David S.K. Magnuson - US grants

psychophysiology; nervous system regeneration; spinal cord injury; electrophysiology; behavioral /social science research tag;

motor neurons; nervous system regeneration; spinal cord injury;

disease /disorder model

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of the Electrophysiology and Behavior CORE (CORE D) is to provide a battery of standard tests to assess the function of animals and their spinal cords after injury and treatment, and to facilitate the development of more specialized tests that may be needed for the COBRE projects. The CORE will provide the following tests: 1. Transcranial magnetic motor evoked potentials (tcMMEPs) to assess action potential conduction in descending axons located in the ventrolateral funiculus in rats and mice. 2. Somatosensory evoked potentials (SSEPs) to assess ascending primary sensory pathways (rats only). 3. Magnetic interenlargement reflexes (MIERs) to assess conduction in ascending propriospinal axons located in the lateral white matter (rats only). 4. Open Field Locomotor Scale (BBB) to assess hindlimb function during overground locomotioin in rats and the Basso Mouse Scale (BMS) for mice. 5. Grid-walking test and horizontal ladder tests to assess sensorimotor function. 6. The Louisville Swimming Scale (LSS;rats only) to assess hindlimb function during swimming. 7. Hindlimb kinematics during overground locomotion and swimming for rats and mice using joint angle, limb excursion and step cycle duration as primary measures. 8. The Hargreave's test to assess thermal hyperalgesia. 9. Electro von Frey hairs to assess mechano-hypersensitivity after injury. In addition the CORE will pursue the development of novel electrophysiological and behavioral assessment tools as needed by specific projects within the COBRE laboratires.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of Core C will be to significantly reduce variability in all Projects of the proposal by providing the expertise, personnel, facilities, equipment, and supplies required to reproducibly perform their surgery and veterinary care procedures. The standardized surgery procedures will include producing contusion and laceration types of spinal cord cord injuries in adult rats and mice plus cell transplantation, injection, neuroanatomical tracing, cranial electrode implantation, euthanasia, perfusion fixation, and tissue dissection. The standardized, daily veterinary care procedures are designed to significantly reduce morbidity and mortality. They will include treating wounds, expressing bladders, preventing urinary tract and other infections, plus providing supplemental fluids and nutrition.

[unreadable] DESCRIPTION (provided by applicant): One of the most promising therapeutic strategies for spinal cord injury is weight-supported treadmill training. This rehabilitation therapy seeks to re-train the spinal cord circuitry below the level of injury to participate in functional locomotion. The mammalian spinal cord, humans included, contains complex neuronal circuitry that participates in the generation of the repeating pattern of motor activity (step-cycle) associated with normal over-ground locomotion. Both animal and human studies have demonstrated that moving the hindlimbs to mimic normal walking, usually on a treadmill with rehabilitation assistants, can lead to improved hindlimb locomotor function. However, the treadmill speed that is used is very slow compared to normal walking and much of the body weight of the animal or patient must be supported externally. Consequently, relatively few step-cycles are generated during a re-training session, certainly far fewer than normal walking. We hypothesized that a re-training strategy that allowed for many more step-cycles to be completed would be more effective and that re-training the locomotor circuitry would be much more successful. Some of the components that are thought to be important for the re-training process include step-cycle number, cutaneous feedback from the foot, limb position, and weight-bearing feedback from the leg. How each of these individual components contribute to successful rehabilitation, and the physiological and cellular mechanisms underlying the re-training process are not known. We have devised a strategy to use buoyancy during swimming to provide weight-support which allows for high numbers of step-cycles to be completed during a rehabilitation session. We have also incorporated a simple approach to provide phasic cutaneous feedback during swimming and partial limb-loading (weight- bearing) during walking in shallow water. We hope to uncover what relative contributions step-cycle number and frequency, cutaneous feedback and limb-loading make to the overall success of a locomotor rehabilitation strategy. In addition, we will begin to look at the mechanisms of rehabilitation associated plasticity using a custom made array to detect changes in mRNA levels in spinal cord tissue following different training protocols. [unreadable] [unreadable] [unreadable]

Animal Model; Animal Models and Related Studies; Animals; Articular Capsule; Articular Range of Motion; Axon; Body Tissues; Body Weight; Bruise; Canes; Capsula Articularis; Cats; Class; Common Rat Strains; Complex; Contusions; Coxa; Custom; Cutaneous; Domestic Cats; Dorsal; EMG; Electromyography; Extremities; Feedback; Feline Species; Felis catus; Felis domestica; Felis domesticus; Felis sylvestris catus; Flexor; Foot; Frequencies (time pattern); Frequency; Generations; Golgi Tendon Organs; Golgi's Tendon Spindle; Hindlimb; Hip; Hip region structure; Human; Human, General; Hydrogen Oxide; Individual; Injury; Investigators; Joint Capsule; Joint Range of Motion; Lead; Learning; Left; Leg; Length; Limb structure; Limbs; Link; Load-Bearing; Loadbearing; Locomotion; Locomotor Activity; Locomotor Recovery; Lumbar Portion of Spinal Cord; Lumbar Spinal Cord; Lumbar spinal cord structure; Mammals, Cats; Mammals, Rats; Man (Taxonomy); Man, Modern; Medulla Spinalis; Messenger RNA; Methods; Modeling; Motor; Motor Activity; Motor Cell; Motor Neurons; Motor output; Movement; Muscle; Muscle Spindles; Muscle Tissue; Myelopathy, Traumatic; NRVS-SYS; Nerve; Nervous; Nervous System; Nervous system structure; Neurologic Body System; Neurologic Organ System; Neuromuscular Spindles; Neurotendinous Organ; Non-Trunk; Numbers; Output; Pathway interactions; Patients; Pattern; Pb element; Pes; Phase; Physical Health Services / Rehabilitation; Physiologic; Physiological; Placement; Position; Positioning Attribute; Principal Investigator; Process; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; RNA, Messenger; Range of Motion, Articular; Rat; Rate; Rattus; Receptor Protein; Recovery of Function; Rehabilitation; Rehabilitation therapy; Rehabilitation, Medical; Relative; Relative (related person); Research Personnel; Researchers; Role Playing; Role Playings; Role playing therapy; Speed; Speed (motion); Spinal Cord; Spinal Cord Trauma; Spinal Trauma; Spinal cord injured; Spinal cord injuries; Spinal cord injury; Spindles, Neurotendinous; Staging; Stress; Stretch Receptors, Muscle; Surface; Swimming; Synovial Capsule; Testing; Therapeutic; Thinking; Thinking, function; Tissues; Training; Walkers; Walking; Walking Sticks; Water; Week; Weight; Weight-Bearing; Weight-Bearing state; Weightbearing; Work; base; body movement; cane, includes canes of all materials, adjustable or fixed, with tip; experiment; experimental research; experimental study; foot; function improvement; functional improvement; functional recovery; heavy metal Pb; heavy metal lead; human study; human subject; improved; injured; mRNA; model organism; motoneuron; neuronal circuitry; pathway; programs; range of motion; receptor; rehab strategy; rehabilitation strategy; rehabilitative; research study; response; role playing (psychodrama); success

? DESCRIPTION (provided by applicant): Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the physiological details of those circuits and their contributions to functional recovery following spinal cord injury (SCI) remain t be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry by selectively and temporarily silencing neurotransmission. We will focus on two classes of spinal cord interneurons that have been described anatomically but remain a mystery functionally. These are the long-ascending propriospinal neurons (LAPNs) and the long descending propriospinal neurons (LDPNs) that together comprise a population we have termed inter-enlargement because they provide direct and indirect connections between the cervical and lumbar enlargements. The LAPNs and LDPNs are assumed to play critical roles in forelimb-hindlimb coordination in quadrupeds and to coordinate arm-swing and upper body-lower body movements in people. We hypothesize that LAPNs and LDPNs provide detailed temporal information about the step cycle and limb movement to the corresponding enlargement and thus play critical roles in forelimb-hindlimb coordination in the normal adult rat and in functional recovery following a contusive SCI. This proposal will directly test these hypotheses. Strong preliminary data unequivocally support the rationale of this proposal. Specifically: Aim 1 will determine the role of LAPNs/LDPNs in locomotion as we will independently silence these pathways bilaterally, ipsilaterally, and commissurally. Sophisticated gait and kinematic analyses, as well as terminal histological analyses will be used to quantify functional deficits. Aim 2 will determine the role of LAPNs/LDPNs in recovered function after SCI. These pathways will be silenced after functional recovery has plateaued following two different injury severities. Aim 3 will determine the role of LAPNs/LDPNs in the process of functional recovery after SCI. LAPN/LDPN networks will be silenced 3-10 and 28-35 days post-SCI, time periods of initial weight bearing and stabilization of locomotor function, respectively. Collectively, the proposed experiments will hopefully delineate how these pathways may be therapeutically targeted for functional recovery after SCI.

Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the functional details of those circuits and their contributions to recovery following spinal cord injury (SCI) remain to be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine these tools with sophisticated gait and kinematic analyses, that includes the full repertoire of speed dependent gaits, to provide the functional and anatomical information necessary for building and refining an advanced neuro- biomechanical computer model of the rat spinal cord, body and limbs. We will focus on two classes of spinal cord interneurons, the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons, that interconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements, and investigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Our preliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gait expression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisingly, silencing these neurons after an incomplete contusion injury results in better overground locomotion, a result that is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-based trans-synaptic labeling we will determine the sensory, descending and propriospinal inputs onto both LAPNs and LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as new anatomical data (Aim 2) to build and refine our computational model (Aim 3). Then, in vivo experiments and computer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissural LAPNs and LDPNs play in locomotor behavior, including the full range of locomotor gaits, and in recovered function after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of long propriospinal neurons represents an important step towards the development of new therapeutic tools for recovery after SCI.