Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke.
ABSTRACT Aged individuals exhibit reduced functional recovery after stroke. We examined the expression profile in aged animals of a recently identified group of growth-associated genes that underlies post-stroke axonal sprouting in the young adult. Basal levels of most growth-promoting genes are higher in aged cortex compared with young adult, and are further induced after stroke. Compared with the young adult, these genes are induced at later time points after stroke. For growth-inhibitory molecules, myelin-associated glycoprotein and ephrin A5 are uniquely induced in the aged brain; chondroitin sulfate proteoglycans and oligodendrocyte myelin glycoprotein are induced at earlier time points; and Nogo-A, semaphorin IIIa and NG2 decline in aged vs. young adult after stroke. The aged brain does not simply have a reduction in growth-associated molecules after stroke, but a completely unique molecular profile of post-stroke axonal sprouting.
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ABSTRACT: The process of brain remodeling after stroke is time- and neural activity-dependent, and the latter makes it inherently sensitive to behavioral experiences. This generally supports targeting early dynamic periods of post-stroke neural remodeling with rehabilitative training (RT). However, the specific neural events that optimize RT effects are unclear and, as such, cannot be precisely targeted. Here we review evidence for, potential mechanisms of, and ongoing knowledge gaps surrounding time-sensitivities in RT efficacy, with a focus on findings from animal models of upper extremity RT. The reorganization of neural connectivity after stroke is a complex multiphasic process interacting with glial and vascular changes. Behavioral manipulations can impact numerous elements of this process to affect function. RT efficacy varies both with onset time and its timing relative to the development of compensatory strategies with the less-affected (nonparetic) hand. Earlier RT may not only capitalize on a dynamic period of brain remodeling but also counter a tendency for compensatory strategies to stamp-in suboptimal reorganization patterns. However, there is considerable variability across injuries and individuals in brain remodeling responses, and some early behavioral manipulations worsen function. The optimal timing of RT may remain unpredictable without clarification of the cellular events underlying time-sensitivities in its effects.Frontiers in Human Neuroscience 06/2014; 8:379. DOI:10.3389/fnhum.2014.00379 · 2.90 Impact Factor
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ABSTRACT: After stroke the central nervous system reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its circuits, form new contacts, erase others, and remap related cortical and spinal cord regions. This plasticity can lead to a surprising degree of spontaneous recovery. It includes the activation of neuronal molecular mechanisms of growth and of extrinsic growth promoting factors and guidance signals in the tissue. Rehabilitative training and pharmacological interventions may modify and boost these neuronal processes, but almost nothing is known on the optimal timing of the different processes and therapeutic interventions and on their detailed interactions. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the therapeutic interventions in accordance with defined plastic time windows. In this review we summarize the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance growth and plasticity, with an emphasis on anti-Nogo-A immunotherapy. We highlight critical time windows of growth and of rehabilitative training and consider different approaches of combinatorial rehabilitative schedules. Finally, we discuss potential future strategies for designing repair and rehabilitation paradigms by introducing a "3 step model": determination of the metabolic and plastic status of the brain, pharmacological enhancement of its plastic mechanisms, and stabilization of newly formed functional connections by rehabilitative training.Frontiers in Human Neuroscience 06/2014; 7:911. DOI:10.3389/fnhum.2013.00911 · 2.90 Impact Factor
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ABSTRACT: Recent human neuroimaging studies indicate that spontaneous fluctuations in neural activity, as measured by functional connectivity magnetic resonance imaging (fcMRI), are significantly affected following stroke. Disrupted functional connectivity is associated with behavioral deficits and has been linked to long-term recovery potential. FcMRI studies of stroke in rats have generally produced similar findings, although subacute cortical reorganization following focal ischemia appears to be more rapid than in humans. Similar studies in mice have not been published, most likely because fMRI in the small mouse brain is technically challenging. Extending functional connectivity methods to mouse models of stroke could provide a valuable tool for understanding the link between molecular mechanisms of stroke repair and human fcMRI findings at the systems level. We applied functional connectivity optical intrinsic signal imaging (fcOIS) to mice before and 72hours after transient middle cerebral artery occlusion (tMCAO) to examine how graded ischemic injury affects the relationship between functional connectivity and infarct volume, stimulus-induced response, and behavior. Regional changes in functional connectivity within the MCA territory were largely proportional to infarct volume. However, subcortical damage affected functional connectivity in somatosensory cortex as much as larger infarcts of cortex and subcortex. The extent of injury correlated with cortical activations following electrical stimulation of the affected forelimb and with functional connectivity in somatosensory cortex. Regional homotopic functional connectivity in motor cortex correlated with behavioral deficits measured using an adhesive patch removal test. Spontaneous hemodynamic activity within the infarct exhibited altered temporal and spectral features in comparison to intact tissue; failing to account for these regional differences significantly affected apparent post-stroke functional connectivity measures. Thus, several results were strongly dependent on how the resting-state data were processed. Specifically, global signal regression alone resulted in apparently distorted functional connectivity measures in the intact hemisphere. These distortions were corrected by regressing out multiple sources of variance, as performed in human fcMRI. We conclude that fcOIS provides a sensitive imaging modality in the murine stroke model; however, it is necessary to properly account for altered hemodynamics in injured brain to obtain accurate measures of functional connectivity.NeuroImage 05/2014; 99. DOI:10.1016/j.neuroimage.2014.05.051 · 6.13 Impact Factor