Abstract
Abnormal reflexes associated with spasticity are considered a major determinant of motor impairments occurring after stroke; however, the mechanisms underlying post-stroke spasticity remain unclear. This may be because of the lack of suitable rodent models for studying spasticity after cortical injuries. Thus, the purpose of the present study was to establish an appropriate post-stroke spasticity mouse model. We induced photothrombotic injury in the rostral and caudal forelimb motor areas of mice and used the rate-dependent depression (RDD) of Hoffmann's reflex (H-reflex) as an indicator of spastic symptoms. To detect motoneuron excitability, we examined c-fos mRNA levels and c-Fos immunoreactivity in affected motoneurons using quantitative real-time reverse transcription PCR and immunohistochemical analysis, respectively. To confirm the validity of our model, we confirmed the effect of the anti-spasticity drug baclofen on H-reflex RDDs 1 week post stroke. We found that 3 days after stroke, the RDD was significantly weakened in the affected muscles of stroke mice compared with sham-operated mice, and this was observed for 8 weeks. The c-fos mRNA levels in affected motoneurons were significantly increased in stroke mice compared with sham-operated mice. Immunohistochemical analysis revealed a significant increase in the number of c-Fos-positive motoneurons in stroke mice compared with sham-operated mice at 1, 2, 4, and 8 weeks after stroke; however, the number of c-Fos-positive motoneurons on both sides of the brain gradually decreased over time. Baclofen treatment resulted in recovery of the weakened RDD at 1 week post stroke. Our findings suggest that this is a viable animal model of post-stroke spasticity.
Highlights
A velocity-dependent increase in muscle tone resulting from stretch reflex hyperexcitability has been proposed as a cardinal feature of spasticity.[7,8] In addition, spinal reflex spasticity is known to be accompanied by weakened rate-dependent depression (RDD) of Hoffmann’s reflex (H-reflex), which is the electrical analog of the tendon jerk reflex and is mediated through monosynaptic pathways in the spinal cord
Given that spasticity develops in conjunction with weakening RDD of the H-reflex, which is gradually abolished following brain and spinal cord injury, RDD is considered a reliable measurement of spasticity in stroke patients and in animal models of spinal cord injury.[9,10,11]
We found that RDDs for the affected muscles were significantly weakened in stroke mice (n 1⁄4 6) compared with sham-operated mice (n 1⁄4 7) 3 days after stroke, and this was still observed on week 8 after stroke (Po0.01, Figure 2b); the RDDs were not significantly weakened at week 3
Summary
A velocity-dependent increase in muscle tone resulting from stretch reflex hyperexcitability has been proposed as a cardinal feature of spasticity.[7,8] In addition, spinal reflex spasticity is known to be accompanied by weakened rate-dependent depression (RDD) of Hoffmann’s reflex (H-reflex), which is the electrical analog of the tendon jerk reflex and is mediated through monosynaptic pathways in the spinal cord. Fulton and Kennard[18] used primates to demonstrate that lesions in both primary and premotor areas can induce spasticity; a rodent model is needed to analyze the precise mechanisms underlying spasticity after cortical injuries, such as those in stroke. We investigated whether spasticity is induced after photothrombotic injury to the rostral and caudal forelimb motor areas of mice, which are considered the premotor and forelimb primary motor cortices in rodents, respectively.[19] Given that enhanced excitability of affected motoneurons has frequently been reported in studies of spasticity after stroke and spinal cord injury, we further examined whether a similar phenomenon occurred in our mouse model of post-stroke spasticity
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