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The cerebellum affects a number of important and complex processes in the organism. It ensures coordination, motor learning and plays an important role in cognitive and affective functions. In the case of cerebellar degeneration, we find not only the movement disorders but also behavioral abnormalities, collectively referred to as cognitive-affective syndrome. The aim of this work was to investigate motor functions during ontogenesis in animal models of hereditary cerebellar degeneration - mutant mice Lurcher and Purkinje cell degeneration using the device for quantitative gait analysis and rotarod. In addition, the effect of physical activity on the extent of ataxia and manifestations in classical behavioral tests was monitored. The results confirmed significant differences in motor skills between mutant and healthy mice; differences were also observed in some gait parameters, especially in walking speed and parameters that correlate with it. The motor functions of most groups of mice did not change during ontogenesis, pcd mice deteriorated their performance on the rotarod. The effect of physical activity was not found, with the exception of Forced swimming test. Physical activity of set intensity did not have any beneficial effect on the motoric manifestations of the mice.

Diploma the 'is deals wi th the research of effect of biofeedback in the form of electrotactile stimulation of tongue in the patients with balance disorders eaused by the cerebellar lesion. For the therapeutic program 4 patients with cerebellar ataxia at the age of38 - 74 years were chosen. Subjects have partieipated in the therapeutic program with the application of biofeedback, they were training postural stability while visual control was excluded and they were using electrotacti le signal on the tongue for orientation. I used neurological tests BESTest and Dynamic Oait Index, questionnaire The Activities- Specific Balance Confidence (ABC) Scale, Dizziness I Tandicap Inventory (D ll) a Visual Analogue Scale (VAS), and examination by stati posturography for evaluation of postural stability in the patients. I supposed that therapy by biofeedback in the form of electrotactile stimulation of tongue improves postural stability in the patients with balance disorders caused by cerebellar lesion. Powered by TCPDF (www.tcpdf.org)

INTRODUCTION This graduation theses considers with the influence of rehabilitation by electrotactile stimulation of the tongue on stability of stance and gait in patients with degenerative cerebellar ataxia. Electrotactile stimulation of the tongue is an innovative method based on biofeedback principle, which uses additive sensory information about the position of the head to train the postural stability METHOD We used this method in six patients (four men and two women) with this disease. Patients went through intensive twelve-day therapy. The duration of the lessons was 30 minutes twice a day. We examined postural stability of the patients by using clinical evaluations (Balance Evaluation Systems Test, Dynamic Gait Index), posturography (modified Clinical Test of Sensory Interaction for Balance) and questionnaires (Activities -specific Balance Confidence, Dizziness Handicap Inventory) before and after the therapy. RESULTS The patients showed significant improvement in both clinical tests after the therapy. The results of posturography measurement are not so definite - the significant improvement was achieved only in some measured parameters. Both questionnaires did not show significant improvement. CONCLUSION The results of this study show, that electrotactile stimulation tongue could have a...

O enriquecimento ambiental (EA) é um modelo experimental capaz de promover a melhora no aprendizado e na formação de memórias hipocampo-dependentes, bem como a redução de manifestações comportamentais relacionadas ao estresse, incluindo a ansiedade. Embora a relação causal entre estresse e ansiedade ainda não está esclarecida, algumas evidências apontem para a importância da sinalização de hormônios glicocorticoides (via receptores GR e MR) no sistema nervoso central, principalmente na amígdala e no hipocampo, além do fator neurotrófico BDNF e de algumas vias de sinalização intracelular, como proteínas quinases MAPK e o fator de transcrição CREB. No presente trabalho verificamos que o EA previne o surgimento de sintomas do tipo ansioso desencadeado por estresse agudo em ratos, efeito verificado imediatamente após o estresse, e que tal efeito pode estar relacionado à modulação, no complexo amigdalóide basolateral, da sinalização nuclear de GR, da atividade de ERK (pertencente à família das MAPK) e de CREB, bem como à alteração na expressão do receptor de BDNF. / Environmental enrichment (EE) is an experimental model that promotes improvements in learning and memory, as well as reduction in stress-induced behaviors, including anxiety. Although the casual relationship between stress and anxiety remains unclear, some studies show the importance of glucocorticoids hormones signaling (via GR and MR receptors) in the central nervous system, primarily in the amygdala and the hippocampus. In addition, the significance of the neurotrophic factor BDNF and some intracellular signaling pathways, such as protein kinases MAPK and the transcription factor CREB, has been described. In this study we found that EE prevents the emergence of anxiety-related behavior triggered by acute stress in rats, an effect observed just after the stress stimulus. This effect may be related to the modulation, in the basolateral amygdala, of nuclear GR signaling, ERK (a MAPK protein) and CREB activity, as well as to changes in the expression of BDNF receptor.

Ainda pouco se sabe sobre as causas do transtorno do espectro autista (TEA) e seus efeitos na funcionalidade cerebral, porém, diversas pesquisas apontam que a condição esteja relacionada à uma conectividade diferenciada entre regiões do cérebro. A conectividade córtico-cerebelar tem sido tema de pesquisas nas últimas décadas em decorrência de novos achados que indicam que esta conectividade está relacionada ao aprendizado e refinamento de diversas funcionalidades do córtex. Acredita-se que uma falha na conectividade córtico-cerebelar poderia estar relacionada à falhas em funções sensorimotoras, cognitivas e emocionais. A investigação de regiões cuja conectividade córtico-cerebelar está alterada no TEA contribui para uma melhor compreensão deste transtorno. Assim, o objetivo deste trabalho é identificar regiões do cérebro cuja conectividade funcional com o cerebelo seja diferente entre indivíduos com desenvolvimento típico (DT) e diagnosticados com TEA. Para isto, utilizamos imagens de ressonância magnética funcional (fMRI) de 708 indivíduos em estado de repouso (432 DT e 276 TEA) com idades entre 6 e 58 anos coletados pelo consórcio ABIDE. Os dados foram pré-processados e divididos conforme regiões anatômicas do cérebro que foram adotadas como regiões de interesse (ROIs). Para determinar a conectividade funcional de cada região do córtex com o cerebelo, aplicamos o método de análise de componentes principais (PCA) nas ROIs do cerebelo e utilizamos um modelo regressão linear para cada ROI do córtex, sendo a série temporal da ROI do córtex a variável resposta e as componentes principais (PCs) do cerebelo as variáveis preditoras. Em seguida, identificamos as regiões com conectividade funcional diferente entre indivíduos com DT e diagnosticados com TEA através de um modelo linear que inclui como covariáveis, idade, gênero e local de coleta do dado. Identificamos cinco regiões do córtex que apresentam reduzida conectividade funcional com o cerebelo nos indivíduos com TEA, sendo elas: (i) giro fusiforme direito, (ii) giro pós-central direito, (iii) giro temporal superior direito e (iv) giro temporal médio direito e (v) esquerdo. Todas as cinco regiões são parte do sistema sensorimotor, e estão relacionadas à funções ligadas à sintomas característicos do quadro de TEA, como: sensibilidade à estímulos sensoriais, dislexia, prosopagnosia (dificuldade para reconhecer faces), dificuldade de compreensão de linguagem e dificuldade de reconhecimento de emoções em faces. Nossos resultados mostram que existem regiões do sistema sensorimotor que apresentam conectividade funcional com o cerebelo atipicamente reduzida em TEA, como corroborado por estudos de imageamento com tarefa específica e como hipotetizado por estudos de conectividade estrutural. Nós acreditamos que a conectividade córtico-cerebelar reduzida dessas regiões esteja prejudicando o processamento e aprendizado de funções sensorimotoras, levando ao surgimento de sintomas típicos do TEA. / Little is known about the causes of autism spectrum disorder (ASD) and its effects on brain functions. Several researches point that it may be related to differentiated connections between brain regions. The cortico-cerebellar connectivity has been theme of researches over the last decade given the new discoveries suggesting that this connection is associated with learning and tuning of diverse brain functionalities. It is believed that cortico-cerebellar connectivity impairment may be related to impairments on sensorimotor, cognitive, and emotional functions. For a better understanding of the condition, we aim at identifying brain regions that present a impaired cortico-cerebellar connectivity between TD and ASD. Thus, our goal is to identify brain regions where the functional connectivity with the cerebellum is different between subjects with typical development (TD) and ASD. We used functional magnetic resonance images (fMRI) of 708 subjects under resting state protocol (432 TD and 276 ASD) with ages between 6 and 58 years old collected by the ABIDE Consortium. Data was pre-processed, splited in anatomical brain regions, which were adopted as regions of interest (ROIs). To establish the functional connectivity of each cortical ROI to the cerebellum, first we applied the principal component analysis (PCA) on cerebellar ROIs. Next, we used a linear regression model to each cortical ROI time series as response variable and the cerebellum principal components (PCs) as the predictive variables. After that, we identified regions of different connections between TD and ASD subjects applying a linear model including age, gender, and data collection site as covariables. We identified five cortical regions with reduced functional connectivity with cerebellum on the ASD subjects, namely: (i) right fusiform gyrus, (ii) right postcentral gyrus, (iii) right superior temporal gyrus, (iv) right middle temporal gyrus, and (v) left middle temporal gyrus. All five regions are part of the sensorimotor system, and contribute to functions typically associated with ASD, such as: sensitivity to external stimulus, dyslexia, prosopagnosia (difficulty to recognize faces), language comprehension impairments, and recognition of emotional expressions impairment. Our results show that there are brain regions with atypical cortico-cerebellar connectivity impairment on ASD, in accordance with results from previous studies of tactography and task driven fMRI. We believe that the decreased cortico-cerebellar connectivity of these regions are affecting the learning process of sensorimotor functionalities, leading to typical ASD symptoms.

Mikrogliazellen stellen die professionellen Phagozyten des zentralen Nervensystems dar und sind maßgeblich bei der Entfernung apoptotischer Neurone aus dem Gewebe beteiligt. Die Erkennungsmechanismen, die zu einer Erkennung und Phagozytose apoptotischer Neurone durch Mikrogliazellen führen, sind bisher unbekannt. In dieser Arbeit wurde mit Hilfe eines Kokulturmodells die Erkennungsmechanismen zwischen primären Mikrogliazellen und apoptotischen Kleinhirnneuronen untersucht. Der apoptotische Zelltod, charakterisiert durch Schrumpfung und Fragmentation der Neuron, durch Kondensation des Chromatins, durch Fragmentation der DNA und durch Präsentation von Phosphatidylserin auf der extrazellulären Seite der Plasmamembran, wurde in den Kleinhirnneuronen durch eine Behandlung mit 100 µM S-Nitrosocystein induziert. Es konnte gezeigt werden, daß apoptotische Neurone keine löslichen Substanzen sekretierten, die chemotaktisch auf Mikrogliazellen wirken. Dies zeigt, daß die Erkennung apoptotischer Neurone über Zell-Zell-Kontakte erfolgt. Zur Untersuchung der beteiligten Erkennungsmechanismen wurden Mikrogliazellen zwei Stunden nach der Induktion des apoptotischen Zelltods zu den Neuronen gegeben und für sechs Stunden in Gegenwart oder Abwesenheit von Liganden kultiviert, die mögliche Rezeptoren zur Erkennung von apoptotischen Neuronen inhibieren. Die Bindung/Phagozytose der apoptotischen Kleinhirnneurone durch Mikrogliazellen wurde mit einer kombinierten DAPI/Propidiumjodid (für apoptotische/nekrotische Zellen) und einer Lektin Färbung (für Mikrogliazellen) durch Auszählung bestimmt. Die Aufnahme apoptotischer Neurone durch Mikrogliazellen wurde durch Galaktose und N-Acetylglukosamin reduziert, was auf eine Erkennung apoptotischer Zellen durch Lektine hindeutet. Weiterhin weist der inhibitorische Effekt von RGDS-Peptiden auf die Bindung/Phagozytose von apoptotischen Neuronen durch Mikrogliazellen auf eine Erkennung durch ein Vitronektinrezeptor hin. Da Mikrogliazellen spezifisch Lipidvesikel, die mit Phosphatidylserin angereichert waren, binden und O-Phospho-L-Serin die Aufnahme von apoptotischen Neuronen durch Mikrogliazellen deutlich inhibierte, erfolgte die Erkennung apoptotischer Neurone hauptsächlich durch einen Phosphatidylserin Rezeptor. Die Expression des PS-Rezeptors auf Mikrogliazellen ist unabhängig vom Aktivierungszustand der Mikrogliazellen in vitro. Die Bindung von PS ist mit einem Anstieg der intrazellulären Kalziumkonzentration in der Mikrogliazelle verbunden und führt nicht zu einer sekretorischen Aktivierung der Mikrogliazelle. Da Astrozyten ebenfalls einen PS-Rezeptor exprimieren, könnten sie als semiprofessionelle Phagozyten ebenfalls eine Bedeutung bei der Aufnahme apoptotischer Neurone einnehmen. Diese Ergebnisse zeigen, daß apoptotische Neurone ein komplexes Oberflächenmuster exprimieren, welches durch unterschiedliche Rezeptorsysteme der Mikrogliazelle erkannt werden kann. Die Erkennung von PS auf apoptotischen Neuronen durch Mikroglia scheint bei diesen untersuchten Rezeptorsystemen die wichtigste Rolle zu spielen. / Microglia are the professional phagocytes of the central nervous system and play a crucial role in removal of apoptotic neurons out offrom the tissue. The recognition mechanisms leading to the recognition and phagocytosis of these apoptotic neurons by microglia are not yet characterized. Here IIn the present work established a co-culture model was established to examine the receptor systems involved in the recognition of apoptotic cerebellar neurons by primary microglia. Treatment with 100 µM S-nitrosocysteine induced apoptosis of cerebellar neurons as indicated by condensation and fragmentation of the neurons, condensation of the chromatin, fragmentation of the DNA and phosphatidylserine exposure to the exoplasmic leaflet of the plasma membrane. It was shown that apoptotic neurons do not release soluble signals that serve to attract microglia. Consequently, contact-dependent interaction between the microglial cell and the apoptotic neuron is required for recognition. For the examination of the receptor systems involved in recognition, microglial cells were added to neurons 2 h after induction of apoptosis induction and co-cultured for 6 h in the presence of ligands that inhibit recognition by binding to their respective receptors. Binding/phagocytosis was determined after combined DAPI/propidium iodide (for apoptotic/necrotic neurons) and lectin staining (for microglia). Uptake of neurons was reduced by galactose or N-acetylglucosamine, suggesting that recognition involves lectins. Furthermore, the inhibition of microglial binding/uptake of apoptotic neurons by RGDS peptide suggesteds a rolethe involvement of a microglial vitronectin receptor. The selective Binding of phosphatidylserine-enriched lipid vesicles on microglial cells and the strong interference of O-phospho-L-serine with the uptake of apoptotic neurons was indicative of an important role for the phosphatidylserine receptor (PS-receptor)As microglia selectively bind lipid vesicles enriches in phosphatidylserine and O-phospho-L-serine interfered in a strong way with the uptake of apoptotic neurons, the recognition of apoptotic neurons is manly dependent on a phosphatidylserine receptor. The expression of the PS-receptor is independent of the activation state of the microglial cell in vitro. The bindigbinding of PS induces an elevation of the intracellular calcium concentration in the microglia but doesid not induce an activationsectretion of (Liste der getesteten Zytokine einsetzen) of the microglial cell in an secretory way. Because of the expression of a PS-receptor, Astrocytes could also play a role in the uptake of apoptotic neurons as semiprofessional phagocytes. In summaryCollectively, these results suggest that apoptotic neurons generate a complex surface signal recognized by different receptor systems on microglia. The recognition of PS on the surface of apoptotic neurons by microglial cells seems to play a major role in the recognition of these apoptotic neuronscells..

Ainda pouco se sabe sobre as causas do transtorno do espectro autista (TEA) e seus efeitos na funcionalidade cerebral, porém, diversas pesquisas apontam que a condição esteja relacionada à uma conectividade diferenciada entre regiões do cérebro. A conectividade córtico-cerebelar tem sido tema de pesquisas nas últimas décadas em decorrência de novos achados que indicam que esta conectividade está relacionada ao aprendizado e refinamento de diversas funcionalidades do córtex. Acredita-se que uma falha na conectividade córtico-cerebelar poderia estar relacionada à falhas em funções sensorimotoras, cognitivas e emocionais. A investigação de regiões cuja conectividade córtico-cerebelar está alterada no TEA contribui para uma melhor compreensão deste transtorno. Assim, o objetivo deste trabalho é identificar regiões do cérebro cuja conectividade funcional com o cerebelo seja diferente entre indivíduos com desenvolvimento típico (DT) e diagnosticados com TEA. Para isto, utilizamos imagens de ressonância magnética funcional (fMRI) de 708 indivíduos em estado de repouso (432 DT e 276 TEA) com idades entre 6 e 58 anos coletados pelo consórcio ABIDE. Os dados foram pré-processados e divididos conforme regiões anatômicas do cérebro que foram adotadas como regiões de interesse (ROIs). Para determinar a conectividade funcional de cada região do córtex com o cerebelo, aplicamos o método de análise de componentes principais (PCA) nas ROIs do cerebelo e utilizamos um modelo regressão linear para cada ROI do córtex, sendo a série temporal da ROI do córtex a variável resposta e as componentes principais (PCs) do cerebelo as variáveis preditoras. Em seguida, identificamos as regiões com conectividade funcional diferente entre indivíduos com DT e diagnosticados com TEA através de um modelo linear que inclui como covariáveis, idade, gênero e local de coleta do dado. Identificamos cinco regiões do córtex que apresentam reduzida conectividade funcional com o cerebelo nos indivíduos com TEA, sendo elas: (i) giro fusiforme direito, (ii) giro pós-central direito, (iii) giro temporal superior direito e (iv) giro temporal médio direito e (v) esquerdo. Todas as cinco regiões são parte do sistema sensorimotor, e estão relacionadas à funções ligadas à sintomas característicos do quadro de TEA, como: sensibilidade à estímulos sensoriais, dislexia, prosopagnosia (dificuldade para reconhecer faces), dificuldade de compreensão de linguagem e dificuldade de reconhecimento de emoções em faces. Nossos resultados mostram que existem regiões do sistema sensorimotor que apresentam conectividade funcional com o cerebelo atipicamente reduzida em TEA, como corroborado por estudos de imageamento com tarefa específica e como hipotetizado por estudos de conectividade estrutural. Nós acreditamos que a conectividade córtico-cerebelar reduzida dessas regiões esteja prejudicando o processamento e aprendizado de funções sensorimotoras, levando ao surgimento de sintomas típicos do TEA. / Little is known about the causes of autism spectrum disorder (ASD) and its effects on brain functions. Several researches point that it may be related to differentiated connections between brain regions. The cortico-cerebellar connectivity has been theme of researches over the last decade given the new discoveries suggesting that this connection is associated with learning and tuning of diverse brain functionalities. It is believed that cortico-cerebellar connectivity impairment may be related to impairments on sensorimotor, cognitive, and emotional functions. For a better understanding of the condition, we aim at identifying brain regions that present a impaired cortico-cerebellar connectivity between TD and ASD. Thus, our goal is to identify brain regions where the functional connectivity with the cerebellum is different between subjects with typical development (TD) and ASD. We used functional magnetic resonance images (fMRI) of 708 subjects under resting state protocol (432 TD and 276 ASD) with ages between 6 and 58 years old collected by the ABIDE Consortium. Data was pre-processed, splited in anatomical brain regions, which were adopted as regions of interest (ROIs). To establish the functional connectivity of each cortical ROI to the cerebellum, first we applied the principal component analysis (PCA) on cerebellar ROIs. Next, we used a linear regression model to each cortical ROI time series as response variable and the cerebellum principal components (PCs) as the predictive variables. After that, we identified regions of different connections between TD and ASD subjects applying a linear model including age, gender, and data collection site as covariables. We identified five cortical regions with reduced functional connectivity with cerebellum on the ASD subjects, namely: (i) right fusiform gyrus, (ii) right postcentral gyrus, (iii) right superior temporal gyrus, (iv) right middle temporal gyrus, and (v) left middle temporal gyrus. All five regions are part of the sensorimotor system, and contribute to functions typically associated with ASD, such as: sensitivity to external stimulus, dyslexia, prosopagnosia (difficulty to recognize faces), language comprehension impairments, and recognition of emotional expressions impairment. Our results show that there are brain regions with atypical cortico-cerebellar connectivity impairment on ASD, in accordance with results from previous studies of tactography and task driven fMRI. We believe that the decreased cortico-cerebellar connectivity of these regions are affecting the learning process of sensorimotor functionalities, leading to typical ASD symptoms.

Abstract available through Journal of Neurologic Physical Therapy.

In the context of fetal alcohol spectrum disorders, we investigated how the nitric oxide (NO) signaling pathway influences intracellular calcium (Ca2+) to mediate alcohol resistance, using a primary cell culture model of cerebellar granule neurons (CGN). Alcohol during fetal brain development triggers abnormally high apoptotic cell death in vulnerable neuronal populations, culminating in serious behavioral and cognitive deficits that persist into adulthood. Prior studies demonstrated that the NO signaling pathway [neuronal nitric oxide synthase → NO → soluble guanylyl cyclase → cyclic guanosine monophosphate → protein kinase G (PKG)] mitigates alcohol toxicity, consequently diminishing neuronal loss both in vivo and in vitro. Endoplasmic reticulum (ER) Ca2+ release, a key apoptotic mechanism, requires the inositol 1,4,5-trisphosphate receptor (IP3R), a known PKG substrate. Our studies focused on this crucial intersection point where the NO signaling cascade can influence Ca2+-mediated apoptotic mechanisms, and exposed a downstream mechanism where NO can moderate alcohol neurotoxicity. We hypothesized that as alcohol disturbs neuronal Ca2+ homeostasis to trigger cell death, the NO signaling pathway counters it by limiting Ca2+ release from the ER. We examined first the role of the phospholipase C (PLC) pathway [PLC → inositol 1,4,5-trisphosphate → IP3R → Ca2+] in developmental neurotoxicity through our in vitro CGN model, extending previous in vivo studies. We found that alcohol terminates developing neurons by eliciting abnormal Ca2+ release from the ER rather than from an extracellular source, via a PLC - IP3R-dependent signaling mechanism. Inhibiting either calcineurin or Ca2+ / calmodulin-dependent protein kinase ii (CaMKii), which participate in parallel Ca2+-activated apoptotic cascades, shielded CGN cultures from alcohol. Blocking the mitochondrial Ca2+ uniporter or the mitochondrial permeability transition pore also provided neuroprotection. That the activated pathways must interact to generate cell death likely explains why inhibiting one of multiple parallel signaling cascades limits alcohol toxicity. We next demonstrated that activating the NO pathway downstream at PKG eliminated both alcohol-related neuronal death and the accompanying rapid rise in intracellular Ca2+, an effect that markedly resembled IP3R inhibition. Experiments that temporally manipulated the addition of PKG activators in relation to alcohol exposure linked PKG's obstruction of alcohol-induced Ca2+ elevations to alcohol resistance. In contrast, brain-derived neurotrophic factor (BDNF), which does not rely on PKG to provide neuroprotection, failed to block alcohol-induced Ca2+ elevations while preventing alcohol toxicity. This indicates that although PKG blocks alcohol-induced Ca2+ elevations, averting these Ca2+ elevations is not necessary for neuroprotection. BDNF may confer alcohol resistance through an as yet unidentified process downstream from the disruption of intracellular Ca2+. In summary, we established that 1) alcohol induces toxic Ca2+ elevations originating from the ER through a PLC - IP3R-dependent pathway, and that 2) PKG-mediated alcohol resistance is linked to preventing the intracellular Ca2+ surges. These findings support the hypothesis that the NO signaling pathway shields developing neurons from alcohol by limiting Ca2+ release from the ER.