Dena Howland - US grants

DESCRIPTION (provided by applicant): The failure of axonal growth in the adult spinal cord has been strongly associated with the presence of chondroitin sulfate proteoglycans (CSPGs) and enzymatic degradation of these molecules in vivo with the enzyme chondroitinase abc has been reported to increase axonal growth in rodent models of central nervous system damage. The central hypothesis to be tested is that intrathecal chondroitinase abc can promote axonal growth that leads to the reconstruction or augmentation of compromised host circuitry and results in enhanced motor function following spinal cord injury. Adult cats will receive low thoracic hemisections and be placed into one of three groups: hemisection-only, de-activated chondroitinase abc or active chondroitinase abc. Cats will be evaluated using a variety of locomotor tasks that demand the involvement of different levels of neural control. These will range from bipedal treadmill locomotion requiring only segmental networks to complex overground runways requiring specific descending supraspinal input. Thus, the type of behavioral recovery seen on these tasks will strongly suggest what neural substrates (pathways) are involved in the recovery process. Cats also will be tested for cough, which is an essential pulmonary defensive reflex that requires premotor input from the medulla. To our knowledge, this is the first effort to determine the influence of any therapeutic agent on spinal cord injury-induced impairment of cough. This will be done using nonterminal, as well as terminal, electrophysiological methods. Basic stains and immunohistochemistry will be used to characterize the lesion sites. Immunohistochemistry, tract tracing, and electrophysiological assays will be used to identify potential mechanisms of plasticity, and quantitatively assess axonal growth and the neuronal populations projecting to and/or past the lesion/treatment site. Results from these studies will allow us to identify the mechanisms of spontaneous recovery and how they may be enhanced or altered by chondroitinase abc treatment. The analyses of these two diverse motor behaviors (locomotion and cough) will allow us to differentiate selective from generalized recovery mechanisms induced by chondroitinase abc. This multi-system approach to recovery and plasticity after chronic spinal cord injury will provide a foundation on which other promising therapies for spinal cord injury can be tested (alone or in combination with chondroitinase abc).

DESCRIPTION (provided by applicant): The failure of axonal growth in the adult spinal cord has been strongly associated with the presence of chondroitin sulfate proteoglycans (CSPGs) and enzymatic degradation of these molecules in vivo with the enzyme chondroitinase abc has been reported to increase axonal growth in rodent models of central nervous system damage. The central hypothesis to be tested is that intrathecal chondroitinase abc can promote axonal growth that leads to the reconstruction or augmentation of compromised host circuitry and results in enhanced motor function following spinal cord injury. Adult cats will receive low thoracic hemisections and be placed into one of three groups: hemisection-only, de-activated chondroitinase abc or active chondroitinase abc. Cats will be evaluated using a variety of locomotor tasks that demand the involvement of different levels of neural control. These will range from bipedal treadmill locomotion requiring only segmental networks to complex overground runways requiring specific descending supraspinal input. Thus, the type of behavioral recovery seen on these tasks will strongly suggest what neural substrates (pathways) are involved in the recovery process. Cats also will be tested for cough, which is an essential pulmonary defensive reflex that requires premotor input from the medulla. To our knowledge, this is the first effort to determine the influence of any therapeutic agent on spinal cord injury-induced impairment of cough. This will be done using nonterminal, as well as terminal, electrophysiological methods. Basic stains and immunohistochemistry will be used to characterize the lesion sites. Immunohistochemistry, tract tracing, and electrophysiological assays will be used to identify potential mechanisms of plasticity, and quantitatively assess axonal growth and the neuronal populations projecting to and/or past the lesion/treatment site. Results from these studies will allow us to identify the mechanisms of spontaneous recovery and how they may be enhanced or altered by chondroitinase abc treatment. The analyses of these two diverse motor behaviors (locomotion and cough) will allow us to differentiate selective from generalized recovery mechanisms induced by chondroitinase abc. This multi-system approach to recovery and plasticity after chronic spinal cord injury will provide a foundation on which other promising therapies for spinal cord injury can be tested (alone or in combination with chondroitinase abc).

DESCRIPTION (provided by applicant): The failure of axonal growth in the adult spinal cord has been strongly associated with the presence of chondroitin sulfate proteoglycans (CSPGs) and enzymatic degradation of these molecules in vivo with the enzyme chondroitinase abc has been reported to increase axonal growth in rodent models of central nervous system damage. The central hypothesis to be tested is that intrathecal chondroitinase abc can promote axonal growth that leads to the reconstruction or augmentation of compromised host circuitry and results in enhanced motor function following spinal cord injury. Adult cats will receive low thoracic hemisections and be placed into one of three groups: hemisection-only, de-activated chondroitinase abc or active chondroitinase abc. Cats will be evaluated using a variety of locomotor tasks that demand the involvement of different levels of neural control. These will range from bipedal treadmill locomotion requiring only segmental networks to complex overground runways requiring specific descending supraspinal input. Thus, the type of behavioral recovery seen on these tasks will strongly suggest what neural substrates (pathways) are involved in the recovery process. Cats also will be tested for cough, which is an essential pulmonary defensive reflex that requires premotor input from the medulla. To our knowledge, this is the first effort to determine the influence of any therapeutic agent on spinal cord injury-induced impairment of cough. This will be done using nonterminal, as well as terminal, electrophysiological methods. Basic stains and immunohistochemistry will be used to characterize the lesion sites. Immunohistochemistry, tract tracing, and electrophysiological assays will be used to identify potential mechanisms of plasticity, and quantitatively assess axonal growth and the neuronal populations projecting to and/or past the lesion/treatment site. Results from these studies will allow us to identify the mechanisms of spontaneous recovery and how they may be enhanced or altered by chondroitinase abc treatment. The analyses of these two diverse motor behaviors (locomotion and cough) will allow us to differentiate selective from generalized recovery mechanisms induced by chondroitinase abc. This multi-system approach to recovery and plasticity after chronic spinal cord injury will provide a foundation on which other promising therapies for spinal cord injury can be tested (alone or in combination with chondroitinase abc).

Extensor muscles of the hind limbs are actively involved in weight support and walking activities. These muscles are extensively linked by inhibitory, force dependent pathways which contribute to the successful execution of a range of functional behaviors, including locomotion. These reflex pathways are thought to arise from Golgi tendon organs and are believed to regulate limb stiffness and promote inter-joint coordination during movements. Weightings of these linkages vary across control, decerebrate animals when quiescent, but obey a proximal to distal gradient during stepping on a treadmill. This finding indicates the strength and distribution of these reflex pathways are subject to modulation in a task-dependent manner. Our preliminary data in animals suggest that spinal cord hemisection alters the normal distribution and a dominant distal-to-proximal inhibitory gradient emerges. Animals with this lesion do not exhibit clasp-knife inhibition, a phenomenon mediated by receptors other than Golgi tendon organs and that results from bilateral injury to the dorsal half of the spinal cord. Changes in the strength and distribution of force feedback that we have observed is correlated with diminished limb stiffness and poor weight acceptance during locomotor tasks ? both of which are problems seen in humans with spinal cord injuries (SCIs). These findings provide new insight into potential mechanisms contributing to disruption of motor function following injury. Our guiding hypothesis is: SCI- induced force-feedback dysregulation results in strong inhibition directed toward proximal muscles and contributes to inadequate limb stiffness during weight support phases of movement. The current application has evolved from collaborative work across two established laboratories, bringing together expertise in SCI, plasticity, force feedback and motor control. The proposed studies are designed to understand and map changes in force feedback control following SCI, characterize associated changes in gait subphases where inhibitory force feedback is thought to be most active across diverse locomotor tasks, and determine which white matter tracts may modulate spinal circuitry responsible for force feedback. Data generated in the proposed projects will be compared with an existing laboratory database containing force feedback findings from control decerebrate preparations. Overall, findings from these studies will explicate the impact of disrupting this intralimb control system on performance, provide critical mechanistic insight likely to be essential for design of the most effective rehabilitation programs for those with SCIs and other neurological disorders, and lay groundwork for development of a new method for testing force feedback in humans