The difficulty with movement initiation, or akinesia, is a cardinal symptom of Parkinson�s disease (PD) and the loss of dopaminergic cells, affecting the function of the basal ganglia, the thalamus and the motor cortex, has long been documented. From a broader perspective, it has been proposed that akinesia is caused by impaired function in different brain areas, inside and outside the basal ganglia, operating as a �behavioural arrest control system� (Klemm, 2001). Several neurotransmitters seem to modulate the activity of this system and, contrasting the well-known effects of dopamine, the involvement of adenosine has only recently emerged, particularly via A2A receptors. Adenosine plays an opposite role to dopamine in the brain: adenosine stimulation at A2A receptors inhibits movement (Ferre et al., 1991a; Hauber and Munkle, 1995; Rimondini et al., 1997), whereas A2A antagonists seem to promote movement (Kanda et al., 2000; Bara-Jimenez et al., 2003; Pinna et al., 2005). Although specific adenosine A2A and dopamine D2 receptors are known to antagonistically interact (Ferre et al., 1997; Fuxe et al., 1998; Ferre et al., 2001), little is known of the involvement of A2A receptors in regulating neural activity in the basal ganglia, a crucial point for the future use of A2A antagonists as adjuvant therapy in Parkinson�s disease. In fact, although it is generally accepted that akinesia results from altered function in the cortico-basal ganglia-cortical loop, as confirmed in several studies reporting changes in basal ganglia activity following dopamine depletion (Blandini et al., 2000; Bevan et al., 2002; Boraud et al., 2002), no study to date has systematically investigated electrophysiological changes in the basal ganglia during akinesia induced by adenosine receptor stimulation. Starting from a common behavioural effect, this study tries to bridge this gap by investigating and comparing, in two basal ganglia structures, the neural substrate of akinesia after acute dopamine D2 receptor blockade and adenosine A2A receptor stimulation. The external segment of the globus pallidus (GP, or simply globus pallidus in the rat) and the substantia nigra pars reticulata (SNr) were chosen as the recording sites because both nuclei are included into the �behavioural arrest control system� and seem to express somewhat complementary functions, as a respective key integrative station and main output of the basal ganglia. Dopamine function was manipulated by acute decrease in availability of dopamine binding sites in the brain, through specific dopamine D2 receptor blockade with systemic injections (1.0 and 1.5 mg/kg) of raclopride(3,5-dichloro-N-[(1-ethylpyrrolidin-2-y)methyl]-2-hydroxy-6-methoxy-benzamide), resulting in akinesia. Conversely, movement was inhibited by specific adenosine A2A receptor stimulation with systemic injections (2.5 and 5.0 mg/kg) of the drug CGS21680 (sodium-2-p-carboxyethylphenylamino-5-N-carboxamidoadenosine). In both situations, behaviour was assessed through specific akinesia tests. Single neuron activity before injection and changes in the firing frequency and firing pattern occurring after injection have been analysed and compared for each cell recorded from GP and SNr, during periods of behavioural rest. Synchronised firing between cell pairs has also been assessed. However, the small number of cell pairs showing correlated firing in each structure after systemic injection of drugs was not statistically relevant for further analysis and interpretation of synchronised firing during drug induced akinesia. In our experiments, both drugs inhibited movement, albeit somewhat differently, with lack of rigidity and �flat� body position after adenosine stimulation. Dopamine blockade decreased mean firing rate and dramatically altered the firing pattern in both investigated structures, generally increasing burst activity (increased percentage of spikes in bursts, mean number of bursts, mean number of spikes per burst, mean intra-burst firing frequency) and decreasing regularity of firing (increased coefficient of variation of the inter-spike intervals). Increased burst activity in the rat basal ganglia in an acute model of parkinsonian akinesia, following systemic raclopride injections, confirmed the importance of changes in the firing pattern in PD. The only electrophysiological effect of systemic A2A stimulation was decreased mean firing rate in the GP, a weak effect that could not propagate towards output stations of the basal ganglia. The lack of changes in the firing pattern, at both input and output levels of the basal ganglia, suggests a correlation with the lack of rigidity in adenosine-stimulation-induced akinesia.

The role of the basal ganglia in human language function remains unknown, despite a corpus of literature documenting the association between vascular lesions of the dominant nonthalamic subcortical (NS) region and disordered language. Theories of subcortical language function have been postulated (e.g., Crosson, 1985; Wallesch & Papagno, 1988), however, research in this field has remained largely data-driven, providing limited descriptions of individuals with vascular NS lesions in terms of performance on standard off-line language measures. This approach has failed to reveal the underlying nature of these language deficits “locally” in terms of various dynamic and temporally constrained linguistic and nonlinguistic component processes. The current series of studies are based largely on the premise that such empirical data has the potential to speak more directly to the cogency of current theories proposing a subcortical role in language or related cognitive functions. The present thesis investigated the performance of individuals with dominant chronic vascular NS lesions, compared to matched control subjects, individuals with Parkinson’s disease (PD) (also assumed to have NS dysfunction) and subjects with cortical lesions (CL), on a series of experiments which allowed for the real-time examination of language processing, manipulating the degree to which automatic and attentional/strategic processing is invoked. The theoretical underpinning of these experiments hinges primarily on the proposed role of frontal-subcortical systems in mediating aspects of language via attentional/strategic mechanisms. Accordingly, it was hypothesised that the locus of impairment for individuals with NS lesions would be centred selectively on those facets of language processing which require increased recourse to these proposed frontal-subcortical cognitive capacities. The language abilities of 15 subjects with chronic dominant NS lesions, 15 matched control subjects, 14 matched subjects with CL, and 12 matched individuals with PD were examined initially on the Western Aphasia Battery (WAB) and the Boston Naming Test (BNT). Most NS subjects were classified as non-aphasic according to the WAB, however, circumscribed deficits were evidenced, typically in generative and confrontation naming. In contrast, the CL group showed significant deficits on most aspects of the WAB compared to matched normal control subjects, and presented with a more severe impairment than NS subjects overall on the WAB and in confrontation naming and repetition. The PD group performance was not significantly different from the matched control group, while PD subjects performed better than the NS group overall on the WAB. The same cohort of NS, CL, PD, and control subjects undertook a battery of complex language measures designed to place a range of higher-order cognitive demands on the language processing system. This battery included subtests from the Test of Language Competence-Expanded Edition (TLC-E), the Test of Word Knowledge (TOWK), and The Word Test-Revised (TWT-R). The NS, CL, and PD subjects presented with marked disturbances in those tasks involving cognitive-linguistic flexibility, sentence formulation, indeterminacy of meaning, and metalinguistic manipulation of the lexical-semantic system. Collectively, the off-line results suggest that those aspects of language processing which are more heavily reliant on higher-order cognitive capacities are selectively compromised in subjects with NS lesions and PD. This assumption was further examined and substantiated in a series of on-line lexical ambiguity priming experiments performed by a subset of the original NS subjects (n = 10), matched control subjects (n = 10), matched CL subjects (n=10), and matched PD subjects (n = 10). When lexical ambiguities were presented in a single word context as word triplets, NS subjects showed rapid nonselective lexical activation, suggesting that intact lexical-semantic information could be accessed via automatic routines, similar to control subjects. Unlike control subjects, however, NS subjects were unable to sustain any form of significant activation, implying a selective impairment in the ability to manipulate lexical-semantic information through attentional/controlled processing. This breakdown was qualitatively different to the controlled processing disturbance evidenced by CL subjects, who maintained nonselective meaning facilitation over time, while PD subjects showed a pattern of selective priming consistent with a reduction in attentional processing. The emerging picture of a dissociation between intact automatic processing and compromised attentional/strategic lexical processing in the NS subjects was further elucidated in an experiment examining the processing of unequibiased lexical ambiguities in isolation. In this study, NS and PD subjects showed rapid nonselective meaning facilitation, again implying intact automatic lexical processing. While control and CL subjects evidenced multiple meaning activation followed by selective facilitation of the dominant meaning, NS and PD subjects were unable to achieve selective meaning facilitation, instead showing a protracted period of nonselective lexical activation. This finding suggested that when ambiguities were encountered in isolation, there was not an absolute breakdown in attentional processing per se, but rather a circumscribed deficit in the selective attentional engagement of the semantic network on the basis of meaning frequency, possibly implicating a disturbance of inhibitory mechanisms within the semantic network. A cross-modal priming experiment was used to investigate how lexical ambiguities were processed and resolved in a biased sentential context. Initially, lexical activation for the neurological patient groups appeared influenced by contextual information to a greater extent than in normal controls, which may indicate delayed lexical decision making or disturbed automatic lexical access. Only the PD and NS individuals failed to then maintain selective facilitation of the contextually appropriate meaning, suggesting a breakdown in the attention-based control and maintenance of semantic activation on the basis of integrated sentential constraints. This finding was extended in another cross-modal priming experiment, where NS and PD subjects appeared unable to use discourse-level information to select meanings and develop topical inferences via attentional/strategic mechanisms, while CL subjects showed a selective disturbance of inference development. The results of this thesis have served to delineate certain dynamic aspects of language processing in individuals with NS lesions in terms of automatic lexical processing components and processes involving the attentional/strategic selection of meaning on the basis of meaning frequency and various types of contextual information. In general, the NS group showed a demarcation between intact automatic processing and a breakdown in attentional/strategic processing which was manifest differently depending on the conditions under which processing was invoked. Furthermore, the performance of NS subjects on attentional operations was able to be dissociated under certain conditions from CL group performance and was similar to the PD group’s performance in certain instances. These preliminary findings are consistent with recent theories proposing a role for frontal-subcortical systems in the “top-down” modulation of semantic processing via executive attentional and strategic mechanisms. Although a disturbance in these systems provides a parsimonious explanation of the NS and PD group performance, such conclusions are drawn tentatively with the caveat that the precise neuropathological basis of cognitive-linguistic deficits in these individuals remains unclear at present.

Thesis (M.S.)--Missouri University of Science and Technology, 2009. / Vita. The entire thesis text is included in file. Title from title screen of thesis/dissertation PDF file (viewed April 13, 2009) Includes bibliographical references (p. 46).

Thesis (M.S.), Wellness Management--University of Central Oklahoma, 2010. / Includes bibliographical references (leaves 39-42).

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 75-91).

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 144-147).

<p>Animals must continuously move through the environment in pursuit of the goals required to maintain homeostasis. In vertebrates, this is accomplished through an ever-changing pattern of muscle contraction in a multipurpose body, and coordinated by a hierarchy of neural circuits acting in parallel. At the lower levels of this hierarchy, spinal circuits control muscle force and length. One level above that, brainstem, midbrain and cortical circuits control various aspects of body configuration as well as a number of self-contained motor functions including locomotion and orientation. A still-higher level of organization is controlled by the basal ganglia, a set of subcortical nuclei that appear to be responsible for continuously orchestrating the extent and direction of various motor programs and body configurations for the sake of controlling a still higher level of perceptual variable, such as proximity to food. In this way, the basal ganglia orchestrate the performance of motor functions to achieve a single goal in the same way that a conductor orchestrates the performance of musicians in a symphony to achieve a single song. </p><p>Despite the continuous and graded nature of animal behavior, researchers have traditionally studied the basal ganglia in the context of highly controlled experimental tasks or neglected to record continuous measures of behavioral outputs. To address this gap, the following experiments were designed investigate role of the basal ganglia in continuously modulating unconstrained goal directed movements. In the first set of experiments (chapter 2), mice stood on a small covered perch which was continuously tipped left and right along the roll plane while neural activity was recorded wirelessly. During each recording session, mice were exposed to slow and fast speeds of postural disturbance. Pressure pads were mounted in the left and right floor of the perch to monitor mouse movement. In both putative dopamine and GABA neurons, we found two basic patterns of neural activity; one class of cell increased firing with tip to the left and decreased with tip to the right while the other class decreased firing with tip to the left and increased with tip to right. This correlation between neural firing rate and instantaneous postural disturbance is continuous and very high. The correlation is seen for both slow and fast disturbances. The majority of cells recorded fell into one of these two categories. Pressure pad readout, as expected, revealed paw forces on the left pad to increase with tilt to the left and decrease with tilt to the right while the opposite pattern was observed on the right pad. These results show continuous and graded modulation of activity in the substantia nigra during performance of an ongoing motor task and suggest that BG outputs, rather than monolithically disinhibiting brainstem motor structures, instead coordinate behavior by continuously specifying desired states of lower systems. </p><p>In the second set of experiments (chapter 3), we employed continuous motion tracking of the head in parallel with neural recording from the substantia nigra pars reticulata during a simple goal-directed task. In this study, mice were water deprived and then positioned on a perch equipped with a movable drinking spout. During each session, mice performed a simple reward-guided task in which sucrose solution was delivered in small quantities after the presentation a cue. The purpose of this task was to elicit voluntary head movements and to investigate the relationship between these continuous movements and the activity of GABA output neurons. A typical reward-directed behavior involved the movement of the whole head and body to collect the sucrose solution following its delivery. However, movements during each individual trial were unique. For all movements, the majority of GABA cells were found to either positively or negatively correlate with either X or Y axis head position vector components. These correlations were very high, and not due to averaging artifacts as trial-by-trial correlation between movement and neural activity can be clearly observed. These correlations were also independent of the presence of a reward. These data show for the first time a continuous and quantitative relationship between basal ganglia output and body posture. It is hypothesized that these signals represent reference signals sent to downstream postural and orientation controllers. In this case a baseline level of GABA activity would represent neutral reference position, and changes in activity above and below this level represent increased or decreased reference positions. </p><p>In the third set of experiments (chapter 4), we recorded from dopamine neurons in the substantia nigra pars compacta during the same task as in chapter 3. The purpose of this task was to investigate the correlation between dopamine activity and movement kinematics during goal-directed behavior. Animals were found to produce movements at the onset of the cue and also at reward delivery. Dopamine-classified cells show phasic firing or pausing at the onset of each of these movements. When compared to head movement kinematics, these patterns of neural activity correlate highly with different vector components of head acceleration and velocity; up, down, left and right. Importantly, these correlations are continuous and exist throughout the entire recording session. These correlations are also independent of the presence of reward. To test the ‘causality’ of these observed patterns, we also employed optogenetics to stimulate substantia nigra dopamine neurons expressing channel rhodopsin 2 (Chr2) while head movements were recorded and quantified. We found that stimulation of ChR2-expressing animals could elicit head movement while stimulation of control animals had no effect. Combined, these data suggest that dopamine is responsible for controlling the velocity of transitions between different body postures.</p> / Dissertation

Orientador: Deilson Elgui Oliveira / Resumo: Durante processos patológicos como o câncer, a atividade migratória de células neoplásicas aumenta, sendo um passo crítico para a disseminação dessas células a órgãos distantes. O processo migratório dessas células depende da formação de protrusões citoplasmáticas chamadas invadopódios, através da nucleação e polimerização de actina e degradação da matriz extracelular (MEC). A MEC é uma rede complexa de proteínas que fornece sustentação e moléculas sinalizadoras responsáveis pela homeostase dos tecidos. Dentre essas proteínas, a fibronectina (FN) é uma glicoproteína multiadesiva fundamental no comportamento celular normal e apresenta-se aumentada no tecido tumoral. Esse trabalho teve como objetivo avaliar a influência da FN, isolada ou em associação com componentes da membrana basal, no processo migratório de células tumorais prostáticas, com ênfase no mecanismo de formação dos invadopódios. Para isso, as linhagens celulares LNCaP e PC-3 foram divididas nos seguintes grupos experimentais: Controle, FN solúvel (10µg/mL), FN coating (10µg/mL), FN+Geltrex e Geltrex com exposição aos componentes por 4 dias. Nas células LNCaP, foi possível observar alterações morfológicas dos grupos expostos a FN (solúvel, coating e em associação com Geltrex) com diminuição na área celular em comparação ao grupo controle. A proliferação celular aumentou nos grupos com recobrimento da superfície (FN coating, FN+Geltrex e Geltrex). Também foi possível observar a diminuição na taxa de motilidade dess... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: During pathological processes like cancer, the migratory activity of neoplasic cells increases, being a critical step for the dissemination of these cells to distant organs. The migratory process depends on the formation of cytoplasmic protrusions called invadopodia, through actin polymerization and extracellular matrix degradation (ECM). ECM is a complex protein network that provides support and molecules responsible for tissue homeostasis. Among these proteins, fibronectin (FN) is an essential adhesive glycoprotein in normal conditions however, is unregulated in tumor tissue. The objective of this study was to evaluate the influence of FN, alone or in association with basement membrane (BM) components, within migratory process of prostatic tumor cells, with emphasis on the mechanism of invadopodia. For this, the LNCaP and PC-3 cell lines were divided into the following experimental groups: Control, FN soluble (10μg / mL), FN coating (10μg / mL), FN + Geltrex and Geltrex. Exposure time was established into 4 days. We could observe morphological alterations of the groups exposed to FN in LNCaP cells, with a decrease in the cellular area in comparison to the control group. Cell proliferation was increased in the groups with surface coating (FN coating, FN + Geltrex and Geltrex). It was also possible to observe a decrease in the motility rate of these cells in all the exposed groups. Key proteins expression important to invadopodia formation (Cortactin, Dynamin-2 and Actin-F) w... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2012-09-05T18:24:07Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 265.pdf: 1025703 bytes, checksum: 4295223082b9c1081e9eef71584442b4 (MD5) Previous issue date: 2005 / A presente tese apresenta dados de taxa meólica basal (TMB) em uma amostra representativa de adultos residentes em Niterói, Rio de Janeiro. A tese é formada por 3 artigos cujos objetivos foram, por ordem: validar o instrumento para avaliação da composição corporal; validar o instrumento de medição da TMB; medir aTMB na população adulta de Niterói e avaliar a adequação de equações de predição da TMB nessa população. (...)

M.A. / The purpose of basal readers is to teach children to read. When a child has the opportunity to learn to read in his native language, his chances on success in learning and reading increase, because the language is known to him. The current policy on education determines that children should receive instruction in their mother-tongue, especially in the first year. Keeping this in view, this study considers the possibility of making translated basal readers available to African languages, and more specifically, to Northern Sotho. Chapter 1 discusses criteria set for proper basal readers and evaluates existing Afrikaans readers accordingly. In Chapter 2, children's literature are discussed in terms of characteristics and background. The development of children's literature in Northern Sotho is briefly discussed as well. Theoretical issues concerning transposition and translation are discussed in Chapter 3 to determine what are involved in transposition and translation and what aspects are transposed and translated. Chapter 4 deals with the empirical application of the theory. Problems transposers and translators are faced with are discussed with the aid of applicable examples.