Timing is likely to be critical in attempts to promote restorative brain plasticity after stroke. Animal studies of stroke have revealed that ischemic injury triggers cascades of growth promoting and inhibiting cellular reactions and prolonged periods of neuroanatomical reorganization. Many ischemia-triggered remodeling events are activity-dependent and sensitive to behavioral manipulations. There is a growing awareness that rehabilitation strategies might capitalize on this sensitivity to optimize stroke outcome, and that this is likely to require that interventions be timed to coincide with more dynamic stages of remodeling, a timing likely to vary with stroke and patient characteristics, including age. However, the specific cellular events underlying time- dependencies in post-stroke rehabilitation continue to be poorly understood, making it impossible to clearly target them to optimize and tailor rehabilitation strategies. This project is focused on understanding how behavioral experiences differentially impact, depending on timing, post-ischemic neural and vascular remodeling events and their coordination, and the relevance of these time-dependencies for long-term outcome. This will be studied in a mouse model of chronic upper extremity (forelimb) impairments resulting from unilateral ischemic motor cortical damage in which functional impairments are improved by motor rehabilitative training of the paretic limb or exacerbated by compensatory skill learning with the nonparetic limb. Repeated in vivo imaging of synaptic elements, vascular microstructure and blood flow will be used together with sensitive behavioral measures, high resolution mapping of motor cortical organization and quantitative light and electron microscopy to reveal time- and age-dependencies in the effects of functionally beneficial and detrimental experiences on neural and vascular remodeling in peri-infarct cortex, and the consequences of these effects for cortical reorganization and behavioral outcome. The central hypothesis of this project is that behavioral experience- and injury-induced neural and vascular plasticity interact in a time- and age-dependent manner to remodel neural connections and vasculature in remaining motor cortex and to influence behavioral outcome.
The specific aims are to test the hypotheses that motor rehabilitative training (1) interacts with post-ischemic neural and vascular plasticity to promote functionally beneficial remodeling of peri-infarct cortex but that this interaction is dependent upon (2) angiogenesis, (3) on its specific timing and duration relative to the onset of ischemic injury, (4) on its timing relative to the development of compensatory skill learning with the nonparetic limb and (5) on the age during which ischemic damage is incurred. The long-term goal of this project is to identify neural and vascular events that create time-dependencies in motor rehabilitative training efficacy so that these events can be targeted to tailor and facilitate the effects of rehabilitative training and to improve long-ter outcome after stroke.
Rehabilitative training approaches remain the primary means of improving function in the chronic period after stroke, but they are far from perfect and there i insufficiently detailed knowledge of their mechanisms to understand what needs to be changed to improve them. This project will reveal neural and vascular events that underlie time- and age-dependencies in motor rehabilitative training effects after stroke. The results will improve our understanding of the brain changes underlying rehabilitation efficacy and reveal new targets for optimizing and tailoring treatments for post-stroke disabilities.
|Martin, P-M; Stanley, R E; Ross, A P et al. (2016) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/Î²-catenin signaling. Mol Psychiatry :|
|Davis, Mitchell A; Gagnon, Louis; Boas, David A et al. (2016) Sensitivity of laser speckle contrast imaging to flow perturbations in the cortex. Biomed Opt Express 7:759-75|
|Jones, Theresa A; Adkins, DeAnna L (2015) Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection. Physiology (Bethesda) 30:358-70|
|Davis, Mitchell A; Dunn, Andrew K (2015) Dynamic light scattering Monte Carlo: a method for simulating time-varying dynamics for ordered motion in heterogeneous media. Opt Express 23:17145-55|
|Kazmi, S M Shams; Wu, Rebecca K; Dunn, Andrew K (2015) Evaluating multi-exposure speckle imaging estimates of absolute autocorrelation times. Opt Lett 40:3643-6|
|Perillo, Evan P; Liu, Yen-Liang; Huynh, Khang et al. (2015) Deep and high-resolution three-dimensional tracking of single particles using nonlinear and multiplexed illumination. Nat Commun 6:7874|
|Bell, Jared A; Wolke, Malerie L; Ortez, Ryan C et al. (2015) Training Intensity Affects Motor Rehabilitation Efficacy Following Unilateral Ischemic Insult of the Sensorimotor Cortex in C57BL/6 Mice. Neurorehabil Neural Repair 29:590-8|
|Tennant, Kelly A; Kerr, Abigail L; Adkins, DeAnna L et al. (2015) Age-dependent reorganization of peri-infarct ""premotor"" cortex with task-specific rehabilitative training in mice. Neurorehabil Neural Repair 29:193-202|
|Schrandt, Christian J; Kazmi, S M Shams; Jones, Theresa A et al. (2015) Chronic monitoring of vascular progression after ischemic stroke using multiexposure speckle imaging and two-photon fluorescence microscopy. J Cereb Blood Flow Metab 35:933-42|
|Kazmi, S M Shams; Balial, Satyajit; Dunn, Andrew K (2014) Optimization of camera exposure durations for multi-exposure speckle imaging of the microcirculation. Biomed Opt Express 5:2157-71|
Showing the most recent 10 out of 15 publications