A connectome of the Drosophila central complex reveals network motifs suitable for flexible navigation and context-dependent action selection
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Evaluation Summary:
It is difficult to overestimate the importance of this paper. The full connectome of the Drosophila central complex is both the beginning and the end of an era. It provides the first comprehensive dataset of arguably the most enigmatic brain region in the insect brain. This endeavor has generated ground truth data for years of functional work on the neural circuits the connectome outlines and constitutes an unparalleled foundation for exploring the structure function relations in nervous systems in general. While significantly going beyond models of central-complex function that existed previously, the authors have to be much credited for incorporating huge amounts of existing knowledge and data into their interpretations, not only work from Drosophila, but also from many other insects. This effort makes this paper not only an invaluable resource on the connectome of the Drosophila central complex, but also a most comprehensive review on the current state of the art in central-complex research. This unifying approach of the paper clearly marks a reset of central-complex research, essentially providing a starting point of hundreds of new lines of enquiry, probably for decades to come.
(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 #1 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Flexible behaviors over long timescales are thought to engage recurrent neural networks in deep brain regions, which are experimentally challenging to study. In insects, recurrent circuit dynamics in a brain region called the central complex (CX) enable directed locomotion, sleep, and context- and experience-dependent spatial navigation. We describe the first complete electron microscopy-based connectome of the Drosophila CX, including all its neurons and circuits at synaptic resolution. We identified new CX neuron types, novel sensory and motor pathways, and network motifs that likely enable the CX to extract the fly’s head direction, maintain it with attractor dynamics, and combine it with other sensorimotor information to perform vector-based navigational computations. We also identified numerous pathways that may facilitate the selection of CX-driven behavioral patterns by context and internal state. The CX connectome provides a comprehensive blueprint necessary for a detailed understanding of network dynamics underlying sleep, flexible navigation, and state-dependent action selection.
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Author Response:
We are glad that the reviewers found the manuscript comprehensive and that they think it will likely be a useful resource for the community. We have made several changes with that in mind, incorporating input from a number of fly CX researchers. In particular:
- We have performed new analyses to improve our descriptions and characterization of phase angles in the PB and FB. Some of these changes, which have to do with the assignment of phase angles within the PB and FB columns, should help prevent any confusion or inconsistency relative to recent papers from the Maimon and Wilson labs.
- Streamlined the Results section focused on dFB and EB sleep-wake circuits to aid in clarity.
- Restructured and expanded the Discussion sections framing the CX as a multifunctional network to better capture previous physiological observations.
- Ad…
Author Response:
We are glad that the reviewers found the manuscript comprehensive and that they think it will likely be a useful resource for the community. We have made several changes with that in mind, incorporating input from a number of fly CX researchers. In particular:
- We have performed new analyses to improve our descriptions and characterization of phase angles in the PB and FB. Some of these changes, which have to do with the assignment of phase angles within the PB and FB columns, should help prevent any confusion or inconsistency relative to recent papers from the Maimon and Wilson labs.
- Streamlined the Results section focused on dFB and EB sleep-wake circuits to aid in clarity.
- Restructured and expanded the Discussion sections framing the CX as a multifunctional network to better capture previous physiological observations.
- Added over 20 videos showing morphological renderings in 3D to help explain key results.
- Analyzed the total number of synapses per region for the PB columnar neurons as a function of the number of neurons in each glomerulus (New Figure 24 S1).
- Characterized the number of type-to-type connections between FB columnar neurons as a function of the percentage of total possible neurons that are actually connected (New Figure 33—figure supplement 1B).
Reviewer #1 (Public Review):
[...] This makes this paper not only an invaluable resource on the connectome of the Drosophila central complex, but also a most comprehensive review on the current state of the art in central-complex research. This unifying approach of the paper clearly marks a reset of central-complex research, essentially providing a starting point of hundreds of new lines of enquiry, probably for decades to come.
We thank the reviewer for their generous comments. We are excited by the prospect of this manuscript being helpful for projects from many labs working in different insects.
[...] The figures are equally overwhelming as the text at first sight, but when taking the time to digest each one in detail, they present the data in a rich and clear manner. The figures are often encyclopedic and will serve as reference about the central complex for years. The summary graphs that are presented in regular intervals are welcome resting places for the reader, helping to digest all the detailed information that has preceded or that will follow.
We realize that the length and complexity of the manuscript makes it difficult to get through and to process. We are glad that the reviewer found the paper’s organization helpful in that regard. Although we have made many additions and edited the text and figures, we have tried to preserve the original organization and the mini-summaries with each section that the reviewer found useful.
The analysis performed in the paper is excellent, comprehensive and should set the standard for any future work on this topic. Also, the text is very honest about the limits of the conclusions that can be reached based on this kind of data, which is important in generating realistic and feasible hypotheses for future experiments.
We appreciate the reviewer’s comments on the analysis. We are making all the analysis code available open source, and have tried to package it in a way that we hope will make it easy for others to use and build upon.
Reviewer #2 (Public Review):
[...] This is a massive work. There are 75 figures, not including supplements, and numerous region and neuron names to keep track of (not to mention visualize). It is impossible to read in a single sitting. So for the purposes of this public review, I highly recommend to any reader that they first find the region of the paper they're interested in and skip to that to view in side-by-side mode. The "generally interested" reader is best served by reading through the Discussion, which has more of the structure-function analyses in it and then referring to the Results as their curiosity warrants.
We thank the reviewer for their comments.
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Reviewer #2 (Public Review):
In this incredibly detailed effort, Hulse, Haberkern, Franconville, Turner-Evans, and coauthors painstakingly and patiently reveal the connectivity of central complex neurons within one "hemibrain" EM-imaged connectome of a fruit fly. This is best read as one of a series of such detailed papers including Scheffer et al., 2020 (which introduces the dataset) and Li et al., 2020 (which focuses on the mushroom body).
The authors achieve two major goals. First, they present a full account of all neurons (by type) present in the central complex and the connections between them (including to and from regions outside the central complex). By necessity, this work only examines such connections within a single animal from whose brain the hemibrain volume was imaged. Nonetheless, the relatively conserved morphology of …
Reviewer #2 (Public Review):
In this incredibly detailed effort, Hulse, Haberkern, Franconville, Turner-Evans, and coauthors painstakingly and patiently reveal the connectivity of central complex neurons within one "hemibrain" EM-imaged connectome of a fruit fly. This is best read as one of a series of such detailed papers including Scheffer et al., 2020 (which introduces the dataset) and Li et al., 2020 (which focuses on the mushroom body).
The authors achieve two major goals. First, they present a full account of all neurons (by type) present in the central complex and the connections between them (including to and from regions outside the central complex). By necessity, this work only examines such connections within a single animal from whose brain the hemibrain volume was imaged. Nonetheless, the relatively conserved morphology of fly neurons (at the scale of which regions they form arbors within) allows the authors to confidently relate their neurons to known examples from genetically labeled lines imaged at the light level. (And in some cases, they are able to show that some neurons with similar morphology can then be further subdivided into different types on the basis of their connectivity). Importantly, the hemibrain dataset contains both sides of the central complex, allowing for a complete analysis.
Secondly, the authors contextualize the observed connectivity patterns within the known functions of the central complex (particularly navigation and sleep/arousal). Appropriately and importantly, they offer detailed explanations for how the circuitry observed can support these functions. In some cases, particularly in their discussion of the fan body, they show how the connectivity patterns can support multiple variations of models of path integration (and more broadly how its architecture supports vector computation in general). These analyses make their central complex connectome a useful map - there is little doubt that it will inspire many future experiments in the fly community.
The only limitations of this work are rooted in the nature of the source material: it's only one animal's brain and because it's EM-based there's often no way to know whether a given cell type (if new) is even excitatory or inhibitory (though, notably, the authors take care to note where this is the case and to offer alternate interpretations of the circuit function). Synaptic strength is another relative unknown (not to mention plasticity rules or modulatory influences). For EM-based connectomes, the number of synapses made between two neurons is considered the basis for determining whether or not they are meaningfully connected. However, this precise number can vary as a function of how complete the reconstructions are (generally, as proofreading progresses, more synapses are found). This work improves on prior hemibrain studies by carefully demonstrating that it is possible to set a threshold on the relative fraction of synaptic contributions within a region in order to identify meaningful connections. (That is, they find that as the number of synapses discovered increases, the relative contribution remains relatively constant).
This is a massive work. There are 75 figures, not including supplements, and numerous region and neuron names to keep track of (not to mention visualize). It is impossible to read in a single sitting. So for the purposes of this public review, I highly recommend to any reader that they first find the region of the paper they're interested in and skip to that to view in side-by-side mode. The "generally interested" reader is best served by reading through the Discussion, which has more of the structure-function analyses in it and then referring to the Results as their curiosity warrants.
Scheffer et al., 2020 is available here: https://elifesciences.org/articles/57443#content Li et al., 2020 is available here: https://elifesciences.org/articles/62576#content
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Reviewer #1 (Public Review):
It is difficult to overestimate the importance of this paper. The full connectome of the Drosophila central complex is both the beginning and the end of an era. It provides the first comprehensive dataset of arguably the most enigmatic brain region in the insect brain. This endeavor has generated ground truth data for years of functional work on the neural circuits the connectome outlines, and constitutes an unparalleled foundation for exploring the structure function relations in nervous systems in general. This will be of great importance far beyond work on the Drosophila brain, and will have far reaching implications for comparative research on insect brains and likely also smoothen the path toward understanding navigation circuits in vertebrate nervous systems. Based on presented data, the paper develops …
Reviewer #1 (Public Review):
It is difficult to overestimate the importance of this paper. The full connectome of the Drosophila central complex is both the beginning and the end of an era. It provides the first comprehensive dataset of arguably the most enigmatic brain region in the insect brain. This endeavor has generated ground truth data for years of functional work on the neural circuits the connectome outlines, and constitutes an unparalleled foundation for exploring the structure function relations in nervous systems in general. This will be of great importance far beyond work on the Drosophila brain, and will have far reaching implications for comparative research on insect brains and likely also smoothen the path toward understanding navigation circuits in vertebrate nervous systems. Based on presented data, the paper develops overarching ideas (at exquisite detail) of how sensory information is transformed into head direction signals, how these signals are used to enable goal direction behavior, how goals are represented, and how internal state can modulate these processes. The connectome enables the authors to base these ideas and their detailed models on actual biological data, where earlier work was forced to indirectly infer or speculate. While significantly going beyond models of central-complex function that existed previously, the authors have to be much credited for incorporating huge amounts of existing knowledge and data into their interpretations, not only work from Drosophila, but also from many other insects. This makes this paper not only an invaluable resource on the connectome of the Drosophila central complex, but also a most comprehensive review on the current state of the art in central-complex research. This unifying approach of the paper clearly marks a reset of central-complex research, essentially providing a starting point of hundreds of new lines of enquiry, probably for decades to come.
Given the type and amount of data presented, the paper is clearly overwhelming. That said, it also clearly needs to be presented in the way it was done, mostly because no single aspect of the function of this neuropil makes as much sense in isolation as it makes sense when viewed in conjunction of all its other functions. The complexity of the neural circuits discussed is clearly reflected in the enormous scope of the paper. Nevertheless, the authors have done a fantastic job in breaking the circuits and their function down into digestible bits. The manuscript is very systematic in its approach and starts with sensory pathways leading to the CX, covering the clearly delineated head direction circuits and then moving on to the more complex and less understood parts, always maintaining a clear link between structure and function. As function is necessarily based on previous work, including that from other species, the results part is interwoven with interpretation, but this is clearly necessary to keep the text readable. The authors have made considerable efforts to provide additional introductions and summaries whenever needed, almost creating nested papers embedded within the overall paper.
The figures are equally overwhelming as the text at first sight, but when taking the time to digest each one in detail, they present the data in a rich and clear manner. The figures are often encyclopedic and will serve as reference about the central complex for years. The summary graphs that are presented in regular intervals are welcome resting places for the reader, helping to digest all the detailed information that has preceded or that will follow.
The analysis performed in the paper is excellent, comprehensive and should set the standard for any future work on this topic. Also, the text is very honest about the limits of the conclusions that can be reached based on this kind of data, which is important in generating realistic and feasible hypotheses for future experiments.
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Evaluation Summary:
It is difficult to overestimate the importance of this paper. The full connectome of the Drosophila central complex is both the beginning and the end of an era. It provides the first comprehensive dataset of arguably the most enigmatic brain region in the insect brain. This endeavor has generated ground truth data for years of functional work on the neural circuits the connectome outlines and constitutes an unparalleled foundation for exploring the structure function relations in nervous systems in general. While significantly going beyond models of central-complex function that existed previously, the authors have to be much credited for incorporating huge amounts of existing knowledge and data into their interpretations, not only work from Drosophila, but also from many other insects. This effort makes this paper …
Evaluation Summary:
It is difficult to overestimate the importance of this paper. The full connectome of the Drosophila central complex is both the beginning and the end of an era. It provides the first comprehensive dataset of arguably the most enigmatic brain region in the insect brain. This endeavor has generated ground truth data for years of functional work on the neural circuits the connectome outlines and constitutes an unparalleled foundation for exploring the structure function relations in nervous systems in general. While significantly going beyond models of central-complex function that existed previously, the authors have to be much credited for incorporating huge amounts of existing knowledge and data into their interpretations, not only work from Drosophila, but also from many other insects. This effort makes this paper not only an invaluable resource on the connectome of the Drosophila central complex, but also a most comprehensive review on the current state of the art in central-complex research. This unifying approach of the paper clearly marks a reset of central-complex research, essentially providing a starting point of hundreds of new lines of enquiry, probably for decades to come.
(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 #1 and Reviewer #2 agreed to share their names with the authors.)
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