Age-dependent reorganization of peri-infarct "premotor" cortex with task-specific rehabilitative training in mice

Abstract

Background: The incidence of stroke in adulthood increases with advancing age, but there is little understanding of how poststroke treatment should be tailored by age.

Objective: The goal of this study was to determine if age and task specificity of rehabilitative training affect behavioral improvement and motor cortical organization after stroke.

Methods: Young and aged mice were trained to proficiency on the Pasta Matrix Reaching Task prior to lesion induction in primary motor cortex with endothelin-1. After a short recovery period, mice received 9 weeks of rehabilitative training on either the previously learned task (Pasta Matrix Reaching), a different reaching task (Tray Reaching), or no training. To determine the extent of relearning, mice were tested once weekly on the Pasta Matrix Reaching Task. Mice then underwent intracortical microstimulation mapping to resolve the remaining forelimb movement representations in perilesion motor cortex.

Results: Although aged mice had significantly larger lesions compared with young mice, Pasta Matrix Reaching served as effective rehabilitative training for both age-groups. Young animals also showed improvement after Tray Reaching. Behavioral improvement in young mice was associated with an expansion of the rostral forelimb area ("premotor" cortex), but we failed to see reorganization in the aged brain, despite similar behavioral improvements.

Conclusions: Our results indicate that reorganization of motor cortex may be limited by either aging or greater tissue damage, but the capacity to improve motor function via task-specific rehabilitative training continues to be well maintained in aged animals.

Keywords: aging; brain mapping; forelimb; motor skills disorders; stroke.

Figure 1

Aged mice are able to learn and perform skilled motor tasks. (A) Examples of mice performing the two rehabilitative training tasks: the PMRT (left) and the Tray Reaching Task (right). (B) Results of post-operative PMRT training trials in young and aged mice. Successful retrievals indicate the number of pasta pieces broken and eaten per training session. (C) Results of PMRT rehabilitative training trials in young and aged mice. (D) Results of Tray Reaching rehabilitative training trials in young and aged mice. Successful retrievals indicate the number of millet seeds grasped and eaten per training session. Gray vertical lines indicate 2 day breaks in rehabilitative training to allow for probe trials on the PMRT and days off of training. *p<0.05, Young vs. Aged. Data are means±S.E.

Figure 2

Endothelin-1 induced infarcts were larger in the aged mouse brain. (A) Interhemispheric volume differences were used to estimate infarct size. (B) Representative nissl-stained coronal sections from young (left) and aged (right) animals. The infarct is outlined in the right hemisphere in both cases. *p<0.05, Young vs. Aged. Data are means±S.E.

Figure 3

Relearning a complex motor skill after ischemia is dependent on the type of rehabilitative training provided. (A) Results of PMRT probe trials throughout the rehabilitative training period in young (A) and aged (B) mice. Successful retrievals indicate the number of pasta pieces broken and eaten per training session. BL=baseline. Data are means±S.E.

Figure 4

Rehabilitative training on the Pasta Matrix Task, but not the Tray Reaching Task, was similarly effective across ages in promoting behavioral improvement. (A-C) Results of PMRT probe trials comparing young and aged animals that received (A) no rehabilitation, (B) Tray Reaching rehabilitation, or (C) PMRT rehabilitation. There was a significant effect of age only in the Tray Rehab condition.

Figure 5

Rehabilitative training on the PMRT resulted in a larger RFA in young mice. (A) CFA areas across age and training conditions. (B) RFA areas across age and training conditions. (C) Representative ICMS-evoked forelimb representations from young mice that received no rehabilitative training (C) and rehabilitative training on the PMRT (D). Grey circles indicate the infarct location. *p<0.05 PM- vs. No-Rehab. Data are means±S.E.