The "good" limb makes the "bad" limb worse: experience-dependent interhemispheric disruption of functional outcome after cortical infarcts in rats

Abstract

Following stroke-like lesions to the sensorimotor cortex in rats, experience with the ipsi-to-lesion (ipsilesional), "nonparetic", forelimb worsens deficits in the contralesional, "paretic", forelimb. We tested whether the maladaptive effects of experience with the nonparetic limb are mediated through callosal connections and the contralesional sensorimotor cortex. Adult male rats with proficiency in skilled reaching with their dominant (for reaching) forelimb received ischemic bilateral sensorimotor cortex lesions, or unilateral lesions, with or without callosal transections. After assessing dominant forelimb function (the paretic forelimb in rats with unilateral lesions), animals were trained with their nonparetic/nondominant forelimb or underwent control procedures for 15 days. Animals were then tested with their paretic/dominant forelimb. In animals with unilateral lesions only, nonparetic forelimb training worsened subsequent performance with the paretic forelimb, as found previously. This effect was not found in animals with both callosal transections and unilateral lesions. After bilateral lesions, training the nondominant limb did not worsen function of the dominant limb compared with controls. Thus, the maladaptive effects of training the nonparetic limb on paretic forelimb function depend upon the contralesional cortex and transcallosal projections. This suggests that this experience-dependent disruption of functional recovery is mediated through interhemispheric connections of the sensorimotor cortex.

Figure 1. Experimental Design

A. Schematic of the reaching chamber. The inner chamber wall and pellet placement are adjusted to train the left versus right limb. This chamber is configured for reaching with the right forelimb. B. A rat aiming and reaching for a banana flavored food pellet. C. Unilateral SMC lesion and corresponding non-paretic (ipsilesional) and paretic (contralesional) forelimbs. Transections of the corpus callosum are not depicted. D. Bilateral SMC lesions and corresponding non-dominant- and dominant-for-reaching forelimbs. E. Time line of experimental procedures. Transections, in Experiment 1, were given at the same time as ischemic lesions.

Figure 2. Nonparetic forelimb training worsens performance of the paretic forelimb in rats without corpus callosum transections

A. Performance during the period of training of the nonparetic, ipsilesional, limb (NonParT) after unilateral SMC lesions in rats with or without callosal transections (CCX). There was no significant difference in acquisition of the skilled reaching task with the nonparetic forelimb between these two groups. The first day of nonparetic limb training was 6 days after lesions. B. After training the nonparetic limb, NonParT rats had major deficits in the paretic, contralesional forelimb compared to control animals. C. In contrast, in rats with unilateral SMC lesions and callosum transections performance with the paretic forelimb was not significantly affected by prior nonparetic forelimb training. Day 1 of the paretic limb training period in B and C corresponds to 22 days after the lesions. Data in panels B and C were calculated as %[(pre-operative- postoperative)/preoperative] successful retrievals per reach attempt. Data in all figures are means ± SEM. * p < .05.

Figure 3. Non-dominant forelimb training in rats with bilateral SMC lesions does not worsen performance of the dominant forelimb

A. Non-dominant limb learning curve of rats with bilateral lesions (Experiment 2). Rats that had learned the task with the dominant limb were learning it for the first time with the non-dominant limb after the lesion. The first training day was 6 days post-lesion. B. Rats with bilateral lesions had a similar rate of re-acquisition of the skilled reaching task with their dominant forelimb regardless of whether they received earlier post-lesion training with the non-dominant forelimb (Bilat_ND) or earlier control procedures (Bilat_Cont). Panel B shows %[(pre-operative-postoperative)/preoperative] successful retrievals per reach attempt. The first dominant limb training day in panel B was 22 days after lesions. Note the differences in scales in comparison to Figure 2.

Figure 4. Representative lesions and callosal transections

A. Experiment 1, representative lesion and corpus callosum transection. B. Representative lesion from Experiment 2. Scale bars for low magnification images in panels A and B are 1 mm. Scale bar in inset is 250μm. * indicates SMC damage.