title: Plasticity beyond peri-infarct cortex: spinal up regulation of structural plasticity, neurotrophins, and inflammatory cytokines during recovery from cortical stroke.
abstract: Stroke induces pathophysiological and adaptive processes in regions proximal and distal to the infarct. Recent studies suggest that plasticity at the level of the spinal cord may contribute to sensorimotor recovery after cortical stroke. Here, we compare the time course of heightened structural plasticity in the spinal cord against the temporal profile of cortical plasticity and spontaneous behavioral recovery. To examine the relation between trophic and inflammatory effectors and spinal structural plasticity, spinal expression of brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured. Growth-associated protein 43 (GAP-43), measured at 3, 7, 14, or 28 days after photothrombotic stroke of the forelimb sensorimotor cortex (FL-SMC) to provide an index of periods of heightened structural plasticity, varied as a function of lesion size and time after stroke in the cortical hemispheres and the spinal cord. Notably, GAP-43 levels in the cervical spinal cord were significantly increased after FL-SMC lesion, but the temporal window of elevated structural plasticity was more finite in spinal cord relative to ipsilesional cortical expression (returning to baseline levels by 28 post-stroke). Peak GAP-43 expression in spinal cord occurred during periods of accelerated spontaneous recovery, as measured on the Montoya Staircase reaching task, and returned to baseline as recovery plateaued. Interestingly, spinal GAP-43 levels were significantly correlated with spinal levels of the inflammatory cytokines TNF-α and IL-6 as well as the neurotrophin NT-3, while a transient increase in BDNF levels preceded elevated GAP-43 expression. These data identify a significant but time-limited window of heightened structural plasticity in the spinal cord following stroke that correlates with spontaneous recovery and the spinal expression of inflammatory cytokines and neurotrophic factors.
authors.affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; Neurochemical Research Unit, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. Electronic address: sist@ualberta.ca.
authors.forename: Bernice
authors.initials: B
authors.lastname: Sist
authors.affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; Faculty of Rehabilitative Medicine, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. Electronic address: karim.fouad@ualberta.ca.
authors.forename: Karim
authors.initials: K
authors.lastname: Fouad
authors.affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; Neurochemical Research Unit, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. Electronic address: iwinship@ualberta.ca.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Winship
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007839:Functional Laterality; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020767:Intracranial Thrombosis / Q000150:complications; D061346:Laser Capture Microdissection; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D010775:Photic Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D020521:Stroke / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
chemical_list: D016207:Cytokines; D019922:GAP-43 Protein; D009414:Nerve Growth Factors
keywords: BDNF; CC; CSC; FL-SMC; GAP-43; IC; IL-6; Inflammation; Ischemia; LSC; NT-3; Neurotrophins; Plasticity; Sensorimotor cortex; Spinal cord; TNF-alpha; TNF-α; brain derived neurotrophic factor; cervical spinal cord; contralesional cortex; forelimb sensorimotor cortex; growth associated protein-43; interleukin 6; ipsilesional cortex; lumbar spinal cord; neurotrophin-3; tumor necrosis factor-alpha