Centripetal integration of past events in hippocampal astrocytes regulated by locus coeruleus
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Abstract
An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, in contrast, has been described as mostly uncoordinated across cellular compartments without clear central integration. Here we report conditional integration of calcium signals in astrocytic distal processes at their soma. In the hippocampus of adult mice of both sexes, we found that global astrocytic activity, as recorded with population calcium imaging, reflected past neuronal and behavioral events on a timescale of seconds. Salient past events, indicated by pupil dilations, facilitated the propagation of calcium signals from distal processes to the soma. Centripetal propagation to the soma was reproduced by optogenetic activation of the locus coeruleus, a key regulator of arousal, and reduced by pharmacological inhibition of α1-adrenergic receptors. Together, our results suggest that astrocytes are computational units of the brain that slowly and conditionally integrate calcium signals upon behaviorally relevant events.
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Thanks for looking so carefully through the supplementary material! :-) The fluorescence is definitely detectable in these regions, but the structures in these regions can not be resolved by our microscopes. We could have made the ROIs of course a bit larger, but the question would be when to stop. Keeping the ROIs sufficiently small ensured that we don't mix too much neighboring astrocytes together. After all, with these ROIs, we mainly wanted to quantify the correlation of activity traces extracted from separate astrocytes. You also mention the "tiling of the field-of-view". In theory, astrocytes do indeed form nice tiles of the entire volume. However, at least from my experience in hippocampus, this tiling is often a bit messy and not very intuitive in a 2D plane. Especially around blood vessels, the tile structure seems to be quite …
Thanks for looking so carefully through the supplementary material! :-) The fluorescence is definitely detectable in these regions, but the structures in these regions can not be resolved by our microscopes. We could have made the ROIs of course a bit larger, but the question would be when to stop. Keeping the ROIs sufficiently small ensured that we don't mix too much neighboring astrocytes together. After all, with these ROIs, we mainly wanted to quantify the correlation of activity traces extracted from separate astrocytes. You also mention the "tiling of the field-of-view". In theory, astrocytes do indeed form nice tiles of the entire volume. However, at least from my experience in hippocampus, this tiling is often a bit messy and not very intuitive in a 2D plane. Especially around blood vessels, the tile structure seems to be quite messed up, and tiling every based on a simple space-filling segmentation would seem quite ill-fated to me. This said, I agree that the manual ROIs that we drew could be improved by other approaches. That's also why we used the unbiased approached based on the activity patterns of single pixels (Fig. 5ff).
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Good point! "Centripetal propagation" is the purely descriptive term. "Centripetal integration" is a term that we use for two reasons: First, it covers our observation that astrocytic activity can be described as temporal integration of past events; the physical shape that this temporal integration takes is the centtripetal propagation. Second, I was personally inspired by the idea of neurons integrating the voltage signals from dendrites into their soma; this analogy was the second reason why we thought that "centripetal integration" might be a good term to describe our finding.
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I'm not an expert for ex vivo work on astrocytes, so I can only speculate. What I know for sure is that astrocytes are quite sensitive, and it could be that they become more "reactive" when they find themselves cut into slices, and therefore behave differently. Astrocytes ex vivo don't receive neuromodulation (as under anesthesia, see our Figure 8a-d), so we don't expect any systematic centripetal propagation. I know also from one of our co-authors (Denise Becker) who performed calcium imaging in astrocytes in vivo as well as in slices, that from her experience astrocytes in slices were always dead silent - similar to astrocytes under anesthesia. Altogether, I believe that the calcium events ex vivo propagating both toward and away from the soma are rare events that occur in parallel to the centripetal events we described in our …
I'm not an expert for ex vivo work on astrocytes, so I can only speculate. What I know for sure is that astrocytes are quite sensitive, and it could be that they become more "reactive" when they find themselves cut into slices, and therefore behave differently. Astrocytes ex vivo don't receive neuromodulation (as under anesthesia, see our Figure 8a-d), so we don't expect any systematic centripetal propagation. I know also from one of our co-authors (Denise Becker) who performed calcium imaging in astrocytes in vivo as well as in slices, that from her experience astrocytes in slices were always dead silent - similar to astrocytes under anesthesia. Altogether, I believe that the calcium events ex vivo propagating both toward and away from the soma are rare events that occur in parallel to the centripetal events we described in our manuscript. In line with that, I have also seen quite rare calcium events that lighted up single astrocytes; I have also seen such events under anesthesia. The main difference is that they were not "global" in the sense that other astrocytes did not respond at the same time. I believe that the three events highlighted with white arrows in Fig. 1f are such events.
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Yes, we were also discussing a lot where to define "global" in the paper and how to make clear that this is not "brain-wide" and not "global within a single astrocyte". It's easy to get confused. But in the case that you mentioned, you are definitely correct. We should in this case, when we refer to this review, better not use the word "global". We will correct this in the future - thanks!
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Thank you. Word was hiding the second part of the sentence behind the figure. It should spell out "These findings are consistent with direct observations from behavioral monitoring that mouth-only movements did not reliably evoke astrocytic responses (Movie 4)".
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Hi Kira, Sorry for the late reply - I did not see your comments until now. I also think there are parallels to some of your findings (Reitman et al., 2023). (Due to the limit for the number of references, we did not cite it along with the current reference 18, and we're expecting that we will have to further cut down references for the final version ...). I think that most of the things that we described in our study might be pretty similar across hippocampus and neocortex. We now also cite one study which replicated our findings of centripetal propagation in cortex (Fedotova et al., 2023). There may be difference in terms of neuromodulation and the action of locus coeruleus vs. acetylcholine (to be investigated). But since both neuromodulators act upon pupil diameter, I would expect very similar findings in cortex and hippocampus.
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Therefore, the propagationof activity from distal processes to the central somadominated the average delay maps but occurred inthe presence of other processes that were averagedout in our analysis.
In ex vivo (acute slice) astrocyte calcium imaging work, several groups have reported astrocyte calcium events that propagate both toward and away from the soma. How do you square that with these findings? Do you think that those may be smaller events that are less detectable in vivo, with more light-scattering, etc? How do you think they may be involved in the integration described here?
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entripetalintegration
I'm curious to know whether "propagation" and "integration" are interchangeable here, or differently defined.
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Therefore, ourobservations support the existing evidence fromother brain areas that increased global astrocyticactivity is triggered by arousal and mediated bynoradrenergic neuromodulation13;
I've interpreted the word "global" to mean "within the recorded astrocytes" in the paper. But here, where you cite a review that includes astrocyte calcium dynamics from other brain regions that differ in some cases, and potentially other definitions of the word "global", it feels slightly misleading.
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These findings are consistent with direct.CC-BY-NC 4.0 International licenseavailable under a(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
I think there may be accidental problems with this sentence as it transitions from page 4–5, because I don't understand the meaning.
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Interestingly, we found that pupil diameterdisplayed the highest correlation with the globalastrocytic signal,
This is exciting because it's very similar to our finding of high correlation between pupil diameter and astrocyte calcium in cortex (Reitman et al, 2023). I'm also interested in whether you think there are differences in this relationship in hippocampus vs cortex.
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ROIs were selected based on mean fluorescence(structural label, top row) and a map of local correlations (functional label, bottom row
I'm interested in how the ROIs don't seem to encompass the outer regions of the astrocyte branches, and thus don't tile the field-of-view. Is that because the fluorescence isn't detectable in these regions?
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