton University, 1993. / Also available in electronic format on the Internet.