Author response:
The following is the authors’ response to the original reviews.
Reviewer #1 (Public Review):
Overall, the manuscript is very well written, the approaches used are clever, and the data were thoroughly analyzed. The study conveyed important information for understanding the circuit mechanism that shapes grid cell activity. It is important not only for the field of MEC and grid cells, but also for broader fields of continuous attractor networks and neural circuits.
We appreciate the positive comments.
(1) The study largely relies on the fact that ramp-like wide-field optogenetic stimulation and focal optogenetic activation both drove asynchronous action potentials in SCs, and therefore, if a pair of PV+ INs exhibited correlated activity, they should receive common inputs. However, it is unclear what criteria/thresholds were used to determine the level of activity asynchronization, and under these criteria, what percentage of cells actually showed synchronized or less asynchronized activity. A notable percentage of synchronized or less asynchronized SCs could complicate the results, i.e., PV+ INs with correlated activity could receive inputs from different SCs (different inputs), which had synchronized activity. More detailed information/statistics about the asynchronization of SC activity is necessary for interpreting the results.
The short answer here is that spiking responses from the pairs of SCs that we sampled appear asynchronous. We now show this in the form of cross-correlograms for all recorded pairs of SCs (Figure 2, Figure Supplement 1). The correlograms lack peaks that would indicate synchronous activation. Thus, while our dataset is not large enough to rule out occasional direct synchronisation of SCs, this appears unlikely to account for synchronised input to PV+INs.
This conclusion is consistent with consideration of mechanisms that could in principle synchronise SCs:
First, if responses to ramping light inputs was fully deterministic, then this could lead to fixed relative timing of spikes fired by different SCs. This is unlikely given the influence of stochastic channel gating on SC spiking (Dudman and Nolan 2009) and is inconsistent with trial to trial variability in spike timing (Figure 2, Figure Supplement 2).
Second, as SCs are glutamatergic they could excite one another. However, excitatory connections between stellate cells are rare (Pastoll et al. 2013; Couey et al. 2013; Fuchs et al. 2016) and when detected they have low amplitude (mean < 0.25 mV; (Winterer et al. 2017)). Our finding that spiking by pairs of SCs is not correlated is consistent with this.
Third, strong interaction between stellate cells mediated by local inhibitory pathways (Pastoll et al. 2013; Couey et al. 2013) could coordinate their activity. The lack of correlation between spiking of pairs of SCs suggests that such coordination is rarely recruited by our ramping protocols. Nevertheless, recruitment of inhibition may happen to some extent as experiments in Figure 4 show that correlated input from SCs to more distant, but not nearby PV+INs, is reduced by blocking inhibitory synapses. Given that we don't find evidence for synchronised spiking of SCs, this additional common input to widely separated PV+INs is instead best explained by recruitment of interneurons that act directly on the target SCs. We have modified Figure 8 to make this clear.
Thus, for experiments with ramping light stimuli, synchronous activation of SCs is unlikely to explain common input to PV+INs. Input from the same SC best explains correlated responses of nearby PV+IN inhibitory populations, while recruitment of an additional inhibitory pathway may contribute to correlated responses of more distant PV+INs.
For experiment using focal stimulation, substantial trial-to-trial variation in SC spike timing argues strongly against deterministic coordination. Indirect coordination of presynaptic neurons is also extremely unlikely given that focal activation is sparse and brief, while inputs from many presynaptic SCs are required to drive a postsynaptic interneuron to spike (e.g. (Pastoll et al. 2013; Couey et al. 2013)). Results from these experiments thus corroborate results from experiments using ramping light stimulation.
In revising the manuscript we have tried to ensure these arguments are clear (e.g. p 5, para 3; p 6, para 2; p 10, para 1).
(2) The hypothesis about the "direct excitatory-inhibitory" synaptic interactions is made based on the GABAzine experiments in Figure 4. In the Figure 8 diagram, the direct interaction is illustrated between PV+ INs and SCs. However, the evidence supporting this "direct interaction" between these two cell types is missing. Is it possible that pyramidal cells are also involved in this interaction? Some pieces of evidence or discussions are necessary to further support the "direction interaction".
Indirect connections between stellate cells mediated via fast spiking inhibitory interneurons are well established by previous studies (e.g. (Pastoll et al. 2013; Couey et al. 2013; Fuchs et al. 2016), and so were not addressed here. Previous work also establishes that connections from stellate cells to pyramidal cells are extremely rare (Winterer et al. 2017). Because the Sim1:Cre mouse line is specific to stellate cells and does not drive transgene expression in pyramidal cells (Sürmeli et al. 2015), it's therefore unlikely that pyramidal cells play a role.
To make these points clearer we have modified the text in the discussion (p 5, para 3; p 10, paras 1 & 2). We have also modified Figure 8 to highlight that the indirect interaction may be best accounted for by inhibitory pathways onto PV+INs rather than via SCs (which our new cross-correlation analyses indicate is unlikely).
Reviewer #2 (Public Review):
In this study, Huang et al. employed optogenetic stimulation alongside paired whole-cell recordings in genetically defined neuron populations of the medial entorhinal cortex to examine the spatial distribution of synaptic inputs and the functional-anatomical structure of the MEC. They specifically studied the spatial distribution of synaptic inputs from parvalbumin-expressing interneurons to pairs of excitatory stellate cells. Additionally, they explored the spatial distribution of synaptic inputs to pairs of PV INs. Their results indicate that both pairs of SCs and PV INs generally receive common input when their relative somata are within 200-300 ums of each other. The research is intriguing, with controlled and systematic methodologies. There are interesting takeaways based on the implications of this work to grid cell network organization in MEC.
We appreciate the positive comments.
(1) Results indicate that in brain slices, nearby cells typically share a higher degree of common input. However, some proximate cells lack this shared input. The authors interpret these findings as: "Many cells in close proximity don't seem to share common input, as illustrated in Figures 3, 5, and 7. This implies that these cells might belong to separate networks or exist in distinct regions of the connectivity space within the same network.". Every slice orientation could have potentially shared inputs from an orthogonal direction that are unavoidably eliminated. For instance, in a horizontal section, shared inputs to two SCs might be situated either dorsally or ventrally from the horizontal cut, and thus removed during slicing. Given the synaptic connection distributions observed within each intact orientation, and considering these distributions appear symmetrically in both horizontal and sagittal sections, the authors should be equipped to estimate the potential number of inputs absent due to sectioning in the orthogonal direction. How might this estimate influence the findings, especially those indicating that many close neurons don't have shared inputs?
Given we find high probabilities of correlated inputs to nearby cells in both planes, our conclusion that nearby cells are likely to receive common inputs appears to be independent of the slice plane. For cells further apart, where the degree of correlated input becomes more variable, it is possible that cell pairs that have low input correlations measured in one slice plane would have high input correlations if measured in a different plane. An argument against this is that as the cell pairs are further apart, it is less likely that an orthogonal axon would intersect dendritic trees of both cells. Nevertheless, we can't rule this out given the data here. We have amended the discussion to highlight this possibility (p 10, para 1). We agree it would be interesting to address this point further with quantitative analyses but this will be difficult without detailed reconstructions of the circuit.
(2) The study examines correlations during various light-intensity phases of the ramp stimuli. One wonders if the spatial distribution of shared (or correlated) versus independent inputs differs when juxtaposing the initial light stimulation phase, which begins to trigger spiking, against subsequent phases. This differentiation might be particularly pertinent to the PV to SC measurements. Here, the initial phase of stimulation, as depicted in Figure 7, reveals a relatively sparse temporal frequency of IPSCs. This might not represent the physiological conditions under which high-firing INs function. While the authors seem to have addressed parts of this concern in their focal stim experiments by examining correlations during both high and low light intensities, they could potentially extract this metric from data acquired in their ramp conditions. This would be especially valuable for PV to SC measurements, given the absence of corresponding focal stimulation experiments.
We understand the gist of the question here as being can differences in correlation scores between initial vs later phases of responses to ramping light inputs be used to infer spatial organisation? These differences are likely to reflect heterogeneity in the spiking of the input neurons, for example through differences in spike threshold, spike frequency adaptation and saturation of spiking (e.g. Figure 2, Figure Supplement 1A, and also see (Pastoll et al. 2020)). We don't expect these differences to have any spatial organisation along the mediolateral axis, and while spike threshold follows a dorsoventral organisation there is nevertheless substantial local variation between neurons (Pastoll et al. 2020). It's therefore unlikely we can use differences in early versus late correlations to make the inferences proposed by the reviewer.
With respect to PV to SC measurements, similar heterogeneity is likely. We note that we were unable to carry out focal stimulation experiments for PV to SC connections as PV neurons did not spike in response to focal optogenetic stimulation.
With respect to physiological conditions, our aim here is simply to assess connectivity in well controlled conditions, e.g. voltage-clamp, minimal spontaneous activity, known neuronal locations, etc. It's not clear that physiological activation patterns would improve on these tests and quite likely data would be noisier and harder to interpret.
(3) Re results from Figure 2: Please fully describe the model in the methods section. Generally, I like using a modeling approach to explore the impact of convergent synaptic input to PVs from SCs that could effectively validate the experimental approach and enhance the interpretability of the experimental stim/recording outcomes. However, as currently detailed in the manuscript, the model description is inadequate for assessing the robustness of the simulation outcomes. If the IN model is simply integrate-and-fire with minimal biophysical attributes, then the findings in Fig 2F results shown in Fig 2F might be trivial. Conversely, if the model offers a more biophysically accurate representation (e.g., with conductance-based synaptic inputs, synapses appropriately dispersed across the model IN dendritic tree, and standard PV IN voltage-gated membrane conductances), then the model's results could serve as a meaningful method to both validate and interpret the experiments.
We appreciate the simulation descriptions were insufficient and have modified the manuscript to include additional details and clarification (p 14, paras 1-3).
We're not sure we follow the logic here with respect to model types. The experiments were carried out in the voltage-clamp recording configuration with the goal of identifying correlated inputs independently from how they are integrated by the postsynaptic neuron. Given that membrane potential doesn't change (and so the CdVm/dt term of the membrane equation = 0), integrate and fire and point conductance-based models both simplify down to summing of input currents. We achieve this by convolving spike times with experimentally measured synaptic current waveforms. An assumption of our approach is that we achieve a reasonable space clamp. We believe this is justified given that stellate cells and PV interneurons are reasonably electrotonically compact, and that our analysis relies on consistent correlations rather than absolute amplitudes or time constants of the postsynaptic response and so should tolerate moderate space clamp errors.
Reviewer #3 (Public Review):
This paper presents convincing data from technically demanding dual whole-cell patch recordings of stellate cells in medial entorhinal cortex slice preparations during optogenetic stimulation of PV+ interneurons. The authors show that the patterns of postsynaptic activation are consistent with dual recorded cells close to each other receiving shared inhibitory input and sending excitatory connections back to the same PV neurons, supporting a circuitry in which clusters of stellate cells and PV+IN interact with each other with much weaker interactions between clusters. These data are important to our understanding of the dynamics of functional cell responses in the entorhinal cortex. The experiments and analysis are quite complex and would benefit from some revisions to enhance clarity.
These are technically demanding experiments, but the authors show quite convincing differences in the correlated response of cell pairs that are close to each other in contrast to an absence of correlation in other cell pairs at a range of relative distances. This supports their main point of demonstrating anatomical clusters of cells receiving shared inhibitory input.
We appreciate the positive comments.
The overall technique is complex and the presentation could be more clear about the techniques and analysis. In addition, due to this being a slice preparation they cannot directly relate the inhibitory interactions to the functional properties of grid cells which was possible in the 2-photon in vivo imaging experiment by Heys and Dombeck, 2014.
We have modified the manuscript to try to improve the presentation (specific changes are detailed below). We agree that an important future challenge is to relate our findings to in vivo observations (p 11, para 2).
Reviewer #1 (Recommendations For The Authors):
Major points
(1) The study largely relies on the fact that ramp-like wide-field optogenetic stimulation and focal optogenetic activation both drove asynchronous action potentials in SCs, and therefore, if a pair of PV+ INs exhibited correlated activity, they should receive common inputs. In Figure 2 and its supplementary figures, the authors also showed examples of asynchronized activity. However, it is unclear to me what criteria/thresholds were used to determine the level of activity asynchronization, and under these criteria, what percentage of cells actually showed synchronized or less asynchronized activity. A notable percentage of synchronized or less asynchronized SCs could complicate the results, i.e., PV+ INs with correlated activity could receive inputs from different SCs (different inputs), which had synchronized activity. Related to this concern, it would also be important to simulate what level of activity asynchronization in SCs could still lead to correlated PV+ IN activity above shuffle, and among the recorded SCs, what percentage of cells belong to this synchronized/less asynchronized category.
We address this point in our response to the public review. In brief, we have added additional cross-correllograms showing that ramp activation of SC pairs does not cause detectable synchronous activation. We also clarify that sensitivity of correlations of some widely separated pairs to GABA-blockers is suggestive of SCs activating common inhibitory inputs to cell pairs.
(2) The above concern is more relevant to the focal stimulation experiments, in which the authors tried to claim that a pair of PV+ INs with correlated activity could receive inputs from the same SCs neurons. The authors also showed that the stimulation patterns leading to the activation of PV+ INs were more similar if PV+ INs had correlated activity (Figure 5D). However, if nearby SCs were more synchronized than distal SCs within this stimulation scale, even though a pair of PV+ INs showed correlated activity, they could still receive inputs from different but nearby SCs. In this case, it would be helpful to quantify the relationship between the level of activity synchronization of SCs and their distances. In Figure 5 Supplementary Figure 1, the data were only provided for 8 cells. If feasible, collecting data from more cells would be needed for the proposed analysis.
We explain in our responses to point 1 above and in the public review that direct synchronisation of SCs is unlikely. This is particularly unlikely for focal stimulation experiments as the timing of responses of individual SCs is extremely variable between trials. Thus, even if there were strong synaptic connections between SCs, which the evidence suggests there is not (Pastoll et al. 2013; Couey et al. 2013; Fuchs et al. 2016), then this would be unlikely to result in reliably timed coordinated firing.
(3) It is unclear what the definition of "common inputs" is. Do they refer to inputs from the same group of cells? If different groups of cells provide synchronized inputs, will the inputs be considered "common inputs" or "different inputs"?
We used "common" in an attempt to be consistent with classic work by Yoshimura et al. and in an attempt to be succinct. Thus, by common input we are referring to cell pairs for which a proportion of their input is from the same presynaptic neuron(s), as opposed to cell pairs for which their input is from different neurons and therefore have no common input. We have attempted to make sure this is clear in the revised manuscript (e.g description of simulations on p 4, para 2).
(4) In the introduction and abstract, it was mentioned that "dense, but specific, direct excitatory-inhibitory synaptic interactions may operate at the scale of grid cell clusters". It is unclear to me how "dense" was demonstrated in the data. Can the authors clarify?
Thanks for flagging this, we were insufficiently clear. We have revised the text to refer to cell pairs for which a proportion of their input is from the same presynaptic neurons (e.g. p 3, para 1), and separately about indirect coordination, by which we mean inputs to cell pairs that appear correlated because of coordination between upstream neurons.
(5) The hypothesis about the "direct excitatory-inhibitory" synaptic interactions is made based on the GABAzine experiments in Figure 4. In the Figure 8 diagram, the direct interaction is illustrated between PV+ INs and SCs. Is there any evidence supporting this "direct interaction"?
The direct interaction from SCs to PV+INs and from PV+INs to SCs were previously demonstrated by experiments with recordings from pairs of neurons (e.g. (Pastoll et al. 2013; Couey et al. 2013; Fuchs et al. 2016; Winterer et al. 2017). Our results in Figures 3-5, which show that exciting SCs by light activation of ChR2 leads to excitation of PV+INs, and in Figure 7, which show that light activation of PV+INs expressing ChR2 leads to inhibition of SCs, are consistent with these previous conclusions. We have modified the manuscript to make sure this is clear (p 2, para 3).
Is it possible that pyramidal cells are also involved in this interaction? If this is unlikely, the author may provide some pieces of evidence (e.g., timing of responses after optogenetic stimulation) or some discussions.
This is unlikely given that previous studies indicate that connections from stellate to pyramidal cells are weak or absent (Winterer et al. 2017). We now clarify this in the Discussion (p 10, para 1).
Minor points (1) Page 4: the last paragraph: the author claimed that CCpeakmean was reduced and CClagvar increased with cell separation. Although the trends are visible in the figures, the author may provide appropriate statistics to support this statement, such as a correlation between cell separation and CCpeakmean CClagvar./
We have inserted summaries of linear model fits into the legends for Figure 3E-F, Figure 5F-H and Figure 7D.
(2) If I understood correctly, in the second last paragraph on page 6, "pairs of SCs" should be changed to "pairs of PV+ INs".
Thanks. Corrected.
(3) Page 9: the 7th line to the end: where is Figure S4?
Corrected to 'Figure 3, Figure Supplement 2'.
(4) Page 27: at the end of figure caption B: two ".
Corrected.
(5) Figures 3A and B: what are the red vertical rectangles?
These are the regions shown on an expanded time base in C and D. This is now clarified in the legend.
(6) Page 28 Figure caption of D and E: (C) and (D) should be (D) and (E).
Corrected.
(7) The first sentence of the third paragraph in INTRODUCTION: 'later' should be 'layer'.
Corrected.
Reviewer #2 (Recommendations For The Authors):
- Some related work has been done by Beed et al. 2013 to map the spatial distribution of inputs to neurons in MEC. Certainly, there are differences in the approaches and the key questions, but the contribution of this study would benefit from a more detailed comparison of the results from Beed vs the current study and should be included in the discussion.
It's hard to include a detailed comparison of results, at least without losing focus, as the two studies address different questions with different approaches. We already noted that 'Local optical activation of unidentified neurons has also been used to infer connectivity principles but with a focus on responses of single postsynaptic neurons (Beed et al., 2013, 2010)'. In addition, we now note that 'Our focal optogenetic stimulation approach also offers insight into the spatial organization of presynaptic neuronal populations, with the advantage, compared to focal glutamate uncaging previously used to investigate connectivity in the MEC (Beed et al., 2013, 2010), that the identity of the presynaptic cell population is genetically defined'.
- There are a few places where the language is ambiguous or needs a more detailed description for clarity. • 3rd paragraph under "Focal activation of SCs generates common input to nearby PV+Ins". The correlation probability description in this paragraph and a similar sentence in the methods are very hard to understand. I had to look up the analysis in Yoshimura et al. 2005 to understand what was done here. It's a nice analysis, but the manuscript could benefit from a more detailed description of this measure in the methods.
We agree, it is a somewhat complex metric and is challenging to explain. In the interests of keeping the main text succinct, we have left the bare bones explanation as it was in the Results, but have expanded the explanation in the Methods. We hope this is now clear.
- " Alternatively, if there is no clear spatial organization of SC to PV+INs connections, then the similarity between stimulus locations for pairs of SCs should have a random distribution." This sentence is hard to understand. I think the use of the phrase "similarity of stimulus location" is a strange phrasing and is driving the confusion in this sentence.
We have replaced this with 'correspondence between active stimulus locations'.
- In the discussion under "Spatial extent and functional organization of L2 circuits" there is a grammatical mistake (seems to be 2x phrasing of "leads to common synaptic input").
Corrected.
- Citation in the introduction/discussion. Introduction: in addition to Gu et al. 2018, Heys et al 2014 also showed there are non-random correlations among putative grid cells as a function of their somatic distance. In the discussion section, in addition to Gu et al. 2018, Heys et al. 2014 showed there is anatomical clustering of grid cells in MEC. This earlier work investigating functional correlations among neurons in the superficial aspect of MEC in vivo should be cited and is particularly relevant in these two sections of the manuscript.
Thanks, we apologise for the oversight. We're well aware of this important study and have now cited it.
-Typo - Paragraph 3 of the intro; "later" should be layer.
Corrected.
-Figure 5 (D-E) there is a typo high correlation probability is D and low correlation is E (text says C/D).
Corrected.
Reviewer #3 (Recommendations For The Authors):
The paper is missing the bibliography section. This makes the review somewhat difficult as some cited papers are not immediately familiar based on the citation.
Thanks and our apologises for making extra work by omitting this. It is now included.
Page 2 - "cell clusters" - they should also cite the paper by Heys and Dombeck, 2014 that shows a spatial scale of inhibitory interactions computed based on correlations of grid cells recorded using 2-photon calcium imaging.
Added (see above).
Page 2 - "later 2 of the MEC" - layer.
Corrected.
Page 2 - "synaptic interactions" - again they should mention the work by Heys and Dombeck, 2014 that indirectly measured the spatial scale of inhibition.
Now cited in this paragraph.
Page 4 "we simulated responses" and Figure 2E - in each simulation - did they fit the magnitude and time constant of the simulated EPSCs to individual EPSCs in the data? Or did they randomly vary these to find the best fit?
The parameters for the simulations are given in the Methods and were chosen to correspond to the experimental values. We have rewritten this section to make the simulation methods clearer. Simulations using different time constants within a physiological range support similar conclusions.
Page 4 - "we identified 35/71" - Are these the cells that appear in yellow as correlated in Figures 3E-F? If so, the text should indicate that these cells are shown in yellow.
We have added this and have also updated the legends for additional clarification.
Figure 2, Figure Supplement 1 - B,C - the following phrase is not clear: "when the 4 / 8 of each neurons inputs from SCs also project to the other neuron (B)," Should the "the" be removed? Also, by 4/8 do they mean 50%, or do they mean 4 to 8?
Thanks, we've reworded to improve the clarity.
E - "receiving presynaptic inputs consisted of 4 overlapping SCs" - should it say "consisting"?
Corrected.
Figure 3, Figure Supplement 1 part E - "the same data as (C )" - should this be the same data as (D)?? I do not see how doing clustering on the shuffled data in (C ) would give two groups, but it makes sense if it is from (D).
That's right, now corrected.
Page 5 - "used action potentials" - this is confusing. Is the word "used" supposed to be there?
Corrected.
Page 5 - "widefield activation experiments" - they should cite the experiments that they are referring to here.
Added.
Page 5 - "effect of blocking" - "Figure 4" - I find it very odd that the agent GABAzine in Figure 4 is not explicitly mentioned in the main text (though it is mentioned in the methods). The main text should indicate that blocking was performed using GABAzine.
Added.
Page and page 14 and Figure 5 - "shifted" - do they mean shuffled?
We do. The classic papers by Yoshimura et al. used shifted so we keep this here so it's clear we've used their approach. We've added additional explanation to try to make sure the meaning is clear.
Figure 5 A, B, D, and E would benefit from a more detailed description. They should state whether the labels "1a" and "1b" and "2a" and "2b" refer to different recorded neurons in each pair. They should indicate that 2a and 2b are a different pair? Are the x, y axes of the images corresponding to anatomical position? Does "B" indicate the location of recordings shown in Figure 5B? The authors probably think this is all obvious, but it is not immediately obvious to the reader.
We have added additional clarification.
Page 8 - "Beed et al." - These papers by Beed ought to be cited in the introduction as well as they are highly relevant.
We now cite Beed et al. 2013 in the Introduction when we discuss local inhibitory input to SCs. While the Beed et al. 2010 paper is an important contribution to understanding about pathways from deep to superficial layers, the introduction focuses on communication between identified pre- and postsynaptic populations within layer 2 and therefore we haven't found a way to cite it without losing focus. We do cite this paper multiple times elsewhere.
Page 10 - "Excitatory-inhibitory interactions" - this summary of attractor models ought to cite the paper by Burak and Fiete as well.
The discussion focuses on models with excitatory-inhibitory connectivity and cites an important paper from the Fiete group. The model by Burak and Fiete, while also important, is purely inhibitory and so is not well constrained by the known circuitry, and therefore could not be correctly cited here.
Page 10 - "be consistent with models…or that focus on pyramidal neurons have also been proposed" - this seems ungrammatical as if two different sentences were merged.
Corrected.
References
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