Flexor Dysfunction Following Unilateral Transient Ischemic Brain Injury Is Associated with Impaired Locomotor Rhythmicity

Functional motor deficits in hemiplegia after stroke are predominately associated with flexor muscle impairments in animal models of ischemic brain injury, as well as in clinical findings. Rehabilitative interventions often employ various means of retraining a maladapted central pattern generator for locomotion. Yet, holistic modeling of the central pattern generator, as well as applications of such studies, are currently scarce. Most modeling studies rely on cellular neural models of the intrinsic spinal connectivity governing ipsilateral flexor-extensor, as well as contralateral coupling inherent in the spinal cord. Models that attempt to capture the general behavior of motor neuronal populations, as well as the different modes of driving their oscillatory function in vivo is lacking in contemporary literature. This study aims at generating a holistic model of flexor and extensor function as a whole, and seeks to evaluate the parametric coupling of ipsilateral and contralateral half-center coupling through the means of generating an ordinary differential equation representative of asymmetric central pattern generator models of varying coupling architectures. The results of this study suggest that the mathematical predictions of the locomotor centers which drive the dorsiflexion phase of locomotion are correlated with the denervation-type atrophy response of hemiparetic dorsiflexor muscles, as well as their spatiotemporal activity dysfunction during in vivo locomotion on a novel precise foot placement task. Moreover, the hemiplegic solutions were found to lie in proximity to an alternative task-space solution, by which a hemiplegic strategy could be readapted in order to produce healthy output. The results revealed that there are multiple strategies of retraining hemiplegic solutions of the CPG. This solution may modify the hemiparetic locomotor pattern into a healthy output by manipulating inter-integrator couplings which are not damaged by damage to the descending drives. Ultimately, some modeling experiments will demonstrate that the increased reliance on intrinsic connectivity increases the stability of the output, rendering it resistant to perturbations originating from extrinsic inputs to the pattern generating center

Asymmetric Walkway: A Novel Behavioral Assay for Studying Asymmetric Locomotion

Behavioral assays are commonly used for the assessment of sensorimotor impairment in the central nervous system (CNS). The most sophisticated methods for quantifying locomotor deficits in rodents is to measure minute disturbances of unconstrained gait overground (e.g., manual BBB score or automated CatWalk). However, cortical inputs are not required for the generation of basic locomotion produced by the spinal central pattern generator (CPG). Thus, unconstrained walking tasks test locomotor deficits due to motor cortical impairment only indirectly. In this study, we propose a novel, precise foot-placement locomotor task that evaluates cortical inputs to the spinal CPG. An instrumented peg-way was used to impose symmetrical and asymmetrical locomotor tasks mimicking lateralized movement deficits. We demonstrate that shifts from equidistant inter-stride lengths of 20% produce changes in the forelimb stance phase characteristics during locomotion with preferred stride length. Furthermore, we propose that the asymmetric walkway allows for measurements of behavioral outcomes produced by cortical control signals. These measures are relevant for the assessment of impairment after cortical damage

Piwil2 (Mili) sustains neurogenesis and prevents cellular senescence in the postnatal hippocampus

Adult neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate has thus important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) have been proposed to control memory and anxiety, but the mechanism remains elusive. Here, we show that Piwil2 (Mili) is essential for proper neurogenesis in the postnatal mouse hippocampus. RNA sequencing of aNPCs and their differentiated progeny reveal that Mili and piRNAs are dynamically expressed in neurogenesis. Depletion of Mili and piRNAs in the adult hippocampus impairs aNPC differentiation toward a neural fate, induces senescence, and generates reactive glia. Transcripts modulated upon Mili depletion bear sequences complementary or homologous to piRNAs and include repetitive elements and mRNAs encoding essential proteins for proper neurogenesis. Our results provide evidence of a critical role for Mili in maintaining fitness and proper fate of aNPCs, underpinning a possible involvement of the piRNA pathway in brain plasticity and successful aging

Piwil2 (Mili) sustains neurogenesis and prevents cellular senescence in the postnatal hippocampus

Adult neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate has thus important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) have been proposed to control memory and anxiety, but the mechanism remains elusive. Here, we show that Piwil2 (Mili) is essential for proper neurogenesis in the postnatal mouse hippocampus. RNA sequencing of aNPCs and their differentiated progeny reveal that Mili and piRNAs are dynamically expressed in neurogenesis. Depletion of Mili and piRNAs in the adult hippocampus impairs aNPC differentiation toward a neural fate, induces senescence, and generates reactive glia. Transcripts modulated upon Mili depletion bear sequences complementary or homologous to piRNAs and include repetitive elements and mRNAs encoding essential proteins for proper neurogenesis. Our results provide evidence of a critical role for Mili in maintaining fitness and proper fate of aNPCs, underpinning a possible involvement of the piRNA pathway in brain plasticity and successful aging