Editorial: Neuro-motor control and feed-forward models of locomotion in humans

“He told me with amusement that when one is walking rapidly each step takes no more than half a second, and in that half second no fewer than 54 muscles are set in motion. I listened in awe. I at once directed my attention to my legs and tried to discover the infernal machine. I thought I had succeeded in finding it. I could not of course distinguish all its 54 parts, but I discovered something terrifically complicated which seemed to get out of order the instant I began thinking about it.” Well-depicted by Svevo in “Confessions of Zeno” (Svevo, 1923, 1989), the act of walking involves many different muscles and the necessity of controlling several degrees of freedom at once. This Research Topic has mainly been focused on the strategies adopted by the central nervous system for reducing the complexity of motor control and compensating for the sensorimotor delays. The studies published within this Research Topic addressed this issue at two levels of investigation, focusing on one side the neural circuitry, such as the so called central pattern generators in the spinal cord and the supraspinal structures, and on the other one on the cognitive processes involved during locomotion

Pathogenic <i>NR2F1</i> variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Funder: National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of OphthalmologyPathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system

Mesenchymal Stem Cells in a Transgenic Mouse Model of Multiple System Atrophy: Immunomodulation and Neuroprotection

Mesenchymal stem cells (MSC) are currently strong candidates for cell-based therapies. They are well known for their differentiation potential and immunoregulatory properties and have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Currently there is no treatment that provides consistent long-term benefits for patients with multiple system atrophy (MSA), a fatal late onset α-synucleinopathy. Principally neuroprotective or regenerative strategies, including cell-based therapies, represent a powerful approach for treating MSA. In this study we investigated the efficacy of intravenously applied MSCs in terms of behavioural improvement, neuroprotection and modulation of neuroinflammation in the (PLP)-αsynuclein (αSYN) MSA model.MSCs were intravenously applied in aged (PLP)-αSYN transgenic mice. Behavioural analyses, defining fine motor coordination and balance capabilities as well as stride length analysis, were performed to measure behavioural outcome. Neuroprotection was assessed by quantifying TH neurons in the substantia nigra pars compacta (SNc). MSC treatment on neuroinflammation was analysed by cytokine measurements (IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, GM-CSF, INFγ, MCP-1, TGF-β1, TNF-α) in brain lysates together with immunohistochemistry for T-cells and microglia. Four weeks post MSC treatment we observed neuroprotection in the SNc, as well as downregulation of cytokines involved in neuroinflammation. However, there was no behavioural improvement after MSC application.To our knowledge this is the first experimental approach of MSC treatment in a transgenic MSA mouse model. Our data suggest that intravenously infused MSCs have a potent effect on immunomodulation and neuroprotection. Our data warrant further studies to elucidate the efficacy of systemically administered MSCs in transgenic MSA models

The interstitium in cardiac repair: role of the immune-stromal cell interplay

Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases

Muscle Synergies in Children Walking and Running on a Treadmill

Muscle synergies reflect the presence of a common neural input to multiple muscles. Steering small sets of synergies is commonly believed to simplify the control of complex motor tasks like walking and running. When these locomotor patterns emerge, it is likely that synergies emerge as well. We hence hypothesized that in children learning to run the number of accompanying synergies increases and that some of the synergies’ activities display a temporal shift related to a reduced stance phase as observed in adults. We investigated the development of locomotion in 23 children aged 2–9 years of age and compared them with seven young adults. Muscle activity of 15 bilateral leg, trunk, and arm muscles, ground reaction forces, and kinematics were recorded during comfortable treadmill walking and running, followed by a muscle synergy analysis. We found that toddlers (2–3.5 years) and preschoolers (3.5–6.5 years) utilize a “walk-run strategy” when learning to run: they managed the fastest speeds on the treadmill by combining double support (DS) and flight phases (FPs). In particular the activity duration of the medial gastrocnemius muscle was weakly correlated with age. The number of synergies across groups and conditions needed to cover sufficient data variation ranged between four and eight. The number of synergies tended to be smaller in toddlers than it did in preschoolers and school-age children but the adults had the lowest number for both conditions. Against our expectations, the age groups did not differ significantly in the timing or duration of synergies. We believe that the increase in the number of muscle synergies in older children relates to motor learning and exploration. The ability to run with a FP is clearly associated with an increase in the number of muscle synergies

Cortical contributions to locomotor primitives in toddlers and adults

The neural locomotor system strongly relies on spinal circuitries. Yet, the control of bipedal gait is accompanied by activity in motor cortex. In human gait control, the functional interaction between these cortical contributions and their spinal counterparts are largely elusive. We focused on four spinal activation patterns during walking and explored their cortical signatures in toddlers and adults. In both groups, cortico-spinal coherence analysis revealed activity in primary motor cortex to be closely related to two of the four spinal patterns. Their corresponding muscle synergies are known to develop around the onset of independent walking. By hypothesis, the cortex hence contributes to the emergence of these synergies. In contrast, the other two spinal patterns investigated here resembled those present during newborn stepping. As expected, they did not show any cortical involvement. Together, our findings suggest a crucial role of motor cortex for independent walking in humans