Jones, R. H. A. | Search bioRxiv

bioRxiv2025

A non-human primate model of Amyotrophic Lateral Sclerosis

Approximately 97% of patients with amyotrophic lateral sclerosis (ALS) have cytoplasmic mislocalization and aggregation of the ubiquitous nuclear protein, TDP-43. Current rodent models of this disease fail to replicate the progressive motor weakness and characteristic histopathology, possibly because of fundamental neuroanatomical and genetic differences between rodents and humans. In this study, the TDP-43 protein was overexpressed in the motor neuron pool of the brachioradialis muscle unilaterally in two six-year-old female rhesus macaques, using an intersectional genetics approach involving infection with genetically modified adeno-associated virus. Magnetic resonance images demonstrated delayed signal hyperintensities limited to the injected brachioradialis that persisted for 6-7 weeks, consistent with motor neuron degeneration and denervation of the targeted muscle. At post-mortem, the virus-mediated focal protein overexpression event was found to induce widespread deposits of pathological phosphorylated TDP-43 throughout the cervical spinal cord and motor cortex bilaterally, indicating an ALS-like spread of proteinopathy from the transfection site.

neuroscience↗

bioRxiv2021

Interfacing Spinal Motor Units in Non-Human Primates Identifies a Principal Neural Component for Force Control Constrained by the Size Principle

Motor units convert the last neural code of movement into muscle forces. The classic view of motor unit control is that the central nervous system sends common synaptic inputs to motoneuron pools and that motoneurons respond in an orderly fashion dictated by the size principle. This view however is in contrast with the large number of dimensions observed in motor cortex which may allow individual and flexible control of motor units. Evidence for flexible control of motor units may be obtained by tracking motor units longitudinally during the performance of tasks with some level of behavioural variability. Here we identified and tracked populations of motor units in the brachioradialis muscle of two macaque monkeys during ten sessions spanning over one month during high force isometric contractions with a broad range of rate of force development (1.8 - 38.6 N{middle dot}m{middle dot}s-1). During the same sessions we recorded intramuscular EMG signals from 16 arm muscles of both limbs and elicited the full recruitment through neural stimulation of the median and deep radial nerves. We found a very stable recruitment order and discharge characteristics of the motor units over sessions and contraction trials. The small deviations from orderly recruitment were observed between motor units with close recruitment thresholds, and only during high rate of force development. Moreover, we also found that one component explained more than ~50% of the motor unit discharge rate variance, and that the remaining components could be described as a time-shifted version of the first, as it could be predicted from the interplay between the size principle of recruitment and one common input. In conclusion, our results show that motoneurons recruitment is determined by the interplay of the size principle and common input and that this recruitment scheme is not violated over time nor by the speed of the contractions.

neuroscience↗