Spontaneous neural synchrony links intrinsic spinal sensory and motor networks during unconsciousness
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Curated by eLife
Evaluation Summary:
This manuscript reports a study that sought evidence of patterned inter-areal activity in the spinal cord of anesthetized rats. This could be a very significant finding, with potentially important scientific and therapeutic implications. However, the Methods lacks some necessary details, and the Results raise substantial issues that need to be resolved. Until these gaps and uncertainties are resolved, it is not possible to evaluate the results and their implications with confidence. Substantial revisions are essential.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
Non-random functional connectivity during unconsciousness is a defining feature of supraspinal networks. However, its generalizability to intrinsic spinal networks remains incompletely understood. Previously, Barry et al., 2014 used fMRI to reveal bilateral resting state functional connectivity within sensory-dominant and, separately, motor-dominant regions of the spinal cord. Here, we record spike trains from large populations of spinal interneurons in vivo in rats and demonstrate that spontaneous functional connectivity also links sensory- and motor-dominant regions during unconsciousness. The spatiotemporal patterns of connectivity could not be explained by latent afferent activity or by populations of interconnected neurons spiking randomly. We also document connection latencies compatible with mono- and disynaptic interactions and putative excitatory and inhibitory connections. The observed activity is consistent with the hypothesis that salient, experience-dependent patterns of neural transmission introduced during behavior or by injury/disease are reactivated during unconsciousness. Such a spinal replay mechanism could shape circuit-level connectivity and ultimately behavior.
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Reviewer #3 (Public Review):
In this paper McPherson and Bandres investigated temporal and regional features of spontaneous neural activity in the spinal cord of anesthetized unconscious rats from multi-unit electrophysiological recordings of neuronal activity in the lumbar spinal cord. Spontaneous temporally correlated neural activity in the mammalian central nervous system during unconsciousness is a feature of supraspinal circuits, and recent studies from resting-state fMRI in the spinal cord of non-human primate and in the human spinal cord indicate that spontaneous activity in the absence of sensory stimulus-evoked activity and spontaneous motor output is also a basic property of spinal cord circuits. Here the authors sought to provide more direct evidence of robust and temporally correlated spontaneous neuronal activity in the in …
Reviewer #3 (Public Review):
In this paper McPherson and Bandres investigated temporal and regional features of spontaneous neural activity in the spinal cord of anesthetized unconscious rats from multi-unit electrophysiological recordings of neuronal activity in the lumbar spinal cord. Spontaneous temporally correlated neural activity in the mammalian central nervous system during unconsciousness is a feature of supraspinal circuits, and recent studies from resting-state fMRI in the spinal cord of non-human primate and in the human spinal cord indicate that spontaneous activity in the absence of sensory stimulus-evoked activity and spontaneous motor output is also a basic property of spinal cord circuits. Here the authors sought to provide more direct evidence of robust and temporally correlated spontaneous neuronal activity in the in vivo mammalian spinal cord by applying correlation-based analyses of activity with single neuron resolution from multi-unit electrophysiological recordings simultaneously in several dorsal and ventral regions of a lumbar spinal cord segment. They successfully demonstrated robust spontaneous activity in these regions, and their correlation analyses of temporal features of this activity, to infer functional connectivity between spontaneously co-active neuronal units, suggests functional connectivity between sensory- and motor-dominant regions of the spinal cord, in addition to intraregional connectivity. This includes finding evidence for mono- and di-synaptic neuronal interactions as well as excitatory and some inhibitory interactions. Evidence is also presented that the spatiotemporal patterns of this spontaneous activity could not be explained theoretically by randomly spiking interconnected neurons, leading the authors to speculate that the spontaneous activity is intrinsic to the spinal cord and may reflect some type of replay of more structured experience-dependent patterns occurring during conscious behavior. The origins and functional significance of this temporally correlated spontaneous activity, however, remain to be determined.
Strengths of the paper include: (1) Clearly presented descriptions of the authors' procedures for recordings of multi-unit electrophysiological activity with a dual-shank 32 channel microelectrode array positioned at lateral and medial regions of the lumbar hemi-cord. (2) Novel reconstructions of functional connectivity maps, from correlation-based analyses, which enabled some topological features of the activity correlations to be represented from microelectrode array geometry and location within the rat spinal cord. (3) Novel results at the single neuron level potentially indicating spontaneous functional connectivity between sensory and motor regions in the unconscious animal. (4) Appropriate discussion of important caveats associated with technical aspects of their correlation analyses including problems for inferring functional connectivity in the presence of polysynaptic connection pathways and shared synaptic inputs as well as limitations of detecting inhibitory connections via correlation-based approaches. (5) Insightful discussion of possible functions of persistent spontaneous connectivity during unconsciousness in the spinal cord including latent activity in spinal central pattern generators or ongoing activity of circuits involved in maintenance/regulation of physiological processes under anesthesia.
Weaknesses of the experimental approach and for potential functional interpretations include (1) the need for more elaboration of technical details about how the temporal correlations of neuronal activity was performed, and (2) electrophysiological measurements were confined to a single lumbar spinal segment, so that origins of the spontaneous activity including interactions between spinal and supraspinal regions, interactions between various spinal segments, and contributions of sensory afferent feedback despite anesthesia, could not be established. While attributing the patterns of spontaneous activity found to reflect intrinsic spinal circuit activity, the authors did not fully explore possible contributions of sensory afferent feedback, for example, by employing local deafferentation.
The results presented in general suggest spontaneous temporally correlated neural activity in the spinal cord during unconsciousness, consistent with the concept that such activity may be a general property of central nervous system circuits.
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Reviewer #2 (Public Review):
This manuscript reports a study that sought evidence of patterned inter-areal activity in the spinal cord of anesthetized rats. This could be a very significant finding, with potentially important scientific and therapeutic implications. However, the Methods lack necessary details, and the Results raise substantial issues that need to be resolved. Until these gaps and uncertainties are resolved, it is not possible to evaluate the results and their implications with confidence. Substantial revisions are essential.
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Reviewer #1 (Public Review):
This report investigates spontaneous neural activity in the spinal cord of healthy adult male Sprague-Dawley rats under anesthesia. Urethane or isoflurane were used, and the effects were compared.
This manuscript is presented as a research advance that builds upon a 2014 eLife publication. It aims to address unresolved questions regarding the nature of spontaneous neural activity in the cord that give rise to observed resting state spinal cord networks in humans (and other species).
The similarity of results across anesthetic agents is important and I agree with the authors' conclusion that this provides strong evidence for persistent synchronous discharges between spinal cord regions during unconsciousness.
Finally, the authors do an appropriate job of describing the weaknesses of the study and how future …
Reviewer #1 (Public Review):
This report investigates spontaneous neural activity in the spinal cord of healthy adult male Sprague-Dawley rats under anesthesia. Urethane or isoflurane were used, and the effects were compared.
This manuscript is presented as a research advance that builds upon a 2014 eLife publication. It aims to address unresolved questions regarding the nature of spontaneous neural activity in the cord that give rise to observed resting state spinal cord networks in humans (and other species).
The similarity of results across anesthetic agents is important and I agree with the authors' conclusion that this provides strong evidence for persistent synchronous discharges between spinal cord regions during unconsciousness.
Finally, the authors do an appropriate job of describing the weaknesses of the study and how future experiments may continue this line of investigation.
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Evaluation Summary:
This manuscript reports a study that sought evidence of patterned inter-areal activity in the spinal cord of anesthetized rats. This could be a very significant finding, with potentially important scientific and therapeutic implications. However, the Methods lacks some necessary details, and the Results raise substantial issues that need to be resolved. Until these gaps and uncertainties are resolved, it is not possible to evaluate the results and their implications with confidence. Substantial revisions are essential.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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