Variations in skeletal morphology have often been used to interpret an organism’s overall activity level when direct observation is not possible. Although skeletal change in response to exercise is well documented, the skeleton’s response to mechanical loading is modulated by several factors (e.g. age, hormones, sex). Additionally, variation in skeletal morphology is partially a result of genetic variation, which is rarely accounted for in inferences of locomotor activity from skeletal remains. However, blood flow to long bones serves as a proxy for bone metabolic activity, which can be used to infer locomotor activity. Long bones receive blood from three sources, with the nutrient artery supplying the bulk of total blood volume in mammals (50-70%). The size of the nutrient artery can be estimated from the dimensions of the nutrient canal, which is present long after the vascular tissue has degenerated. The literature on nutrient canals is sparse, with most studies consisting of anatomical descriptions from surgical proceedings, and only a few studies investigating the links between nutrient canals and physiology or behavior. Moreover, no study to date has accurately modelled the size and shape of the nutrient canal. For this study, mice from an artificial selection experiment for high voluntary wheel-running behavior were used. High Runner mice from the experiment are known to differ in both metabolic and locomotor activity, with mice from HR lines having increased VO2max and increased voluntary wheel-running behavior when compared to controls. 137 femora from mice of the 11th generation of this selection experiment were µCT scanned. Three-dimensional reconstructions of nutrient canals were measured for minimum cross-sectional area (an index of blood flow). Nutrient canals varied far more in number and shape than prior descriptions would indicate. Canals adopted non-linear shape and pathing as they traversed from the periosteum to the medullary cavity, occasionally even branching within the cortical bone. Additionally, mice from both HR and control lines had more than four nutrient canals per femur. Mice from HR lines had significantly larger nutrient canal area than controls, which was not the result of an increase in the number of nutrient canals, but rather an increase in their average size. This study demonstrates that mice with an evolutionary history of increased locomotor activity and metabolic rate have a concomitant increase in the size of their nutrient canals.

The central complex is a prominent neuropil found in the middle of the insect brain. It is considered as a higher center for motor control and information processing. Multiple neuropeptides and neurotransmitters are produced in neurons of the central complex, however, distribution patterns and functional roles of signaling substances in this brain region are poorly known. Thus, this thesis focuses on the distribution of signaling substances and on modulatory roles of neuropeptides in the central complex of Drosophila. Immunocytochemistry in combination with GAL4/UAS technique was used to visualize various signaling substances in the central complex. We revealed different central-complex neurons expressing the neuropeptides; Drosophila tachykinin (DTK), short neuropeptide F (sNPF), myoinhibitory peptide (MIP), allatostatin A, proctolin, SIFamide, neuropeptide F and FMRFamide. Subpopulations of DTK, sNPF and MIP-expressing neurons were found to co-localize a marker for acetylcholine. In addition, five metabotropic neurotransmitter receptors were found to be expressed in distinct patterns. Comparison of receptor/ligand distributions revealed a close match in most of the structures studied. By using a video-tracking assay, peptidergic modulation of locomotor behavior was studied. Different DTK and sNPF-expressing neurons innervating the central complex were revealed to modulate spatial distribution, number of activity-rest phases and activity levels, suggesting circuit dependent modulation. Furthermore, neurosecretory cells in the Drosophila brain that co-express three types of neuropeptides were shown to modulate stress responses to desiccation and starvation. In summary, we have studied two different neuropeptides (DTK and sNPF) expressed in interneuronal circuits and neurosecretory cells of the Drosophila brain in more detail. We found that these neuropeptides display multiple actions as neuromodulators and circulating hormones, and that their actions depend on where they are released. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Manuscript.

Orientador: Lilian Teresa Bucken Gobbi / Banca: Renato de Moraes / Banca: Luciane Aparecida Pascucci Sande de Souza / Resumo: Este estudo teve como objetivo analisar o comportamento locomotor de pacientes com DP na tarefa de subir e descer degraus. Para isso, dois estudos foram desenvolvidos. Estudo 1: objetivou verificar, por meio de análise qualitativa, a percepção subjetiva de facilidade/dificuldade para subir e descer degraus, a frequência de uso de escadas, o tipo de escadas utilizadas no dia a dia, a frequência de quedas neste ambiente e a relação entre a facilidade/dificuldade percebida para subir e descer degraus, o nível de atividade física, o estágio e comprometimento da DP. Participaram deste estudo 50 pacientes com DP, nos estágios leve e moderado da escala de Hohen e Yahr. Após avaliação clínica, foram aplicados 2 questionários: 1) questionário diagnóstico, com perguntas abertas e fechadas, que buscou investigar sobre o uso de escadas no dia a dia e o número de quedas (NQ) por pacientes com DP. 2). Questionário de Baecke Modificado para Idosos, para avaliar o nível de atividade física (NAF) dos pacientes. Os dados foram tratados através de porcentagem de ocorrência, teste de correlação de Spearman e regressão linear múltipla. Os resultados do Estudo 1 indicaram que pacientes com DP percebem a descida dos degraus como mais desafiadora e, que o nível de atividade física e a incidência de quedas influenciam a percepção de facilidade/dificuldade para subir (R2= 0,260; p=0,001; NAF/β= -0,313; p=0,016; NQ/β= 0,393; p=0,003) e para descer (R2= 0,233; p=0,002; NAF/β= -0,386; p=0,004; NQ/β= 0,279; p=0,034) degraus. Estudo 2: objetivou analisar o comportamento locomotor, por meio de análise cinemática e cinética, na tarefa de subir e descer degraus; indicar as principais diferenças no comportamento das forças externas de reação do solo, verticais e ântero-posteriores, entre as duas tarefas; identificar a estratégia de uso do corrimão... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to analyze the locomotor behavior of people with Parkinson's disease (PD) in the task of going up and down stairs. Two studies were conducted to achieve this purpose. Study 1 aimed to verify, through qualitative analysis, the subjective perception of facility/difficulty to go up and down stairs, the frequency of stairs utilization, the stairs features the patients used every day, the falls frequency in this environment and the relationship among the perceived facility/difficulty to go up and down stairs, the physical activity level and the PD stage and impairment. Fifty people with PD (mild and moderate levels in the Hohen and Yahr rating scale) participated in Study 1. After clinic assessment, participants answered two questionnaires: (1) An assessment questionnaire with open and closed questions to investigate the everyday stairs utilization and the falls incidence (FI), and (2) the modified Baecke questionnaire for older people to assess the physical activity level (PAL). The data were treated by the occurrence percentage, Spearman correlation test and multiple regression analyses. The results revealed that people with PD perceived more challenging going down stairs than up stairs and the physical activity level and the falls incidence affected the perception of facility/difficulty to go up (R2= 0.260; p=0.001; NAF/β= -0.313; p=0.016; NQ/β= 0.393; p=0.003) and down (R2= 0.233; p=0.002; NAF/β= -0.386; p=0.004; NQ/β= 0.279; p=0.034) stairs. Study 2 aimed to analyze the locomotor features using kinematic and kinetic tools while going up and down stairs, to indicate the major differences in the behavior of the ground reaction external forces, verticals and anterior-posteriors, between the two tasks; to identify the strategy of handrail use and the perceived facility/difficulty in going up and down stairs, and to observe the relationship... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:22:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-09Bitstream added on 2014-06-13T19:28:18Z : No. of bitstreams: 1 teixeiraarroyo_c_me_rcla.pdf: 2571699 bytes, checksum: 30bfe0b8c13e9a64db4ab400e27f7271 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Este estudo teve como objetivo analisar o comportamento locomotor de pacientes com DP na tarefa de subir e descer degraus. Para isso, dois estudos foram desenvolvidos. Estudo 1: objetivou verificar, por meio de análise qualitativa, a percepção subjetiva de facilidade/dificuldade para subir e descer degraus, a frequência de uso de escadas, o tipo de escadas utilizadas no dia a dia, a frequência de quedas neste ambiente e a relação entre a facilidade/dificuldade percebida para subir e descer degraus, o nível de atividade física, o estágio e comprometimento da DP. Participaram deste estudo 50 pacientes com DP, nos estágios leve e moderado da escala de Hohen e Yahr. Após avaliação clínica, foram aplicados 2 questionários: 1) questionário diagnóstico, com perguntas abertas e fechadas, que buscou investigar sobre o uso de escadas no dia a dia e o número de quedas (NQ) por pacientes com DP. 2). Questionário de Baecke Modificado para Idosos, para avaliar o nível de atividade física (NAF) dos pacientes. Os dados foram tratados através de porcentagem de ocorrência, teste de correlação de Spearman e regressão linear múltipla. Os resultados do Estudo 1 indicaram que pacientes com DP percebem a descida dos degraus como mais desafiadora e, que o nível de atividade física e a incidência de quedas influenciam a percepção de facilidade/dificuldade para subir (R2= 0,260; p=0,001; NAF/β= -0,313; p=0,016; NQ/β= 0,393; p=0,003) e para descer (R2= 0,233; p=0,002; NAF/β= -0,386; p=0,004; NQ/β= 0,279; p=0,034) degraus. Estudo 2: objetivou analisar o comportamento locomotor, por meio de análise cinemática e cinética, na tarefa de subir e descer degraus; indicar as principais diferenças no comportamento das forças externas de reação do solo, verticais e ântero-posteriores, entre as duas tarefas; identificar a estratégia de uso do corrimão... / The aim of this study was to analyze the locomotor behavior of people with Parkinson’s disease (PD) in the task of going up and down stairs. Two studies were conducted to achieve this purpose. Study 1 aimed to verify, through qualitative analysis, the subjective perception of facility/difficulty to go up and down stairs, the frequency of stairs utilization, the stairs features the patients used every day, the falls frequency in this environment and the relationship among the perceived facility/difficulty to go up and down stairs, the physical activity level and the PD stage and impairment. Fifty people with PD (mild and moderate levels in the Hohen and Yahr rating scale) participated in Study 1. After clinic assessment, participants answered two questionnaires: (1) An assessment questionnaire with open and closed questions to investigate the everyday stairs utilization and the falls incidence (FI), and (2) the modified Baecke questionnaire for older people to assess the physical activity level (PAL). The data were treated by the occurrence percentage, Spearman correlation test and multiple regression analyses. The results revealed that people with PD perceived more challenging going down stairs than up stairs and the physical activity level and the falls incidence affected the perception of facility/difficulty to go up (R2= 0.260; p=0.001; NAF/β= -0.313; p=0.016; NQ/β= 0.393; p=0.003) and down (R2= 0.233; p=0.002; NAF/β= -0.386; p=0.004; NQ/β= 0.279; p=0.034) stairs. Study 2 aimed to analyze the locomotor features using kinematic and kinetic tools while going up and down stairs, to indicate the major differences in the behavior of the ground reaction external forces, verticals and anterior-posteriors, between the two tasks; to identify the strategy of handrail use and the perceived facility/difficulty in going up and down stairs, and to observe the relationship... (Complete abstract click electronic access below)

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A fundamental goal in neurobiology is to understand the development and organization of neural circuits that drive behavior. In the embryonic spinal cord, the first motor activity is a slow coiling of the trunk that is sensory-independent and therefore appears to be centrally driven. Embryos later become responsive to sensory stimuli and eventually locomote, behaviors that are shaped by the integration of central patterns and sensory feedback. In this thesis I used a simple vertebrate model, the zebrafish, to investigate in three manners how developing spinal networks control these earliest locomotor behaviors. For the first part of this thesis, I characterized the rapid transition of the spinal cord from a purely electrical circuit to a hybrid network that relies on both chemical and electrical synapses. Using genetics, lesions and pharmacology we identified a transient embryonic behavior preceding swimming, termed double coiling. I used electrophysiology to reveal that spinal motoneurons had glutamate-dependent activity patterns that correlated with double coiling as did a population of descending ipsilateral glutamatergic interneurons that also innervated motoneurons at this time. This work (Knogler et al., Journal of Neuroscience, 2014) suggests that double coiling is a discrete step in the transition of the motor network from an electrically coupled circuit that can only produce simple coils to a spinal network driven by descending chemical neurotransmission that can generate more complex behaviors. In the second part of my thesis, I studied how spinal networks filter sensory information during self-generated movement. In the zebrafish embryo, mechanosensitive sensory neurons fire in response to light touch and excite downstream commissural glutamatergic interneurons to produce a flexion response, but spontaneous coiling does not trigger this reflex. I performed electrophysiological recordings to show that these interneurons received glycinergic inputs during spontaneous fictive coiling that prevented them from firing action potentials. Glycinergic inhibition specifically of these interneurons and not other spinal neurons was due to the expression of a unique glycine receptor subtype that enhanced the inhibitory current. This work (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggests that glycinergic signaling onto sensory interneurons acts as a corollary discharge signal for reflex inhibition during movement. v In the final part of my thesis I describe work begun during my masters and completed during my doctoral degree studying how homeostatic plasticity is expressed in vivo at central synapses following chronic changes in network activity. I performed whole-cell recordings from spinal motoneurons to show that excitatory synaptic strength scaled up in response to decreased network activity, in accordance with previous in vitro studies. At the network level, I showed that homeostatic plasticity mechanisms were not necessary to maintain the timing of spinal circuits driving behavior, which appeared to be hardwired in the developing zebrafish. This study (Knogler et al., Journal of Neuroscience, 2010) provided for the first time important in vivo results showing that synaptic patterning is less plastic than synaptic strength during development in the intact animal. In conclusion, the findings presented in this thesis contribute widely to our understanding of the neural circuits underlying simple motor behaviors in the vertebrate spinal cord. / Un objectif important en neurobiologie est de comprendre le développement et l'organisation des circuits neuronaux qui entrainent les comportements. Chez l'embryon, la première activité motrice est une lente contraction spontanée qui est entrainée par l'activité intrinsèque des circuits spinaux. Ensuite, les embryons deviennent sensibles aux stimulations sensorielles et ils peuvent éventuellement nager, comportements qui sont façonnées par l'intégration de l'activité intrinsèque et le rétrocontrôle sensoriel. Pour cette thèse, j'ai utilisé un modèle vertébré simple, le poisson zèbre, afin d'étudier en trois temps comment les réseaux spinaux se développent et contrôlent les comportements locomoteurs embryonnaires. Pour la première partie de cette thèse j'ai caractérisé la transition rapide de la moelle épinière d'un circuit entièrement électrique à un réseau hybride qui utilise à la fois des synapses chimiques et électriques. Nos expériences ont révélé un comportement embryonnaire transitoire qui précède la natation et qu'on appelle « double coiling ». J'ai démontré que les motoneurones spinaux présentaient une activité dépendante du glutamate corrélée avec le « double coiling » comme l'a fait une population d'interneurones glutamatergiques ipsilatéraux qui innervent les motoneurones à cet âge. Ce travail (Knogler et al., Journal of Neuroscience, 2014) suggère que le « double coiling » est une étape distincte dans la transition du réseau moteur à partir d'un circuit électrique très simple à un réseau spinal entrainé par la neurotransmission chimique pour générer des comportements plus complexes. Pour la seconde partie de ma thèse, j'ai étudié comment les réseaux spinaux filtrent l'information sensorielle de mouvements auto-générés. Chez l'embryon, les neurones sensoriels mécanosensibles sont activés par un léger toucher et ils excitent en aval des interneurones sensoriels pour produire une réponse de flexion. Par contre, les contractions spontanées ne déclenchent pas ce réflexe même si les neurones sensoriels sont toujours activés. J'ai démontré que les interneurones sensoriels reçoivent des entrées glycinergiques pendant les contractions spontanées fictives qui les empêchaient de générer des potentiels d'action. L'inhibition glycinergique de ces interneurones, mais pas des autres neurones spinaux, est due à l'expression d'un sous-type de récepteur glycinergique unique qui augmente iii le courant inhibiteur. Ce travail (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggère que la signalisation glycinergique chez les interneurones sensoriels agit comme un signal de décharge corolaire pour l'inhibition des réflexes pendant les mouvements auto- générés. Dans la dernière partie de ma thèse, je décris le travail commencé à la maîtrise et terminé au doctorat qui montre comment la plasticité homéostatique est exprimée in vivo aux synapses centrales à la suite des changements chroniques de l'activité du réseau. J'ai démontré que l'efficacité synaptique excitatrice de neurones moteurs spinaux est augmentée à la suite d’une diminution de l'activité du réseau, en accord avec des études in vitro précédentes. Par contre, au niveau du réseau j'ai démontré que la plasticité homéostatique n'était pas nécessaire pour maintenir la rythmicité des circuits spinaux qui entrainent les comportements embryonnaires. Cette étude (Knogler et al., Journal of Neuroscience, 2010) a révélé pour la première fois que l'organisation du circuit est moins plastique que l'efficacité synaptique au cours du développement chez l'embryon. En conclusion, les résultats présentés dans cette thèse contribuent à notre compréhension des circuits neuronaux de la moelle épinière qui sous-tendent les comportements moteurs simples de l'embryon.