1985 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuromuscular Plasticity: Recovery After Spinalization @ University of California Los Angeles
The Program Project consists of six individual projects with a core facility. Fourteen investigators from four departments from the University of California at Los Angeles and at Irvine and the Jet propulsion laboratory of Pasadena are contributing the the research program. We have described in this proposal research efforts designed to continue studies on the plasticity of the neuromuscular system. The models being used to probe mammalian neuromuscular plasticity are chronic, completely low thoracic spinalized cats with and without exercise, spinalization plus deafferentation, horizontal spinal transection (separating dorsal and ventral funiculus, lumbar spinal cord isolation and compensatory hypertrophy (removal of synergistic muscles). A major emphasis in these studies is to identify the components of the neuromuscular system that are malleable, and to determine the factors that appear to be responsible for inducing the observed changes. A variety of experimental approaches are being incorporated. These approaches range from analyses of whole body function to subcellular disciplines; for example, detailed behavioral assessments that are tightly linked to specific neural and muscular events, biomechanics, neurophysiology, biochemistry, muscle physiology, vascular physiology and neuroanatomy. The integration and orientation of these multidisciplinary studies to mammalian neuromuscular plasticity should provide a better understanding of the potential of this system to recover functionally, to determine the plastic potential of some motor programs, and to identify some of the neural and muscular components that might be responsible for th changes in the motor output of the hindlimb neuromuscular system after selected lesions.
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1986 — 1991 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuromuscular Plasticity: Functional Recovery @ University of California Los Angeles
The Program consists of four individual projects and a core facility. Eight investigators from five departments and three universities are contributing to the proposed projects. The fundamental points of emphasis are on the plasticity of the neuromuscular system in response to spinal lesions and the consequences of the plasticity or lack of it to locomotor capabilities. The experimental models to be used in addition to normal cats are: low thoracic complete spinalization, surgical isolation of the lumbar cord, partial deafferentation, partial denervation of muscle, self-reinnervation of muscle, and surgical removal of synergistic muscles. Variations of these models include three forms of training, passive hindlimb oscillation and static posture maintenance of spinalized cats and hindlimb oscillation of spinally isolated cats. The plasticity of movement control will be studied at the systemic level by carefully assessing force, velocity, length and electromyographic pattern of individual muscles. Cellular responses of and within motor units and of muscles will be studied in an effort to define mechanisms that might play a role in the induction of the neuromuscular adaptations. These studies should provide further data suggesting that the clinical benefits of optimizing post-neural lesion care can be significant. Further, these studies should provide important data which identifies the features of the rehabilitation procedures that are particularly effective.
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1.009 |
1992 — 2002 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuromuscular Plasticity--Recovery After Spinalization @ University of California Los Angeles
The Program Project Grant (PPG) extends prior studies by the investigators on neuronal and muscular activity-dependent plasticity associated with locomotion following a complete thoracic spinal cord injury (SCI). The three Research Proposals and supportive Core Projects together, will help identify factors that limit locomotor recovery after SCI and elements that may be promoted through physical and biological interventions to enhance the function of persons with SCI. We will address issue ranging from mechanisms for regulation of protein expression in muscle fibers and neurons of rats to optimization of rehabilitation procedures for SCI patients. A project assesses neurotrophic and electro-mechanical influences on the regulation of muscle mass, protein expression, phenotype and function in rats after lower spinal cord isolation. A project examines adaptations of inhibitory neurotransmitters, glycine and GABA, in flexor and extensor spinal pathways associated with spinal rats learning to step or stand. A project studies the effect of kinetics and kinematics on the motor output of the lower extremities during weight-supported stepping and how sensory information can be used to optimize the recovery of locomotion of SCI patients. Projects parallels aspects of in investigation of muscle adaptations and in study of the effects of step training on neuronal activity. The Administrative Core I coordinates all organizational, personnel and budgetary aspects of the PPG. The Animal Core coordinates animal surgeries, training and provides premium care for control and SCI rats for Projects. The 11 scientists participating are from UCLA and UCI. Four UCLA Departments, Biomathematics, Biostatistics, Neurology and Physiological Science will participate with support from the Brain Research Institute which has administered the PPG since 1980. The long term objectives of the PPG continue to be the identification of the 1) physiological and molecular mechanisms for inducing use-dependent neural and muscular plasticity associated with SCI and 2) optimal procedures for functional recovery after SCI. The inability to fully bear weight during standing and stepping, the inability to initiate swing, and the absence of weight bearing on the muscle can be key deficits following SCI. Identification of such limiting factors associated with flexion and extension are essential to understanding the mechanisms of motor recovery following SCI. These factors will be studied using a combination of behavioral, physiological and biochemical approaches.
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1998 — 2002 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuroplasticity of Flexor and Extensor Spinal Pathway @ University of California Los Angeles
Recovery of hindlimb motor function after complete mid-thoracic spinal cord transection is highly dependent on routinely practiced motor skills. Development of use-dependent therapeutic procedures to facilitate recovery of motor function following injury has advanced to testing stages with human patients, but little is known about the adaptations in the spinal cord that can account for this recovery. In the present study, behavioral, physiological and biochemical adaptations that occur as a result of the hindlimbs of neonatal transected rats acquiring the ability to step or stand will be examined. Motion analysis and electromyograms will be used to quantify the activation of motor pools. We will test whether improvements in stepping and standing are associated with a loss of glycinergic and GABAergic inhibition in spinal pathways. Biochemical adaptations in the glycinergic and GABAergic systems that occur in lumbar spinal cord and/or dorsal root immunohistochemistry. Because limitations in flexion and/or extension of the hindlimb can limit the ability to step or to stand, the identification of specific biochemical changes associated with flexor and extensor neural pathways would represent an important advance toward understanding the neural substrates of motor recovery following spinal cord injury. To address this issue dorsal root ganglion neurons and motor neurons of extensor and flexor pathways will be identified using retrograde labeling of the soleus and tibialis anterior, respectively. Therefore, we will be able to identify changes in GABAergic and glycinergic properties of pathways associated with primarily flexion versus extension in transected rats that have acquired skills that require the use of flexors and extensors in different ways, i.e. standing versus stepping. Results from the proposed studies will provide a better understanding of how spinal neural pathways that control posture and locomotion are influenced by use-dependent mechanisms. These results will provide a framework around which strategies for pharmacologically modulating these tasks can be developed.
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2002 — 2003 |
Edgerton, V. Reggie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Robotically Generated Locomotion in Rodents @ University of California Los Angeles
DESCRIPTION (provided by applicant): The adult mammalian lumbar spinal cord can learn to step in the absence of descending input from the brain. The ability of the spinal cord to learn is an extremely important finding for tens of thousands of spinal cord injured patients, as it could mean the difference between being confined to a wheelchair or being able to stand and take some steps. Understanding how to teach the spinal cord to step through effective rehabilitative training has immediate clinical application in itself and can also play a crucial role in enhancing the efficacy of other potential therapeutic interventions for spinal cord injuries. One method of rehabilitative training, i.e. body weight supported locomotion on a treadmill, has been successful in enhancing locomotor recovery in spinal cord injured animals. There is growing evidence that this form of training can also be used to improve walking in humans that have suffered a stroke or spinal cord injury. The success of training, however, depends on the generation of appropriate patterns of sensory information during weight bearing stepping. We hypothesize that repetitive stimulation of key load and phase-related afferent signals during step training reinforces the circuits in the lumbar spinal cord that generate locomotion. We propose to use a robotic system to enhance the locomotor training of spinally transected rats to step on a treadmill. The robotic system provides precise control of weight bearing and of the forces applied to the hindlimbs during stepping. The robotic system will be used to test the effectiveness of maximizing load-related sensory information during stepping by continually adapting weight bearing and by enhancing weight bearing beyond what is possible with current weight support techniques. The robotic system will also be used to determine the effects of imposing patterns of hindlimb coordination on the recovery of stable and consistent stepping and will also determine the extent that mechanical assistance during training should be provided in order to facilitate the generation of stepping. The findings will provide a needed behavioral foundation for future research that identifies the specific neurophysiological and molecular mechanisms underlying sensory-enhanced spinal learning. These data will also provide insight into development of body weight support control and manual (or robotic) intervention for human locomotor training.
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1.009 |
2003 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuromuscular Plasticity: Recovery After Spinalization @ University of California Los Angeles
DESCRIPTION (provided by applicant): The Program Project Grant (PPG) continues to be focused on the plasticity of neural and muscular tissue with the plasticity being studied from the regulation of gene expression to locomotion. The principal objectives are to understand the mechanism of neuromuscular plasticity in response to spinal cord injury (SCI). The PPG strategies incorporate models of SCI with the use of mice, rats and humans. Project I will focus on the role neural activity-dependent and neural activity-independent factors play in the control of genes that express muscle proteins. The molecular events that control muscle atrophy and how these genes respond to specific electro-mechanical stimulation patterns will be determined. A novel approach to our studies of locomotion in Projects II-V is the use of newly developed robotic technology to quantify and control locomotion. In Project II we will determine whether the spinal cord uses a modular strategy to generate a kinematically correct step cycle, even when the step cycle is mechanically perturbed. In addition, initial efforts will be made to localize the neural populations that execute the necessary corrective responses to the perturbation and to determine if the learning-related events utilize similar biochemical strategies to those found for learning in the hippocampus. Project III is focused on defining the ultrastructural synaptic reorganization around flexor and extensor motoneurons following SCI and step training. Project IV is designed to identify the effects of the loss of selected descending and ascending spinal pathways on locomotor performance, how step training will modulate this effect and the role of astrocytes in mediating those effects. In Project V, we will study neuromotor control properties to motor task specific training in humans with a complete SCI. These projects will be supported by three Cores: an Administrative (Core A), Animal (Core B) and Data Processing (Core C) Core.
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1.009 |
2003 |
Edgerton, V. Reggie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Serotonergic Facilitation &Robotics in Spinal Learning @ University of California Los Angeles
DESCRIPTION (provided by applicant): Although it is clear that the functional properties of the sensory-motor pathways in the lumbosacra spinal cord that control posture and locomotion are activity-dependent and can even learn to step and to stand, little is known about what features of the activity are critical in defining the motor potential of a completely spinalized animal. In the present proposal, we will examine the level of specificity of the proprioceptive input to the adult mouse spinal cord in learning to step and to stand using adaptive control strategies of robotic devices. We will also determine the feasibility of using a serotonergic agonist, quipazine, to alter the functional state of the spinal cord to facilitate learning to step and stand in the adult spinal mouse. We will also examine whether the quipazine-induced effects are manifested via direct stimulation of central pattern generation or by facilitation of proprioceptive feedback processing. We will use a new generation of robotic devices to facilitate learning to step and to stand. We hypothesize that the combination of the robotic and pharmacological interventions used concomitantly will enable the spinal animal to regain stepping and standing ability to a higher level, more rapidly than has been previously recognized. The results from these studies are expected to demonstrate a new paradigm for optimizing the recovery of motor function in mice that can be readily translated to humans with neuromotor disorder such as spinal cord injury and stroke.
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1.009 |
2003 |
Edgerton, V. Reggie |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Spinal Plasticity of a Corrective Kinematic Response @ University of California Los Angeles
Motor learning in the mammalian spinal cord following a complete spinal cord transection (ST) suggests a remarkable level of neuronal plasticity in the absence of supraspinal input. For example, ST cats and rats can learn to perform motor tasks such as stepping and standing. Furthermore, the spinal cord can sense, respond to, and successfully learn to overcome a perturbation to the step cycle. The neural mechanisms that underlie these complex decision-making events within the spinal cord are unknown. The central hypothesis of this proposal is that the mammalian lumbar spinal cord has the capability to normalize the kinematics of the hindlimbs in response to a perturbation in the swing phase of a step cycle, and that these adaptive events are mediated by molecular mechanisms similar to those associated with learning in the brain. The ability of the spinal cord to generate a corrective kinematic response will be examined using a robotic system developed in this laboratory, which will impose a programmed perturbation during the step cycle and then to quantify the kinematic response. The proposed experiments will characterize the kinematic and physiological adaptations to swing phase force field induced learning by the lumbar spinal cord in ST rats. Selective neural substrates and specific pathways associated with the adaptive responses will be examined using pharmacological, anatomical and biochemical approaches to gain insight into the physiological and molecular mechanisms to which these learning and memory events can be attributed. Phosphorylated cyclic AMP binding element protein will be measured using Western blots and immunohistochemistry in retrogradely identified flexor and extensor motor pools that execute kinematic control. Biochemical adaptations in the signaling pathways in the lumbar spinal cord will be correlated with dose dependent inhibition of the response using protein synthesis inhibitors. These studies will allow us to begin to identify physiological and cellular events that may underlie spinal motor learning, and provide a framework around which strategies for use-dependent therapeutic procedures following neural injury in human patients can be developed. It is apparent that in order to facilitate recovery of motor function after spinal cord injury or stroke, it is important to train the motor task behavior in a kinematically correct pattern. Understanding the physiological and cellular mechanisms by which motor learning occurs will provide a better understanding of how spinal neural pathways that control posture and locomotion are influenced by use-dependent mechanisms.
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