2013 — 2017 |
Cote, Marie-Pascale |
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. |
Electrophysiology
Address; Aftercare; Animals; Axon; axon regeneration; behavior test; Behavioral; Cells; cost; Data; Data Collection; Electrophysiology (science); Equipment; Experimental Designs; Goals; Histology; Human Resources; Individual; Injury; innovation; Laboratories; Mediating; Methods; Modeling; Molecular; Motor; Natural regeneration; Outcome; Preparation; Principal Investigator; Procedures; Process; programs; Recovery; Recovery of Function; repaired; research study; sensorimotor system; Sensory; Spinal Cord; Spinal cord injury; spinal pathway; Synapses; Techniques; Testing; Therapeutic Intervention; Training; Transplantation;
|
1 |
2015 — 2019 |
Cote, Marie-Pascale |
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. |
Chloride Homeostasis and Motor Recovery After Sci
? DESCRIPTION (provided by applicant): Spasticity is a debilitating condition which affects ~75% of individuals with a spinal cord injury (SCI). Among incapacitating symptoms of spasticity is hyperreflexia which ultimately interfere with residual motor function and hamper motor recovery after SCI. Activity-based therapies are routinely integrated in SCI rehabilitation programs and result in a reduction of hyperreflexia and spasticity. The mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve motor function are, however, poorly understood. Persisting alterations in the action of GABA on post-synaptic targets are a signature of CNS injuries and disorders including seizure, epilepsy, Alzheimer disease, autism spectrum disorders, neuropathic pain and the development of spasticity after SCI. The inhibitory action of GABA depends on intracellular chloride concentration [Cl-]i, which is largely determined by the expression of 2 cation-chloride cotransporters (CCCs), KCC2 and NKCC1. Changing the density or activity of these transporters directly affects [Cl-]i and ultimately determines whether GABA has an inhibitory or excitatory effect. We recently found that plasticity in chloride homeostasis is involved in reflex recovery induced by exercise after SCI. Our results suggest that an increase in the expression level of KCC2 in lumbar motoneurons (MN), and subsequent decrease in [Cl-]i contributed to the restoration of spinal inhibition and reflex modulation. Plasticity in the lumbar spinal inhibitory system not only impact transmission in reflex pathways, but greatly influences walking ability after SCI. The objective of this project is to determine if the restoration of spinal inhibition through a return to chloride homeostasis is an effective target to enhance locomotor recovery after SCI. We hypothesized that after SCI 1) the decrease in KCC2/NKCC1 expression ratio in lumbar MNs contributes to the emergence of large persistent inward currents (PICs) and spasms that are recovered with step-training; 2) the increase in KCC2/NKCC1 expression ratio in lumbar MNs triggered by step-training contributes to locomotor recovery; 3) pharmacologically increasing the KCC2/NKCC1 expression ratio in lumbar MNs improves locomotor recovery and enhance the effect of step-training. The involvement of chloride homeostasis in motor impairment after SCI and recovery with step-training will be tested using KCC2 and NKCC1 pharmacological blockers, exercise and a combination of these treatments. This will lead the way for novel therapeutic perspectives for diuretics and other drugs that, in reducing the levels of [Cl-]i, reinstate the hyperpolarizing action of GABA and behaviorally relevant oscillations that are strongly dependent on GABAergic networks. This project has direct relevance to the design and implementation of future treatment and rehabilitation programs for SCI. It will define the involvement of a specific molecular pathway in both the impairment and recovery of spinal excitability and locomotion after SCI. This project will identify possible new targets to enhance pharmacological management of SCI and improve locomotor function when combined with rehabilitation programs.
|
1 |
2021 |
Cote, Marie-Pascale |
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. |
Mechanisms of Action Contributing to Decrease Spasticity and Improve Motor Recovery With Repeated Transcutaneous Stimulation After Spinal Cord Injury
Spasticity is a debilitating condition which emerges in up to ~75% of individuals with spinal cord injury (SCI), with most experiencing spastic episodes one year after injury. Current pharmacological approaches to decrease spasticity (i.e. baclofen, tizanidine, botulinum toxin) lead to significant undesirable side effects such as sedation and dizziness. More importantly, they also induce a profound depression of spinal reflex excitability which significantly reduces muscle activity and impedes conventional rehabilitative efforts. There is therefore a critical need to identify alternate avenues. The last decade has seen a critical breakthrough in the SCI field with the use of stimulation-based therapies, in particular epidural stimulation, to further modulate the excitability of spinal networks and enhance functional recovery after SCI. Although promising, these treatments are invasive, costly, and require highly skilled and specialized teams. In contrast, non-invasive transcutaneous spinal cord stimulation (tSCS) has the potential to be rapidly adapted in clinical rehabilitation settings. This project is designed to advance our understanding of the neuroplasticity triggered by 6 weeks of repeated lumbar tSCS initiated acutely, to prevent the development of spasticity, or chronically, to decrease spasticity once spinal hyperexcitability has fully developed. Aim 1 will determine if tSCS contributes to decrease spasticity/hyperreflexia through restoring spinal inhibition in lumbar spinal networks. Behavioral correlates of spasticity will be monitored over time. In a terminal experiment, the effect of tSCS on spinal inhibitory pathways (homosynaptic depression, reciprocal inhibition, and presynaptic inhibition) will be correlated to the reorganization of inhibitory/excitatory inputs to motoneurons and primary afferents. Aim 2 will determine if tSCS restores motor-evoked potentials (MEPs) originating from above and below the injury after SCI. During a terminal experiment, MEPs initiated by a stimulation to the spinal cord below or above the injury will be recorded as well as synaptic transmission in the cortico-reticulospinal pathway. The modulatory effect of proprioceptive feedback on the MEPs of various origin will also be evaluated. The contribution of primary afferents (VGlut1+/paravalbumin) and descending tracts (vGi) to increased motor output and normalization of the SCI-induced facilitation of proprioceptive afferents will be evaluated. Because spastic symptoms, such as spasms and uncontrollable reflexes, render rehabilitation and activity-based therapies such as locomotor training challenging and less effective, Aim 3 will determine if decreasing spasticity with tSCS prior to the initiation of a step-training program improves locomotor recovery. Spasticity and locomotor recovery will be evaluated over time and will be correlated to the return of spinal inhibition and cortico-reticulospinal transmission. The proposed research project is consistent with the goals of the NIH/NINDS by addressing a current gap in knowledge and delineating the mechanisms of tSCS. Understanding the mechanisms underlying the beneficial effect of non-invasive interventions is critical to optimize evidence-based clinical practice and fast-track its use in the SCI community.
|
1 |