Post-stroke protection from maladaptive effects of learning with the non-paretic forelimb by bimanual home cage experience in C57BL/6 mice

Abstract

Behavioral experience, in the form of skilled limb use, has been found to impact the structure and function of the central nervous system, affecting post-stroke behavioral outcome in both adaptive and maladaptive ways. Learning to rely on the less-affected, or non-paretic, body side is common following stroke in both humans and rodent models. In rats, it has been observed that skilled learning with the non-paretic forelimb following ischemic insult leads to impaired or delayed functional recovery of the paretic limb. Here we used a mouse model of focal motor cortical ischemic injury to examine the effects of non-paretic limb training following unilateral stroke. In addition, we exposed some mice to increased bimanual experience in the home cage following stroke to investigate the impact of coordinated dexterous limb use on the non-paretic limb training effect. Our results confirmed that skilled learning with the non-paretic limb impaired functional recovery following stroke in C56BL/6 mice, as it does in rats. Further, this effect was avoided when the skill learning of the non-paretic limb was coupled with increased dexterous use of both forelimbs in the home cage. These findings further establish the mouse as an appropriate model in which to study the neural mechanisms of recovery following stroke and extend previous findings to suggest that the dexterous coordinated use of the paretic and non-paretic limb can promote functional outcome following injury. Keywords: experience-dependent plasticity, learned nonuse, motor cortex, motor rehabilitation, stroke

Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

“…Representative pattern changes can be observed in Figure 3B. The ability of the PMRT to mimic learned non-use effects in mice is demonstrated by impaired recovery of the affected limb following less-affected limb training 13,20 . As a result, only successful reaches with the affected limb are analyzed.…”

“…As a result, only successful reaches with the affected limb are analyzed. Results from mice with ischemic lesions to the sensorimotor cortex suggest that two weeks of less-affected limb training following ischemic stroke impairs affected limb use for at least seven days 13 . As demonstrated in Figure 4, mice that receive less-affected limb training for 15 days after unilateral ischemic insult exhibit fewer successful reach attempts over seven days of affected limb assessment.…”

“…The equipment required for the task can be constructed fairly reasonably in house, data collection does not require a large amount of space or financial resources, and the task is simple enough for undergraduate students to reliably collect data. Further, the PMRT is sensitive to even small behavioral deficits 3,13 . This protocol provides a simple and effective way to assess motor skill learning, promote behavioral recovery following injury, and mimic learned non-use phenomena in an established murine model of stroke.…”

“…In addition to being an effective behavioral assessment of post-stroke function, the PMRT has been established as an effective rehabilitative strategy to promote improved functional outcome following sensorimotor stroke 15 . The PMRT can also be used to effectively mimic learned non-use of the affected limb and therefore offer insight into behavioral manipulations that may improve functional recovery despite initial over-reliance on the less-affected limb 13 .…”

“…For example, following a unilateral stroke that affects upper extremity function, humans tend to develop a reliance on their less-affected limb 9,10 . While improving a person's ability to function in the short term, this learned non-use of the affected limb may impede its ultimate recovery potential, as demonstrated in animal models [11][12][13] . These findings in animals have helped to inform the development and use of constraint-induced movement therapy in humans 14 .…”