Abstract:Elaborate behaviours are produced by tightly controlled flexor-extensor motor neuron activation patterns. Motor neurons are regulated by a network of interneurons within the spinal cord, but the computational processes involved in motor control are not fully understood. The neuroanatomical arrangement of motor and premotor neurons into topographic patterns related to their controlled muscles is thought to facilitate how information is processed by spinal circuits. Rabies retrograde monosynaptic tracing has bee… Show more
“…In the best animal we recovered 51 transsynaptically labeled interneurons with no evidence of degenerative phenotypes. These cells were found at the same locations, and in similar proportions as was reported by other groups using injections in younger animals where more cells were labeled (Stepien et al, 2010; Tripodi et al, 2011; Ronzano et al, 2022). The interneuron sample included cells in the Renshaw area (n=6 or 11.8%), LVII (15, 29.4%), dorsal horn medial LV (7, 13.7%), dorsal horn LI to LIV (20, 39.2%), and the contralateral spinal cord (3, 5.9%: 1 in LX and 2 in LVIII).…”
Spinal cord interneurons play a crucial role in shaping motor output, but their precise identity and circuit connectivity remain unclear. Focusing on the cardinal class of inhibitory V1 interneurons, we define the diversity of four major V1 subsets according to timing of neurogenesis, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdating delineates two early-born (Renshaw and Pou6f2) and two late-born V1 clades (Foxp2 and Sp8) suggesting sequential neurogenesis gives rise to different V1 clades. Neurogenesis did not correlate with motoneuron targeting. Early-born Renshaw cells and late-born Foxp2-V1 interneurons both tightly coupled to motoneurons, while early-born Pou6f2-V1 and late-born Sp8-V1 interneurons did not. V1-clades also greatly differ in cell numbers and diversity. Lineage labeling of the Foxp2-V1 clade shows it contains over half of all V1 interneurons and provides the largest inhibitory input to motoneuron cell bodies. Foxp2-V1 subgroups differ in neurogenesis and proprioceptive input. Notably, one subgroup defined by Otp expression and located adjacent to the lateral motor column exhibits substantial input from proprioceptors, consistent with some Foxp2-V1 cells at this location forming part of reciprocal inhibitory pathways. This was confirmed with viral tracing methods for ankle flexors and extensors. The results validate the previous V1 clade classification as representing unique interneuron subtypes that differ in circuit placement with Foxp2-V1s forming the more complex subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for the ontogenetic and phylogenetic origins of their diversity.SIGNIFICANCE STATEMENTSpinal interneuron diversity and circuit organization represents a key challenge to understand the neural control of movement in normal adults and also during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits, acting on motoneurons either directly or via premotor networks. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion and this is reflected in the size and heterogeneity of the Foxp2-V1 clade which is closely associated to limb motor pools. We show Foxp2-V1 interneurons establish the densest and more direct inhibitory synaptic input to motoneurons, especially on cell bodies. This is of further importance because deficits on motoneuron cell body inhibitory V1 synapses and on Foxp2-V1 interneurons themselves have recently been shown to be affected at early stages of pathology in motor neurodegenerative diseases like amyotrophic lateral sclerosis.
“…In the best animal we recovered 51 transsynaptically labeled interneurons with no evidence of degenerative phenotypes. These cells were found at the same locations, and in similar proportions as was reported by other groups using injections in younger animals where more cells were labeled (Stepien et al, 2010; Tripodi et al, 2011; Ronzano et al, 2022). The interneuron sample included cells in the Renshaw area (n=6 or 11.8%), LVII (15, 29.4%), dorsal horn medial LV (7, 13.7%), dorsal horn LI to LIV (20, 39.2%), and the contralateral spinal cord (3, 5.9%: 1 in LX and 2 in LVIII).…”
Spinal cord interneurons play a crucial role in shaping motor output, but their precise identity and circuit connectivity remain unclear. Focusing on the cardinal class of inhibitory V1 interneurons, we define the diversity of four major V1 subsets according to timing of neurogenesis, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdating delineates two early-born (Renshaw and Pou6f2) and two late-born V1 clades (Foxp2 and Sp8) suggesting sequential neurogenesis gives rise to different V1 clades. Neurogenesis did not correlate with motoneuron targeting. Early-born Renshaw cells and late-born Foxp2-V1 interneurons both tightly coupled to motoneurons, while early-born Pou6f2-V1 and late-born Sp8-V1 interneurons did not. V1-clades also greatly differ in cell numbers and diversity. Lineage labeling of the Foxp2-V1 clade shows it contains over half of all V1 interneurons and provides the largest inhibitory input to motoneuron cell bodies. Foxp2-V1 subgroups differ in neurogenesis and proprioceptive input. Notably, one subgroup defined by Otp expression and located adjacent to the lateral motor column exhibits substantial input from proprioceptors, consistent with some Foxp2-V1 cells at this location forming part of reciprocal inhibitory pathways. This was confirmed with viral tracing methods for ankle flexors and extensors. The results validate the previous V1 clade classification as representing unique interneuron subtypes that differ in circuit placement with Foxp2-V1s forming the more complex subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for the ontogenetic and phylogenetic origins of their diversity.SIGNIFICANCE STATEMENTSpinal interneuron diversity and circuit organization represents a key challenge to understand the neural control of movement in normal adults and also during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits, acting on motoneurons either directly or via premotor networks. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion and this is reflected in the size and heterogeneity of the Foxp2-V1 clade which is closely associated to limb motor pools. We show Foxp2-V1 interneurons establish the densest and more direct inhibitory synaptic input to motoneurons, especially on cell bodies. This is of further importance because deficits on motoneuron cell body inhibitory V1 synapses and on Foxp2-V1 interneurons themselves have recently been shown to be affected at early stages of pathology in motor neurodegenerative diseases like amyotrophic lateral sclerosis.
“…Thus we do not consider stretch reflex signals from II afferents, or tendon tension signals from Golgi tendon organs [37, 38]. Another key limitation is that our spinal circuit is simplified in the extreme and does not consider the divergent and convergent branching of Ia, Ib and II afferent signals to multiple homonymous and heteronymous interneuronal pathways within and across muscles and limbs, where monosynaptic inputs to even antagonist motor neuron pools are largely overlapping [37, 80, 81], and even the α, β, γ classification of MNs is evolving [82]. Future work is needed to further our investigations of the fusimotor system.…”
The primary motor cortex does not uniquely or directly produceα-MN drive to muscles during voluntary movement. Rather,α-MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input is velocity-dependent stretch reflexes in lengthening (antagonist) muscles, which are thought to be inhibited by the shortening (agonist) muscles. It remains an open question, however, the extent to which velocity-dependent stretch reflexes disrupt voluntary movement, and whether and how they are inhibited in limbs with numerous mono- and multi-articular muscles where agonist and antagonist roles become unclear and can switch during a movement. We used a computational model of aRhesus Macaquearm to simulate movements with feedforwardα-MN commands only, and with added velocity-dependent stretch reflex feedback. We found that velocity-dependent stretch reflex caused movement-specific, typically large and variable disruptions to the arm endpoint trajectories. In contrast, these disruptions became small when the velocity-dependent stretch reflexes were simply scaled by theα-MN drive to each muscle (equivalent to anα-MN excitatory collateral to its homologousγ-MNs, but distinct fromα − γco-activation). We argue this circuitry is more neuroanatomically tenable, generalizable, and scalable thanα − γco-activation or movement-specific reciprocal inhibition. We propose that this mechanism at the homologous propriospinal level, by locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb, could be a critical low-level enabler of learning, adaptation, and performance via cerebellar and cortical mechanisms.SignificanceThe problem of muscle afferentation has long been an unsolved problem, and a foundation of voluntary motor control. How unmodulated velocity-dependent stretch reflexes disrupt voluntary movement and how they should be inhibited in limbs with numerous mono- and multi-articular muscles remain unclear. Here we demonstrate the cost of unregulated velocity-dependent reflexes, and propose a low-level propriospinal mechanism that can regularize these errors and enables motor learning and performance. Our results suggest that this spinal level mechanism of scaling dynamicγ-MN by the homologousα-MN collateral provides a generalizable mechanism that could be a low-level enabler of accurate and predictable movements that locally stabilizes and complements the synthesis and competition among cortical, subcortical or propriospinal projections toα-MN pools
“…Although it is tempting to infer that correlated discharge rates reflect a command signal transmitted by descending pathways, earlier studies on motor unit synchronization emphasized the significant role of premotor interneurons in contributing to the correlated discharge times of motor units (Datta et al, 1991;Nordstrom et al, 1992). The interneurons that synapse onto motor neurons have divergent projections to motor neuron pools throughout the spinal cord, including those that innervate synergist and antagonist muscles (Ronzano et al, 2021(Ronzano et al, , 2022. These spinal premotor interneurons are presumed to coordinate activity across multiple pools of motor neurons, which may contribute to the correlated discharge rates of motor units in different muscles (Lemay et al, 2001;Mussa-Ivaldi et al, 1994;Puskár & Antal, 1997;Salmas & Cheung, 2023).…”
The purpose of our study was to investigate the influence of a stretch intervention on the common modulation of discharge rate among motor units in the calf muscles during a submaximal isometric contraction. The current report comprises a computational analysis of a motor unit dataset that we published previously (Mazzo et al., 2021). Motor unit activity was recorded from the three main plantar flexor muscles while participants performed an isometric contraction at 10% of the maximal voluntary contraction force before and after each of two interventions. The interventions were a control task (standing balance) and static stretching of the plantar flexor muscles. A factorization analysis on the smoothed discharge rates of the motor units from all three muscles yielded three modes that were independent of the individual muscles. The composition of the modes was not changed by the standing‐balance task, whereas the stretching exercise reduced the average correlation in the second mode and increased it in the third mode. A centroid analysis on the correlation values showed that most motor units were associated with two or three modes, which were presumed to indicate shared synaptic inputs. The percentage of motor units adjacent to the seven centroids changed after both interventions: Control intervention, mode 1 decreased and the shared mode 1 + 2 increased; stretch intervention, shared modes either decreased (1 + 2) or increased (1 + 3). These findings indicate that the neuromuscular adjustments during both interventions were sufficient to change the motor unit modes when the same task was performed after each intervention.
imageKey points
Based on covariation of the discharge rates of motor units in the calf muscles during a submaximal isometric contraction, factor analysis was used to assign the correlated discharge trains to three motor unit modes.
The motor unit modes were determined from the combined set of all identified motor units across the three muscles before and after each participant performed a control and a stretch intervention.
The composition of the motor unit modes changed after the stretching exercise, but not after the control task (standing balance).
A centroid analysis on the distribution of correlation values found that most motor units were associated with a shared centroid and this distribution, presumably reflecting shared synaptic input, changed after both interventions.
Our results demonstrate how the distribution of multiple common synaptic inputs to the motor neurons innervating the plantar flexor muscles changes after a brief series of stretches.
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