Age-associated changes to neuronal dynamics involve a disruption of excitatory/inhibitory balance in C. elegans
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Evaluation Summary:
This study reports ageing associated decline in coordinated whole brain dynamics of the nematode C. elegans. It is interesting to a broad range of scientists studying neuronal circuit dynamics, the processes of ageing and neurodegenerative diseases. The work provides an impressive amount of whole brain imaging experiments and is the first single cell resolution whole brain imaging study in any organism that reports how whole brain dynamics change over the course of ageing.
(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. The reviewers remained anonymous to the authors.)
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Abstract
In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. Caenorhabditis elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies. In addition, we measure a specific loss of inhibitory signaling that occurs early in the aging process and alters the systems’ critical excitatory/inhibitory balance. These effects are recapitulated with mutation of the calcium channel subunit UNC-2/CaV2α. We find that manipulation of inhibitory GABA signaling can partially ameliorate or accelerate the effects of aging. The effects of aging are also partially mitigated by disruption of the insulin signaling pathway, known to increase longevity, or by a reduction of caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age that leads to breakdown in global neuronal dynamics and functional decline.
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Evaluation Summary:
This study reports ageing associated decline in coordinated whole brain dynamics of the nematode C. elegans. It is interesting to a broad range of scientists studying neuronal circuit dynamics, the processes of ageing and neurodegenerative diseases. The work provides an impressive amount of whole brain imaging experiments and is the first single cell resolution whole brain imaging study in any organism that reports how whole brain dynamics change over the course of ageing.
(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. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
In this manuscript, Birak and colleagues report single cell resolution whole brain imaging experiments in immobilized C. elegans at different ageing stages. It was shown previously that, under similar imaging conditions, animals exhibit brain-wide activity correlations and vigorous neuronal dynamics that evolve on a low dimensional manifold, visualised by principal components analyses (PCA). The transitions in network activity states were previously interpreted as motor command states, that correspond to forward-, backward- and turning- motor commands. The authors show that with increased ageing, the frequency of these transitions declines, the manifolds in PCA states appear less organized and specifically negative pair-wise correlations are reduced. They interpret this result as an ageing associated …
Reviewer #1 (Public Review):
In this manuscript, Birak and colleagues report single cell resolution whole brain imaging experiments in immobilized C. elegans at different ageing stages. It was shown previously that, under similar imaging conditions, animals exhibit brain-wide activity correlations and vigorous neuronal dynamics that evolve on a low dimensional manifold, visualised by principal components analyses (PCA). The transitions in network activity states were previously interpreted as motor command states, that correspond to forward-, backward- and turning- motor commands. The authors show that with increased ageing, the frequency of these transitions declines, the manifolds in PCA states appear less organized and specifically negative pair-wise correlations are reduced. They interpret this result as an ageing associated excitatory/inhibitory (E/I) imbalance caused by a decline in inhibitory signalling. They provide some experiments (imaging in unc-2 mutants, and in the presence of a GABAR agonist), the results of which are consistent with this interpretation.
The work provides an impressive amount of whole brain imaging experiments, and to the best of my knowledge is the first single cell resolution whole brain imaging study in any organism that reports how whole brain dynamics change over the course of ageing. The findings are therefore of broader interest. However, I think that the conclusions from their analyses results are premature and allow for alternative interpretations, which can be addressed with additional more detailed analyses. The genetic and pharmacological manipulations do not fully phenocopy or compensate the age associated changes in neuronal dynamics, therefore these results rather provide only indirect evidence for their conclusions, which could be more critically discussed.
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Reviewer #2 (Public Review):
The study in "Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in_C. elegans_" attempts a hard task: To quantify changes in brain dynamics during aging. They do so in the nematode _C. elegans_, which has the advantage of allowing `whole brain` imaging, i.e., imaging of a large number of neurons in the head ganglion of the worm. A major strength of the paper is its deep rooting in the literature which establishes the context for the study with respect to both aging studies in the nematode as well as from other species.
Using statistical analyses of the temporal neuronal dynamics, the authors find that the brain dynamics slow down with age and the balance between excitation and inhibition changes. Overall, the study manages to effectively combine genetics and neural imaging to …
Reviewer #2 (Public Review):
The study in "Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in_C. elegans_" attempts a hard task: To quantify changes in brain dynamics during aging. They do so in the nematode _C. elegans_, which has the advantage of allowing `whole brain` imaging, i.e., imaging of a large number of neurons in the head ganglion of the worm. A major strength of the paper is its deep rooting in the literature which establishes the context for the study with respect to both aging studies in the nematode as well as from other species.
Using statistical analyses of the temporal neuronal dynamics, the authors find that the brain dynamics slow down with age and the balance between excitation and inhibition changes. Overall, the study manages to effectively combine genetics and neural imaging to quantify changes in an aging brain. They convincingly demonstrate slowed dynamics as worms get older and suggest a role for the unc-2 /ced-4 pathway in changing the inhibitory connections.
Yet, these data are difficult to interpret: Brain dynamics are measured by imaging an encoded indicator GCaMP. The expression level of this indicator is also subject to age-dependent changes in expression level and possibly changes in the intracellular environment (e.g., pH). As much of the quantification is sensitive to the signal-to-noise ratio of the measured signals, this confounds the results. Similarly, some measures are sensitive to the inherent autocorrelation of the signal, and the slow-down in dynamics over age is possibly sufficient to effect the observed changes in all other metrics they use to compare between neural activity under different conditions.
The paper is interesting, in that it attempts to connect the dynamics and system organization of brain dynamics with a molecular mechanism that is active during aging. However, at this point the deeper interpretation of specific findings hinges on the metrics being independent of the measured signal, and this is not convincingly demonstrated.
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Reviewer #3 (Public Review):
Although whole brain activity imaging is recently available in C. elegans, it is still difficult to map each cell activity to known neuronal cell identity. Without cell ID information, we cannot interpret the activity data in the context of neuronal circuits or statistically discuss neuronal activities across multiple individuals. The present study provides an excellent representation of age-dependent changes in the whole brain activity by calculating three indices: angular change in PCA trajectory, power spectral densities, and neuron pair correlation, without cell identification. In addition, they found age-dependent changes in anticorrelated neuron pairs, while almost no change in positively correlated pairs was observed. Furthermore, by integrating genetic and pharmacological analyses, they showed that …
Reviewer #3 (Public Review):
Although whole brain activity imaging is recently available in C. elegans, it is still difficult to map each cell activity to known neuronal cell identity. Without cell ID information, we cannot interpret the activity data in the context of neuronal circuits or statistically discuss neuronal activities across multiple individuals. The present study provides an excellent representation of age-dependent changes in the whole brain activity by calculating three indices: angular change in PCA trajectory, power spectral densities, and neuron pair correlation, without cell identification. In addition, they found age-dependent changes in anticorrelated neuron pairs, while almost no change in positively correlated pairs was observed. Furthermore, by integrating genetic and pharmacological analyses, they showed that reduction of GABA signaling via the CaV2/caspase pathway may be the cause of the changes. Still, additional experiments are needed to show whether the observed whole brain activity changes are indeed controlled by these gene products.
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