Silencing long-descending inter-enlargement propriospinal neurons improves hindlimb stepping after contusive spinal cord injuries
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eLife assessment
This is an important paper that evaluates the roles of long descending propriospinal neurons in the recovery of walking ability after spinal cord injury. The data are convincing overall though some weaknesses in the evaluation of the completeness of the synaptic silencing strategy were identified. The data will be of interest to those who study spinal circuitry and its role in locomotor function after spinal cord injury.
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Abstract
Spinal locomotor circuitry is comprised of rhythm generating centers, one for each limb, that are interconnected by local and long-distance propriospinal neurons thought to carry temporal information necessary for interlimb coordination and gait control. We showed previously that conditional silencing of the long ascending propriospinal neurons (LAPNs) that project from the lumbar to the cervical rhythmogenic centers (L1/L2 to C6), disrupts right-left alternation of both the forelimbs and hindlimbs without significantly disrupting other fundamental aspects of interlimb and speed-dependent coordination (Pocratsky et al., 2020). Subsequently, we showed that silencing the LAPNs after a moderate thoracic contusive spinal cord injury (SCI) resulted in better recovered locomotor function (Shepard et al., 2021). In this research advance, we focus on the descending equivalent to the LAPNs, the long descending propriospinal neurons (LDPNs) that have cell bodies at C6 and terminals at L2. We found that conditional silencing of the LDPNs in the intact adult rat resulted in a disrupted alternation of each limb pair (forelimbs and hindlimbs) and after a thoracic contusion SCI significantly improved locomotor function. These observations lead us to speculate that the LAPNs and LDPNs have similar roles in the exchange of temporal information between the cervical and lumbar rhythm generating centers, but that the partial disruption of the pathway after SCI limits the independent function of the lumbar circuitry. Silencing the LAPNs or LDPNs effectively permits or frees-up the lumbar circuitry to function independently.
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eLife assessment
This is an important paper that evaluates the roles of long descending propriospinal neurons in the recovery of walking ability after spinal cord injury. The data are convincing overall though some weaknesses in the evaluation of the completeness of the synaptic silencing strategy were identified. The data will be of interest to those who study spinal circuitry and its role in locomotor function after spinal cord injury.
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Reviewer #1 (Public Review):
This manuscript reports a series of studies that evaluate the role of long descending propriospinal neurons arising in the cervical spinal cord that project axons to the lumbar spinal cord in locomotor function recovery after spinal cord injury. The experiment uses several different evaluations of gait including BBB, ladder rung walk tests, and kinematics to compare walking before and after synaptic silencing of long descending propriospinal neurons projecting axons to L2. The data reveal that silencing of these neurons mildly improves walking function. The experiments are carefully described and well-controlled. The use of several different methods to evaluate locomotor function is a strength as is a well-thought-out approach to synaptic silencing. The data support the conclusions proposed by the authors. …
Reviewer #1 (Public Review):
This manuscript reports a series of studies that evaluate the role of long descending propriospinal neurons arising in the cervical spinal cord that project axons to the lumbar spinal cord in locomotor function recovery after spinal cord injury. The experiment uses several different evaluations of gait including BBB, ladder rung walk tests, and kinematics to compare walking before and after synaptic silencing of long descending propriospinal neurons projecting axons to L2. The data reveal that silencing of these neurons mildly improves walking function. The experiments are carefully described and well-controlled. The use of several different methods to evaluate locomotor function is a strength as is a well-thought-out approach to synaptic silencing. The data support the conclusions proposed by the authors. There are caveats to be considered in interpreting the results which are thoughtfully and thoroughly articulated in the discussion.
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Reviewer #2 (Public Review):
The manuscript by Shepard et al. expands on prior recent publications by the group which demonstrated that silencing long ascending propriospinal neurons (LAPNs) disrupts left-right coordination in certain contexts in uninjured rats but improves locomotion following thoracic contusion. Here, the same reversible silencing strategy is used but instead targeted to the long descending propriospinal neurons (LDPNs). Interlimb coordination and several other locomotor metrics are examined in both uninjured and SCI conditions. The effects of LDPN silencing were quite similar to those of LAPN silencing with a few notable differences. In intact rats, the deficits were observed following silencing on both high and low-friction surfaces. The effects are stronger during the second Dox administration than during the first …
Reviewer #2 (Public Review):
The manuscript by Shepard et al. expands on prior recent publications by the group which demonstrated that silencing long ascending propriospinal neurons (LAPNs) disrupts left-right coordination in certain contexts in uninjured rats but improves locomotion following thoracic contusion. Here, the same reversible silencing strategy is used but instead targeted to the long descending propriospinal neurons (LDPNs). Interlimb coordination and several other locomotor metrics are examined in both uninjured and SCI conditions. The effects of LDPN silencing were quite similar to those of LAPN silencing with a few notable differences. In intact rats, the deficits were observed following silencing on both high and low-friction surfaces. The effects are stronger during the second Dox administration than during the first in intact, and possibly the opposite after SCI. Also, the reversal of deficits by silencing after SCI was more modest.
The major strengths of the study are the methodology and research design employed. The reversible silencing of a specific population of neurons identified by the locations of their somata and terminals is powerful. This also allowed for comparisons of pre-/post-silencing in the same subject both in uninjured and SCI conditions. The primary shortcoming of the study is the lack of histological analysis to demonstrate the degree of loss and/or whether there is any selectivity or bias towards functional subclasses of neurons that are shown to be LDPNs, even at the level of ipsilateral/contralateral and transmitter phenotype.
The presented data support the major conclusions of the study. It is interesting that silencing the LDPNs or the LAPNs, disrupting communication in either direction, has similar effects and that these effects are predominantly related to cross-cord coordination at each girdle. Additionally, the long propriospinal neurons, LDPNs in particular, are thought to be potential targets for relays and adaptive plasticity after spinal cord injury. However, their silencing after SCI leads to locomotor improvements rather than exacerbated of dysfunction. Whether this is due to an imbalance of spared projection neurons, maladaptive plasticity/sprouting, or other mechanism is of interest for future studies targeting spared projections to enhance functional recovery.
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Reviewer #3 (Public Review):
This study aims at determining the contribution of propriospinal neurons projecting from cervical to lumbar segments to the coordination of inter-limb coordination. In addition, the impact of silencing these neurons on motor parameters affected by spinal cord injury was assessed. While the study contains many important data describing the contribution of these propriospinal neurons, there is little information about the underlying circuit mechanisms.
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