Najet Serradj

Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j.

The development of motor skills was studied at different stages in the life of the mouse, focusing on three key aspects of motor development: early rhythmic motor activities prior to the acquisition of quadruped locomotion, motor skills in young adults, and the effect of aging on motor skills. The age-related development pattern was analysed and compared in two strains of major importance for genomic studies (C57Bl6/j and 129/sv). Early rhythmic air-stepping activities by l-dopa injected mice showed similar overall development in both strains; differences were observed with greater beating frequency and less inter-limb coordination in 129/sv, suggesting that 129/sv had a different maturation process. Performance on the rotarod by young adult C57Bl6/j gradually improved between 1 and 3 months, but then declined with age; performance on the treadmill also declined with an age-related increase in fatigability. Overall performance by 129/sv mice was lower than C57Bl6/j, and the age-related pattern of change was different, with 129/sv having relatively stable performance over time. Inter-strain differences and their possible causes, in particular the role of dopaminergic pathways, are discussed together with repercussions affecting mutant phenotyping procedures.

EphrinB3/EphA4-mediated guidance of ascending and descending spinal tracts.

The spinal cord contains many descending and ascending longitudinal tracts whose development appears to be controlled by distinct guidance systems. We identified a population of dorsal spinal neurons marked by coexpression of the transcription factor Zic2 and the guidance receptor EphA4. Zic2+;EphA4+ neurons are surrounded by mechanosensory terminals, suggesting innervation by mechanoreceptor afferents. Their axons form an ipsilateral ascending pathway that develops during embryogenesis and projects within the ventral aspect of the dorsal funiculus, the same location as the descending corticospinal tract (CST), which develops postnatally. Interestingly, the same guidance mechanism, namely, ephrinB3-induced EphA4 forward signaling, is required for the guidance of both ascending and descending axon tracts. Our analysis of conditional EphA4 mutant mice also revealed that the development of the dorsal funiculus occurs independently of EphA4 expression in descending CST axons and is linked to the distribution of Zic2+;EphA4+ spinal neurons and the formation of the ascending pathway.

Activity-Based Therapies for Repair of the Corticospinal System Injured during Development

This review presents the mechanistic underpinnings of corticospinal tract (CST) development, derived from animal models, and applies what has been learned to inform neural activity-based strategies for CST repair. We first discuss that, in normal development, early bilateral CST projections are later refined into a dense crossed CST projection, with maintenance of sparse ipsilateral projections. Using a novel mouse genetic model, we show that promoting the ipsilateral CST projection produces mirror movements, common in hemiplegic cerebral palsy (CP), suggesting that ipsilateral CST projections become maladaptive when they become abnormally dense and strong. We next discuss how animal studies support a developmental “competition rule” whereby more active/used connections are more competitive and overtake less active/used connections. Based on this rule, after unilateral injury the damaged CST is less able to compete for spinal synaptic connections than the uninjured CST. This can lead to a progressive loss of the injured hemisphere’s contralateral projection and a reactive gain of the undamaged hemisphere’s ipsilateral CST. Knowledge of the pathophysiology of the developing CST after injury informs interventional strategies. In an animal model of hemiplegic CP, promoting injured system activity or decreasing the uninjured system’s activity immediately after the period of a developmental injury both increase the synaptic competitiveness of the damaged system, contributing to significant CST repair and motor recovery. However, delayed intervention, despite significant CST repair, fails to restore skilled movements, stressing the need to consider repair strategies for other neural systems, including the rubrospinal and spinal interneuronal systems. Our interventional approaches harness neural activity-dependent processes and are highly effective in restoring function. These approaches are minimally invasive and are poised for translation to the human.

EphA4-Mediated Ipsilateral Corticospinal Tract Misprojections Are Necessary for Bilateral Voluntary Movements But Not Bilateral Stereotypic Locomotion

In this study, we took advantage of the reported role of EphA4 in determining the contralateral spinal projection of the corticospinal tract (CST) to investigate the effects of ipsilateral misprojections on voluntary movements and stereotypic locomotion. Null EphA4 mutations produce robust ipsilateral CST misprojections, resulting in bilateral corticospinal tracts. We hypothesize that a unilateral voluntary limb movement, not a stereotypic locomotor movement, will become a bilateral movement in EphA4 knock-out mice with a bilateral CST. However, in EphA4 full knock-outs, spinal interneurons also develop bilateral misprojections. Aberrant bilateral spinal circuits could thus transform unilateral corticospinal control signals into bilateral movements. We therefore studied mice with conditional forebrain deletion of the EphA4 gene under control by Emx1, a gene expressed in the forebrain that affects the developing CST but spares brainstem motor pathways and spinal motor circuits. We examined two conditional knock-outs targeting forebrain EphA4 during performance of stereotypic locomotion and voluntary movement: adaptive locomotion over obstacles and exploratory reaching. We found that the conditional knock-outs used alternate stepping, not hopping, during overground locomotion, suggesting normal central pattern generator function and supporting our hypothesis of minimal CST involvement in the moment-to-moment control of stereotypic locomotion. In contrast, the conditional knock-outs showed bilateral voluntary movements under conditions when single limb movements are normally produced and, as a basis for this aberrant control, developed a bilateral motor map in motor cortex that is driven by the aberrant ipsilateral CST misprojections. Therefore, a specific change in CST connectivity is associated with and explains a change in voluntary movement.

Motor Experience Reprograms Development of a Genetically-Altered Bilateral Corticospinal Motor Circuit

Evidence suggests that motor experience plays a role in shaping development of the corticospinal system and voluntary motor control, which is a key motor function of the system. Here we used a mouse model with conditional forebrain deletion of the gene for EphA4 (Emx1-Cre:EphA4tm2Kldr), which regulates development of the laterality of corticospinal tract (CST). We combined study of Emx1-Cre:EphA4tm2Kldr with unilateral forelimb constraint during development to expand our understanding of experience-dependent CST development from both basic and translational perspectives. This mouse develops dense ipsilateral CST projections, a bilateral motor cortex motor representation, and bilateral motor phenotypes. Together these phenotypes can be used as readouts of corticospinal system organization and function and the changes brought about by experience. The Emx1-Cre:EphA4tm2Kldr mouse shares features with the common developmental disorder cerebral palsy: bilateral voluntary motor impairments and bilateral CST miswiring. Emx1-Cre:EphA4tm2Kldr mice with typical motor experiences during development display the bilateral phenotype of “mirror” reaching, because of a strongly bilateral motor cortex motor representation and a bilateral CST. By contrast, Emx1-Cre:EphA4tm2Kldr mice that experienced unilateral forelimb constraint from P1 to P30 and tested at maturity had a more contralateral motor cortex motor representation in each hemisphere; more lateralized CST projections; and substantially more lateralized/independent reaching movements. Changes in CST organization and function in this model can be explained by reduced synaptic competition of the CST from the side without developmental forelimb motor experiences. Using this model we show that unilateral constraint largely abrogated the effects of the genetic mutation on CST projections and thus demonstrates how robust and persistent experience-dependent development can be for the establishment of corticospinal system connections and voluntary control. Further, our findings inform the mechanisms of and strategies for developing behavioral therapies to treat bilateral movement impairments and CST miswiring in cerebral palsy.

Corticospinal circuit plasticity in motor rehabilitation from spinal cord injury

Restoring corticospinal function after spinal cord injury is a significant challenge as the corticospinal tract elicits no substantive, spontaneous regeneration, and its interruption leaves a permanent deficit. The corticospinal circuit serves multiple motor and sensory functions within the mammalian nervous system as the direct link between isocortex and spinal cord. Maturation of the corticospinal circuit involves the refinement of projections within the spinal cord and a subsequent refinement of motor maps within the cortex. The plasticity of these cortical motor maps mirrors the acquisition of skilled motor learning, and both the maps and motor skills are disrupted following injury to the corticospinal tract. The motor cortex exhibits the capacity to incorporate changes in corticospinal projections induced by both spontaneous and therapeutic-mediated plasticity of corticospinal axons through appropriate rehabilitation. An understanding of the mechanisms of corticospinal plasticity in motor learning will undoubtedly help inform strategies to improve motor rehabilitation after spinal cord injury.

Postnatal training of 129/Sv mice confirms the long-term influence of early exercising on the motor properties of mice

A previous study showed that motor experiences during critical periods of development durably affect the motor properties of adult C57BL/6J mice. However, dependence on early environmental features may vary with the genetic profile. To evaluate the contribution of the genetic background on external influences to motricity, we performed the same experiment in a 129/Sv mouse strain that show a strongly different motor profile. Mice were subjected to endurance training (enriched environment or forced treadmill), hypergravity (chronic centrifugation), or simulated microgravity (hindlimb unloading) between postnatal days 10 and 30. They were then returned to standard housing until testing at the age of nine months. The endurance-trained mice showed a fast-slow shift in the deep zone of the tibialis. In addition, mice reared in the enriched environment showed a modified gait and body posture, and improved performance on the rotarod, whereas forced treadmill training did not affect motor output. Hypergravity induced a fast-slow shift in the superficial zone of the tibialis, with no consequence on motor output. Hindlimb unloading provoked an increased percentage of immature hybrid fibres in the tibialis and a shift in the soleus muscle. When compared with similarly reared C57BL/6J mice, 129/Sv mice showed qualitative differences attributable to the lower efficiency of early training due to their lower basal motor activity level. Nevertheless, the results are essentially consistent in both strains, and support the hypothesis that early motor experience influences the muscle phenotype and motor output.