Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Abstract

Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/DFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

How Can You Mend a Broken Brain? - Neurorestorative Approaches to Stroke Recovery

“…For example, each of the individual elements of enriched rehabilitation (exercise, socialization, cognitive stimulation, reach training) has some therapeutic potential but collectively provide a powerful intervention by acting upon multiple complementary processes of neuroplasticity (e.g., upregulation of growth factors, angiogenesis, dendritic sprouting) [27,63]. This was illustrated in a recent experiment showing that ER, but not enriched environments or reach training alone, strongly activated neurons in layer II and III peri-infarct cortex [64], a region thought to be critical for recovery of sensory-motor function [4,65,66]. These findings indicate that a combination of environmental enrichment and task-specific rehabilitation targeting the main functional deficit (i.e., skilled reaching) most effectively increases neuronal activity around the lesion.…”

Synergistic Effects of Enriched Environment and Task-Specific Reach Training on Poststroke Recovery of Motor Function

“…51 The combined reaching+enrichment rehabilitation paradigm that we used in the present study has been previously shown to induce greater activation of layer II and III neurons in the perilesional cortex than either reaching alone or enrichment alone. 41 However, this previous study did not demonstrate that the increased neural activity induced by this combination therapy translated to improved functional outcomes. The complementary evidence of Clarke et al, 41 and the present study support emerging views that encouraging reorganization of the peri-infarct area 52 and using multifactorial combination therapies 27,30 may be critical for maximizing poststroke recovery of function.…”

“…41 However, this previous study did not demonstrate that the increased neural activity induced by this combination therapy translated to improved functional outcomes. The complementary evidence of Clarke et al, 41 and the present study support emerging views that encouraging reorganization of the peri-infarct area 52 and using multifactorial combination therapies 27,30 may be critical for maximizing poststroke recovery of function. This concept is underscored by recent evidence that further combination of reaching+enrichment with application of neuroplasticity-promoting factors accelerates the rate of recovery beyond what is possible with only reachi ng+enrichment.…”

“…Males were used to replicate the rehabilitation conditions of a previous related experiment. 41 All behavioral training and testing was performed during the dark cycle. Rats (n=7-8 per group after exclusion criteria) were matched according to poststroke deficits in skilled reaching and randomized into 4 groups: sham, stroke+enrichment, stroke+reach training, and stroke+enrichment+reach training.…”

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

“…Similarly, rats housed in EE show increased formation of dendritic branches and spines in layer II/III motor neurons compared with standardly housed animals [17]. However, it is important to note that ER produces a more selective and more robust use-dependent activation of layer II/III motor neurons in peri-infarct cortex, as revealed by activation of the immediate early gene, FosB/ΔFosB [18], than EE or reach training (individual components of ER). In fact, the latter interventions were no more effective than standard housing in inducing FosB/ΔFosB expression.…”