Krysciak, K. | bioRxiv Science

bioRxiv2024

Anodal tsDCS restores the structure and function of the disrupted proprioceptive Ia synapses on spinal motoneurons in the SOD1 G93A mouse model of ALS

An imbalance between cells intrinsic excitability and synaptic excitation levels is the basis of spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a restoration of the deficient Ia synaptic excitation of spinal MNs was achieved by applying acute trans-spinal direct current stimulation (tsDCS) to presymptomatic SOD1 G93A mice. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 animals can provoke spinal MN neuroplasticity and reduce the disease burden. Anodal, cathodal or sham polarisation of 100 {micro}A was applied to P30-P35 SOD1 G93A mice; passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of polarized animals was used to test the impact of our intervention on Ia synapse morphology, MN intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs, coupled with a significant upregulation of vesicular glutamate transporter levels and GlurR4 subunits of AMPA receptors at the Ia synapse. On the other hand, cathodal polarisation failed to induce any significant alteration to Ia synapse morphology but did increase both peak and plateau input resistance and recovered the abnormal paired-pulse ratio. Unexpectedly, the changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular pathways ctivity and did not decrease the disease burden. Altogether our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which nevertheless appears insufficient to alter disease dynamics. HighlightsO_LI14-days of trans-spinal direct current stimulation (tsDCS) alters the electrophysiological properties and morphology of Ia proprioceptive synapses on spinal MNs in SOD1 G93A mouse model of ALS C_LIO_LIAnodal (depolarising) tsDCS increases MN synaptic excitation and restores the postsynaptic elements of the Ia synapse C_LIO_LICathodal (hyperpolarising) tsDCS increases MN input resistance but does not impact Ia synapse morphology C_LIO_LIBoth anodal and cathodal tsDCS fail to significantly modify the cellular burden of the disease C_LI

neuroscience↗

bioRxiv2020

Effect of synchronization of firings of different motor unit types on the force variability in a model of the rat medial gastrocnemius muscle

Oscillations of muscle force, observed as physiological tremors, rely upon the synchronized firings of active motor units (MUs). This study aimed to investigate the effects of synchronizing the firings of three types of MUs on force development using a mathematical model of the rat medial gastrocnemius muscle. The model was designed based on the actual proportion and physiological properties of MUs and motoneurons innervating the muscle. The isometric muscle and MU forces were simulated by a model predicting non-synchronized firing of a pool of 57 MUs (including eight slow, 23 fast resistant to fatigue, and 26 fast fatigable) to ascertain a maximum excitatory signal when all MUs were recruited into the contraction. The mean firing frequency of each MU depended upon the twitch contraction time, whereas the recruitment order was determined according to increasing forces (the size principle). The synchronization of firings of individual MUs was simulated using four different modes and inducing the synchronization of firings within three time windows ({+/-} 2, {+/-} 4, and {+/-} 6 ms) for four different combinations of MUs. The synchronization was estimated using two parameters, the correlation coefficient and the cross-interval synchronization index. The four scenarios of synchronization increased the values of the root-mean-square, range, and maximum force in correlation with the increase of the time window. Greater synchronization index values resulted in higher root-mean-square, range, and maximum of force outcomes for all MU types as well as for the whole muscle output; however, the mean spectral frequency of the forces decreased, whereas the mean force remained nearly unchanged. The range of variability and the root-mean-square of forces were higher for fast MUs than for slow MUs; meanwhile, the relative values of these parameters were highest for slow MUs, indicating their important contribution to muscle tremor, especially during weak contractions. Author summaryThe synchronization of firings of motor units (MUs), the smallest functional elements of skeletal muscle increases fluctuations in muscle force, known as physiological tremor, which can disturb high-precision movements. In this study, we adopted a recently proposed muscle model consisting of MUs of three different types (fast fatigable, fast resistant to fatigue, and slow) to study four different scenarios of MU synchronization during a steady level of excitatory input to motoneurons. The discharge patterns were synchronized between pairs of MUs by shifting in time individual pulses, which occurred within a short time interval, and a degree of synchronization was then estimated. The increased synchronization index resulted in increased force variability for all MU types as well as for the whole muscle output; however, the mean force levels remained nearly unchanged, whereas the frequencies of the force oscillations were decreased. The absolute range of force variability was higher for fast than for slow MUs, indicating their dominant influence on muscle tremor at strong contractions, but the highest relative increase in force variability was observed for synchronized slow MUs, indicating their significant contribution to tremor during weak contractions, in which only slow MUs are active.

bioinformatics↗