Introdução: A Locomoção tem como uma das características básicas a ritmicidade. Entre os mecanismos que envolvem seu controle destaca-se o conceito de um gerador de padrão central (GPC) capaz de gerar atividades neurais e musculares rítmicas. A técnica de treino locomotor com suspensão de peso na esteira (TLSP) utiliza esse conceito e emerge como uma estratégia terapêutica efetiva após a lesão medular (LM) em humanos em função do alto nível de automatismo do sistema nervoso, podendo ser esperadas diferentes respostas em lesões completas e incompletas. Portanto, uma análise detalhada das respostas biomecânicas obtidas durante o TLSP pode servir como base para compreensão do controle neural da locomoção humana. Objetivos: Caracterizar, a partir de parâmetros biomecânicos, a marcha com suspensão parcial de peso e assistência manual em indivíduos com lesões medulares completas e incompletas. Método: 40 indivíduos (20 com LM e 20 sem lesão) foram divididos em quatro grupos: Lesão Medular ASIA A (GLA), Lesão Medular ASIA B (GLB), Lesão Medular ASIA C e D (GLC) e Grupo Controle (GC) composto por sujeitos sem lesão. Durante o TLSP, ambos os grupos foram submetidos ao mesmo protocolo, com suspensão do peso corporal, duração total do treino e velocidades pré-definidas. Foram coletados dados de eletromiografia de superfície e a análise cinemática foi realizada por meio de 7 centrais inerciais. As análises foram realizadas por meio de análise de variância múltipla (MANOVA) Resultados: Em relação às variáveis cinemáticas o GC apresentou menor tempo de apoio em relação ao GLA não havendo diferenças entre os outros grupos com lesão medular. Quanto à ativação muscular o GLA e GLB apresentaram maior atividade de músculos proximais com co-contrações, GLC atividade proximal similar à GLA, GLB e distal similar ao GC que apresentou níveis mais baixos de atividade muscular com maior atividade distal em relação a proximal. Para o momento do pico de atividade, o GC apresentou momento antecipado para músculos proximais, atrasado para músculos distais em relação aos grupos com LM. Conclusão: Quando comparados ao GC, os grupos com LM apresentaram maiores amplitudes de sinal eletromiográfico, provavelmente pelo fato de o GC realizar a tarefa de forma mais eficiente com menor demanda de ativação muscular. Não foi possível reconhecer padrões rítmicos de ativação nos grupos com LM / Introduction: The locomotion has a characteristic the rhythmicity. Concerning the understanding of the mechanisms involving its control, the concept of a central pattern generator (GPC) capable of generating neural and muscular rhythmic activities stands out. The body weight support treadmill training (BWSTT) technique uses this concept and emerges as an effective therapeutic strategy after spinal cord injury (LM) in humans due to the high level of automatism of the nervous system, and different responses can be expected in complete and incomplete injuries. Therefore, a detailed analysis of the biomechanical responses obtained during BWSTT may serve as a basis for understanding the neural control of human locomotion. Objectives: To characterize, from biomechanical parameters, treadmill gait with body weight support in individuals with complete and incomplete spinal cord injury. Method: 40 individuals (20 with LM and 20 without lesion) were divided into four groups: ASIA A (GLA), ASIA B (GLB), ASIA C and D (GLC) and Control Group (GC) composed of subjects without injury. During BWSTT, both groups were submitted to the same protocol, with pre-defined body weight suspension, total training duration and speeds. Surface electromyography data were collected and kinematic analysis was performed by means of 7 inertial power plants. The analyzes were performed through multiple variance analysis (MANOVA). Results: In the kinematic variables, the CG presented less support time in relation to the GLA and there were no differences between the other groups with spinal cord injury. As for muscle activation, GLA and GLB presented higher activity of proximal muscles with co-contractions, GLC presented similar proximal activity similar to GLA, GLB and distal similar to GC, which presented lower levels of muscular activity with greater distal activity in relation to proximal muscles. For the moment of peak activity, the GC presented early moment for proximal muscles, delayed to distal muscles in relation to the groups with LM. Conclusion: When compared to CG, the groups with LM presented higher amplitudes of electromyographic signal, probably because the CG performed the task more efficiently with less demand for muscle activation. It was not possible to recognize rhythmic patterns of activation in the LM groups

Each neuron needs to maintain a careful balance between the changes implicit in experience, and the demands of stability required by its function. This balance tips depending on the neuronal system, but in any role, disease or neural disorders can develop when the regulatory mechanisms involved in neuronal stability fail. The objective of this thesis was to characterize mechanisms underlying neuronal stability and activity maintenance, in the hopes that further understanding of these processes might someday lead to novel interventions for neurological disorders. The pyloric circuit of decapod crustaceans controls the rhythmic contractions of the foregut musculature, and has long been recognized as an excellent model system in which to study neuronal network stability. Recent experimental evidence has shown that each neuronal cell type of this circuit exhibits a unique set of positive linear correlations between ionic membrane conductances, which suggests that coordinated expression of ion channels plays a role in constraining neuronal electrical activity. In Aim 1, we hypothesized a causal relationship between expressed conductance correlations and features of cellular identity, namely electrical activity type. We partitioned an existing database of conductance-based model neurons based on various measures of intrinsic activity to approximate distinctions between biological cell types. We then tested individual conductance pairs for linear dependence to identify correlations. Similar to experimental results, each activity type investigated had a unique combination of correlated conductances. Furthermore, we found that populations of models that conform to a specific conductance correlation have a higher likelihood of exhibiting a particular feature of electrical activity. We conclude that regulating conductance ratios can support proper electrical activity of a wide range of cell types, particularly when the identity of the cell is well-defined by one or two features of its activity. The phenomenon of pyloric network recovery after removal of top-down neuromodulatory input--a process termed decentralization--is seen as a classic model of homeostatic change after injury. After decentralization, the pyloric central pattern generator briefly loses its characteristic rhythmic activity, but the same activity profile is recovered 3-5 days later via poorly understood homeostatic changes. This re-emergence of the pyloric rhythm occurs without the full pre-decentralization set of fixed conductance ratios. If conductance ratios stabilize pyloric activity before decentralization as we showed in Aim 1, then other mechanisms must account for the return of the pyloric rhythm after network recovery. Based on vertebrate studies demonstrating a role for the extracellular matrix (ECM) in activity regulation, we hypothesized in Aim 2 that the ECM was participating in activity maintenance in the stomatogastric nervous system. We used the enzyme chondroitinase ABC (chABC) to degrade extracellular chondroitin sulfate (CS) in the stomatogastric ganglion while in organ culture. Our results are the first to demonstrate the presence of CS in the crustacean nervous system via immunochemistry. Furthermore, we show that while ongoing activity is not disrupted by chABC treatment, recovery of pyloric activity after decentralization was significantly delayed without intact extracellular CS. Our results are the first to show that CS has a role in neuronal activity maintenance in crustaceans, and suggest that CS may be involved in initiating or directing activity maintenance needed in times of neuronal stress.

The purpose of this dissertation was to gain insight into spinal sensory regulation during locomotion. To this end, I developed a novel in vitro spinal cord-hindlimb preparation (SCHP) composed of the isolated in vitro neonatal rat spinal cord oriented dorsal-up with intact hindlimbs locomoting on a custom-built treadmill or instrumented force platforms. The SCHP combines the neural and pharmacological accessibility of classic in vitro spinal cord preparations with intact sensory feedback from physiological hindlimb movements. thereby expanding our ability to study spinal sensory function. I then validated the efficacy of the SCHP for studying behaviorally-relevant, sensory-modulated locomotion by showing the impact of sensory feedback on in vitro locomotion. When locomotion was activated by serotonin and N-methyl D-aspartate, the SCHP produced kinematics and muscle activation patterns similar to the intact rat. The mechanosensory environment could significantly alter SCHP kinematics and muscle activitation patterns, showing that sensory feedback regulates in vitro spinal function. I further demonstrated that sensory feedback could reinforce or initiate SCHP locomotion. Using the SCHP custom-designed force platform system, I then investigated how presynaptic inhibition dynamically regulates sensory feedback during locomotion and how hindlimb mechanics influence this regulation. I hypothesized that contralateral limb mechanics would modulate presynaptic inhibition on the ipsilateral limb. My results indicate that contralateral limb stance-phase loading regulates ipsilateral swing-phase sensory inflow. As contralateral stance-phase force increases, contralateral afferents act via a GABAergic pathway to increase ipsilateral presynaptic inhibition, thereby inhibiting sensory feedback entering the spinal cord. Such force-sensitive contralateral presynaptic inhibition may help preserve swing, coordinate the limbs during locomotion, and adjust the sensorimotor strategy for task-specific demands. This work has important implications for sensorimotor rehabilitation. After spinal cord injury, sensory feedback is one of the few remaining inputs available for accessing spinal locomotor circuitry. Therefore, understanding how sensory feedback regulates and reinforces spinally-generated locomotion is vital for designing effective rehabilitation strategies. Further, sensory regulation is degraded by many neural insults, including spinal cord injury, Parkinson's disease, and stroke, resulting in spasticity and impaired locomotor function. This work suggests that contralateral limb loading may be an important variable for restoring appropriate sensory regulation during locomotion.

Spinal cord injuries (SCI) sever communication between supraspinal centers and the central pattern generator (CPG) responsible for locomotion. Because the CPG is intact and retains the ability to initiate locomotor activity, it can be accessed electrically and pharmacologically. The goal of this thesis was to identify and characterize a novel spinal cord surface site along the sacral dorsal column (sDC) for electrically evoking locomotor-like activity in the neonatal rat spinal cord. Stimulation of the sDC robustly activated rhythmic left-right alternation in flexor-related ventral roots that was dependent on the activation of high-threshold C fiber afferents. The C fibers synapsed onto spinal neurons, which project to the lumbar segments as part of a pathway dependent on purinergic, adrenergic, and cholinergic receptor activation. In ventral roots containing only somatic efferents, rhythmic activity was rarely recruited. However, in ventral roots containing both autonomic and somatic efferents, sacral dorsal column stimulation recruited autonomic efferent rhythms, which subsequently recruited somatic efferent motor rhythms. The efferent rhythms revealed a half-center organization with very low stimulation frequencies, and the evoked alternating bursts entrained to the stimuli. Similar entrainment was seen when sDC stimuli were applied during ongoing neurochemically-induced locomotor rhythms. The rhythmic patterns evoked by sDC stimulation operated over a limited frequency range, with a discrete burst structure of fast-onset, frequency-independent peaks. In comparison, neurochemically-induced locomotor bursts operated over a wide frequency range and had slower time to peaks that varied with burst frequency. The overall findings support the discovery of an autonomic efferent pattern generator that is recruited by sacral visceral C fiber afferents. It is hoped that this research will advance the understanding of afferent activation of the lumbar central pattern generator and potentially provide insight useful for future development and design of neuroprosthetic devices.

<p>Locomotion is one of the most important behaviours and requires interaction between sensors at various levels of the nervous system and the limb muscles of an animal. The basic neural rhythm for locomotion in mammals has been shown to arise from local neural networks residing in the spinal cord and these networks are known as central pattern generators (CPGs). However, during the locomotion, these centres are constantly interacting with the sensory feedback signals coming from muscles, joints and peripheral skin receptors in order to adapt the stepping to varying environmental conditions. Conceptual models of mammalian locomotion have been constructed using</p><p>mathematical models of locomotor subsystems based on the abundance of neurophysiological evidence obtained primarily in the cat. Several aspects of locomotor control using the cat as an animal model have been investigated employing computer simulations and here we use the same approach to address number of questions or/and hypotheses related to rhythmic locomotion in quadrupeds. Some of the involve questions are, role of mechanical linkage during deafferented walking, finding inherent stabilities/instabilities of muscle-joint interactions during normal walking, estimating phase dependent controlability of muscle action over joints.</p><p>This thesis presents the basics of a biologically realistic model of mammalian locomotion and summarises methodological approaches in modelling quadruped locomotor subsystems such as CPGs, limb muscles and sensory pathways. In the first appended article, we extensively discuss the construction details of the three-dimensional computer simulator for the study of the hind leg neuro-musculo-skeletal-control system and its interactions during normal walking of the cat. The simulator with the walking model is programmed in Python scripting language with other supported open source libraries such as Open Dynamics Engine (ODE) for simulating body dynamics and OpenGL for three dimensional graphical representation. We have examined the</p><p>functionality of the simulator and the walking model by simulating deafferented walking. It was possible to obtain a realistic stepping in the hind legs even without sensory feedback to the two controllers (CPGs) for each leg. We conclude that the mechanical linkages between the legs also play a major role in producing alternating gait.</p><p>The use of simulations of walking in the cat for gaining insights into more complex interactions between the environment and the neuro-muscular-skeletal system is important especially for questions where a direct neurophysiological experiment can not be performed on a real walking animal. For instance, it is experimentally hard to isolate individual mechanisms without disrupting the natural walking pattern. In the second article, we introduce a different approach where we use the walking model to identify what control is necessary to maintain stability in the musculo-skeletal system. We show that the actions of most of the hindlimb muscles over the joints have an inherent stability during stepping, even without the involvement of proprioceptive feedback mechanisms. In addition, we observe that muscles generating movements in the ankle joint of the hind leg must be controlled by neural mechanisms, which may involve supraspinal structures, over the whole step cycle.</p>

Spinal cord integrates somatosensory information and generates coordinated motor responses. Temporal integration can be used for discrimination of important stimuli from noise. Here it is shown that temporal integration of somatosensory inputs in sub second time scale is possible without changes of intrinsic properties of motoneurons. The activity of premotor neurons increases during temporal integration and can be a mechanism for short term information storage in spinal cord. Suppression of motor activity after painful somatosensory stimulus is called cutaneous silent period. This motor suppression is well described in humans and used for diagnostics. However it is not known if the suppression of motor activity is due to inhibition of motoneurons or reduction of excitatory drive from premotor neurons. Here it is shown that motoneurons are inhibited during cutaneous silent period. Neural networks of spinal cord not only process somatosensory information but generate locomotion and reflexes too. It is accepted that neural networks controlling front and hind limb movements are located in cervical and lumbar enlargements respectfully. Here it is shown that thoracic segments of spinal cord contribute to hind limb movements as well. It means that neural network generating movements is much more widely distributed than previously thought. / Nugaros smegenys gauna somatosensorinę informaciją, ją integruoja ir generuoja motorinius atsakus. Disertacijoje parodoma, kad somatosensorinių įėjimų viršsekundinė laikinė integracija nugaros smegenų neuronų tinkle vyksta ne dėl motorinių neuronų vidinių savybių kitimo. Laikinės integracijos metu padidėja priešmotorinių neuronų aktyvumas ir tai gali lemti informacijos apie somatosensorinį įėjimą saugojimą. Somatosensorinis tylos periodas – tai motorinio aktyvumo slopinimas po skausmingo stimulo. Jis plačiai aprašytas žmonėse, bei taikomas diagnostikoje. Nepaisant plataus taikymo, somatosensorinio tylos periodo mechanizmai nėra ištirti – nebuvo žinoma ar šis motorinio aktyvumo slopinimas vyksta slopinant motorinius neuronus, ar eliminuojant motorinių neuronų žadinimą. Disertacijoje parodoma, kad somatosensorinio tylos periodo metu motoriniai neuronai yra slopinami. Be somatosensorinės informacijos apdorojimo nugaros smegenų neuronų tinklai užtikrina judėjimo ir refleksų valdymą. Yra priimta, kad priekines ir užpakalines galūnes valdantys neuronų tinklai išsidėstę atitinkamai nugaros smegenų kaklinės ir strėnų sričių išplatėjimuose. Disertacijoje parodoma, kad ir krūtininiai nugaros smegenų segmentai prisideda prie užpakalinių galūnių motorinio aktyvumo generavimo. Tai leidžia manyti, kad neuronų tinklas generuojantis judesius yra išplitęs labiau, nei manyta iki šiol.

Nugaros smegenys gauna somatosensorinę informaciją, ją integruoja ir generuoja motorinius atsakus. Disertacijoje parodoma, kad somatosensorinių įėjimų viršsekundinė laikinė integracija nugaros smegenų neuronų tinkle vyksta ne dėl motorinių neuronų vidinių savybių kitimo. Laikinės integracijos metu padidėja priešmotorinių neuronų aktyvumas ir tai gali lemti informacijos apie somatosensorinį įėjimą saugojimą. Somatosensorinis tylos periodas – tai motorinio aktyvumo slopinimas po skausmingo stimulo. Jis plačiai aprašytas žmonėse, bei taikomas diagnostikoje. Nepaisant plataus taikymo, somatosensorinio tylos periodo mechanizmai nėra ištirti – nebuvo žinoma ar šis motorinio aktyvumo slopinimas vyksta slopinant motorinius neuronus, ar eliminuojant motorinių neuronų žadinimą. Disertacijoje parodoma, kad somatosensorinio tylos periodo metu motoriniai neuronai yra slopinami. Be somatosensorinės informacijos apdorojimo nugaros smegenų neuronų tinklai užtikrina judėjimo ir refleksų valdymą. Yra priimta, kad priekines ir užpakalines galūnes valdantys neuronų tinklai išsidėstę atitinkamai nugaros smegenų kaklinės ir strėnų sričių išplatėjimuose. Disertacijoje parodoma, kad ir krūtininiai nugaros smegenų segmentai prisideda prie užpakalinių galūnių motorinio aktyvumo generavimo. Tai leidžia manyti, kad neuronų tinklas generuojantis judesius yra išplitęs labiau, nei manyta iki šiol. / Spinal cord integrates somatosensory information and generates coordinated motor responses. Temporal integration can be used for discrimination of important stimuli from noise. Here it is shown that temporal integration of somatosensory inputs in sub second time scale is possible without changes of intrinsic properties of motoneurons. The activity of premotor neurons increases during temporal integration and can be a mechanism for short term information storage in spinal cord. Suppression of motor activity after painful somatosensory stimulus is called cutaneous silent period. This motor suppression is well described in humans and used for diagnostics. However it is not known if the suppression of motor activity is due to inhibition of motoneurons or reduction of excitatory drive from premotor neurons. Here it is shown that motoneurons are inhibited during cutaneous silent period. Neural networks of spinal cord not only process somatosensory information but generate locomotion and reflexes too. It is accepted that neural networks controlling front and hind limb movements are located in cervical and lumbar enlargements respectfully. Here it is shown that thoracic segments of spinal cord contribute to hind limb movements as well. It means that neural network generating movements is much more widely distributed than previously thought.

La première partie de cette thèse présente une revue historique sur les méthodes d'enregistrements d'activité neuronale, suivie par une étude sur une nouvelle technique d'imagerie pour le poisson zèbre : la microscopie par nappe laser 2 photon. En combinant, les avantages de la microscopie 2 photon et l'imagerie par nappe de lumière, le microscope par nappe laser 2 photon garantie des enregistrements à haute vitesse avec un faible taux de lésions photoniques et permet d'éviter l'une des principales limitations du microscope à nappe laser 1 photon: la perturbation du système visuel. La deuxième partie de cette thèse traite de la navigation dirigée. Après une revue exhaustive sur la chemotaxis, la phototaxis et la thermotaxis, nous présentons des résultats qui révèlent les bases neuronales de la phototaxis chez le poisson zèbre. Grace à des expériences de comportement en réalité-virtuelle, des enregistrements d'activité neuronale, des méthodes optogénétiques et des approches théoriques, ce travail montre qu'une population auto-oscillante située dans le rhombencéphale appelée l'oscillateur du cerveau postérieur (HBO) fonctionne comme un pacemaker des saccades oculaires et contrôle l'orientation des mouvements de nage du poisson zèbre. Ce HBO répond à la lumière en fonction du contexte moteur, biaisant ainsi la trajectoire du poisson zèbre vers les zones les plus lumineuses de son environnement (phototaxis). La troisième partie propose une discussion sur les bases neuronales des saccades oculaires chez les vertébrés. Nous concluons ce manuscrit avec des résultats préliminaires suggérant que chez le poisson zèbre, le même HBO est impliqué dans les processus de thermotaxis. / The first part of this thesis presents an historical overview of neural recording techniques, followed by a study on the development of a new imaging method for zebrafish neural recording: two-photon light sheet microscopy. Combining the advantages of two-photon point scanning microscopy and light sheet techniques, the two-photon light sheet microscope warrants a high acquisition speed with low photodamage and allows to circumvent the main limitation of one-photon light sheet microscopy: the disturbance of the visual system. The second part of the thesis is focused on goal-directed navigation in zebrafish larvae. After an exhaustive review on chemotaxis, phototaxis and thermotaxis in various animal models, we report a study that reveals the neural computation underlying phototaxis in zebrafish. Combining virtual-reality behavioral assays, volumetric calcium recordings, optogenetic stimulation, and circuit modeling, this work shows that a self-oscillating hindbrain population called the hindbrain oscillator (HBO) acts as a pacemaker for ocular saccades, controls the orientation of successive swim-bouts during zebrafish larva navigation, and is responsive to light in a state-dependent manner such that its response to visual inputs varies with the motor context. This peculiar response to visual inputs biases the fish trajectory towards brighter regions (phototaxis). The third part provides a discussion on the neural basis of ocular saccades in vertebrates. We conclude with some recent preliminary results on heat perception in zebrafish suggesting that the same hindbrain circuit may be at play in thermotaxis as well.

La locomotion se définit par des mouvements répétés et coordonnés des membres droits et gauches et des muscles antagonistes d’une même articulation. L’activité locomotrice des rongeurs est générée par des groupes de neurones localisés dans la partie antérieure de l’élargissement lombaire; ce réseau de cellules est appelé Central Pattern Generator (CPG). Au cours de cette thèse, les études entreprises chez le rat nouveau-né ont eu pour but d’étudier les mécanismes cellulaires impliqués dans la genèse du rythme locomoteur. Le courant sodique persistant (INaP) joue un rôle important dans la genèse d’activités rythmiques de plusieurs structures supraspinales et notamment celles impliquées dans la mastication et la respiration. Curieusement, son existence et son implication dans la genèse d’activités rythmiques dans les structures du CPG locomoteur spinal n’ont jamais été abordées. A l’aide d’études électrophysiologiques, la thèse démontre l’existence de INaP et le caractérise pour la première fois au sein du CPG locomoteur. Ce courant est indispensable à la genèse du rythme locomoteur et joue un rôle fondamental dans l’émergence d’activités pacemakers au sein du CPG. Ces activités pacemakers émergent dans un contexte physiologique où des fluctuations dans la composition ionique du milieu extracellulaire interviennent au cours d’une activité locomotrice. L’ensemble de ces données suggère que le « cœur » du générateur de rythme pourrait être composé d’interneurones présentant une activité pacemaker dépendante de INaP dont la modulation pourrait être un élément fondamental à la fois dans le déclenchement et la modulation de l’activité locomotrice. / Identification of the cellular mechanisms underlying the generation of the locomotor rhythm is of longstanding interest to physiologists. Hindlimb locomotor movements are generated by lumbar neuronal networks, referred to as central pattern generators (CPG). Although rhythm generation mechanisms within the CNS can vary, the activation of a subthreshold depolarizing conductance is always needed to start the firing of individual neurons. Among various subthreshold membrane conductances, the persistent sodium current (INaP) is involved in rhythmic activity of numerous supraspinal neurons such as those involved in the generation of masticatory and respiratory rhythm. The thesis was aimed at identifying and characterizing INaP in the neonatal rodent locomotor CPG, determining its importance in shaping neuronal firing properties and its role in the operation of the locomotor circuitry. Using electrophysiological studies the thesis has characterized INaP for the first time in the locomotor CPG. This current is essential to the generation of the locomotor rhythm and plays a fundamental role in the emergence of pacemaker activity within the CPG. These pacemaker activities emerge in a physiological context in which fluctuations in the ionic composition of the extracellular environment occur during locomotion. This study provides evidence that INaP generates pacemaker activities in CPG interneurons and new insights into the operation of the locomotor network with a critical implication of INaP in stabilizing the locomotor pattern.

Locomotion is one of the most important behaviours and requires interaction between sensors at various levels of the nervous system and the limb muscles of an animal. The basic neural rhythm for locomotion in mammals has been shown to arise from local neural networks residing in the spinal cord and these networks are known as central pattern generators (CPGs). However, during the locomotion, these centres are constantly interacting with the sensory feedback signals coming from muscles, joints and peripheral skin receptors in order to adapt the stepping to varying environmental conditions. Conceptual models of mammalian locomotion have been constructed using mathematical models of locomotor subsystems based on the abundance of neurophysiological evidence obtained primarily in the cat. Several aspects of locomotor control using the cat as an animal model have been investigated employing computer simulations and here we use the same approach to address number of questions or/and hypotheses related to rhythmic locomotion in quadrupeds. Some of the involve questions are, role of mechanical linkage during deafferented walking, finding inherent stabilities/instabilities of muscle-joint interactions during normal walking, estimating phase dependent controlability of muscle action over joints. This thesis presents the basics of a biologically realistic model of mammalian locomotion and summarises methodological approaches in modelling quadruped locomotor subsystems such as CPGs, limb muscles and sensory pathways. In the first appended article, we extensively discuss the construction details of the three-dimensional computer simulator for the study of the hind leg neuro-musculo-skeletal-control system and its interactions during normal walking of the cat. The simulator with the walking model is programmed in Python scripting language with other supported open source libraries such as Open Dynamics Engine (ODE) for simulating body dynamics and OpenGL for three dimensional graphical representation. We have examined the functionality of the simulator and the walking model by simulating deafferented walking. It was possible to obtain a realistic stepping in the hind legs even without sensory feedback to the two controllers (CPGs) for each leg. We conclude that the mechanical linkages between the legs also play a major role in producing alternating gait. The use of simulations of walking in the cat for gaining insights into more complex interactions between the environment and the neuro-muscular-skeletal system is important especially for questions where a direct neurophysiological experiment can not be performed on a real walking animal. For instance, it is experimentally hard to isolate individual mechanisms without disrupting the natural walking pattern. In the second article, we introduce a different approach where we use the walking model to identify what control is necessary to maintain stability in the musculo-skeletal system. We show that the actions of most of the hindlimb muscles over the joints have an inherent stability during stepping, even without the involvement of proprioceptive feedback mechanisms. In addition, we observe that muscles generating movements in the ankle joint of the hind leg must be controlled by neural mechanisms, which may involve supraspinal structures, over the whole step cycle. / QC 20101111