Information flow, cell types and stereotypy in a full olfactory connectome
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Evaluation Summary:
This study is a tour-de-force that makes a major contribution to the field. It provides a wealth of information about connectivity in the Drosophila olfactory system, identifying a variety of novel features of its neural organization. The study provides a careful analysis of the practically important and biologically interesting question of stereotypy among animals which previous connectomic studies of the fly brain lacked. A variety of interesting hypotheses are generated. Finally, it establishes a paradigm for the analysis other neural systems.
(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 #2 agreed to share their name with the authors.)
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Abstract
The hemibrain connectome provides large-scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster . Using this data set, we provide a complete description of the Drosophila olfactory system, covering all first, second and lateral horn-associated third-order neurons. We develop a generally applicable strategy to extract information flow and layered organisation from connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. Leveraging a second data set we provide a first quantitative assessment of inter- versus intra-individual stereotypy. Comparing neurons across two brains (three hemispheres) reveals striking similarity in neuronal morphology across brains. Connectivity correlates with morphology and neurons of the same morphological type show similar connection variability within the same brain as across two brains.
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Reviewer #3 (Public Review):
This analysis is enormous in scope. That said, approximately half the glomeruli were either truncated or had very fragmented ALRNs. The authors may wish to reserve use of the term "full" in the title ("....a full olfactory connectome") until a subsequent paper.
ALRN-ALRN connectivity seems very interesting. It would be helpful to provide more information about this in the text (line 148 or so). The information in Fig. 3D is hard for non-specialists to interpret. Does the connectivity show any patterns? Is it stereotyped? Do the connections make functional sense?
One intriguing finding is the "shortcuts" between the olfactory and motor systems that could be used for behaviors that are hard-wired or require fast responses. These may be particularly relevant to thermosensory and hygrosensory input, but can the …
Reviewer #3 (Public Review):
This analysis is enormous in scope. That said, approximately half the glomeruli were either truncated or had very fragmented ALRNs. The authors may wish to reserve use of the term "full" in the title ("....a full olfactory connectome") until a subsequent paper.
ALRN-ALRN connectivity seems very interesting. It would be helpful to provide more information about this in the text (line 148 or so). The information in Fig. 3D is hard for non-specialists to interpret. Does the connectivity show any patterns? Is it stereotyped? Do the connections make functional sense?
One intriguing finding is the "shortcuts" between the olfactory and motor systems that could be used for behaviors that are hard-wired or require fast responses. These may be particularly relevant to thermosensory and hygrosensory input, but can the authors say anything about what kind of olfactory information flows through these shortcuts? For example, the ALRNs that respond to wasp odorants have been identified. Please note that most readers do not know what kind of odorants project to individual glomeruli, e.g. "DC4" .
Fig. 8C It's hard to know how confident to be of the neurotransmitter assignments here. It would be helpful to provide in the text a statement about what assumptions these assignments are based on. In the same vein, line 380 refers to "a neurotransmitter prediction pipeline". Some kind of reference should be provided here.
line 522 "This suggests that thermo/hygrosensation might employ labeled lines whereas olfaction uses population coding to affect motor output." This brings up the question of whether very narrowly tuned ORNs such as the one signaling geosmin show any differences in connectivity from broadly tuned ORNs.
lines 94-96 Graph traversal model. Some more discussion of this model and its underlying assumptions would be helpful. Are the results influenced by the lack of some of the glomeruli from the dataset?
Fig. 7D Can the authors provide more discussion of the possible functional significance of the two uPN types?
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Reviewer #2 (Public Review):
Here are three notable examples (among a long list of new discoveries). (1) The authors provided a comprehensive description of the antennal lobe local interneuron (LN) network for the first time, providing a "final" counts of neuronal number and type of LNs as well as the preference for the input and output partners of each LN type. (2) They introduced "layer" as a quantitative parameter to describe how many synapses away on average a particular neuron or neuron type is from the sensory world. A few interesting new discoveries from this analysis include that on average, multi-glomerular antennal lobe projection neurons (PNs) are further away from the sensory world than uniglomerular PNs; inhibitory lateral horn neurons are closer to the sensory world than excitatory lateral horn neurons. (3) By leveraging …
Reviewer #2 (Public Review):
Here are three notable examples (among a long list of new discoveries). (1) The authors provided a comprehensive description of the antennal lobe local interneuron (LN) network for the first time, providing a "final" counts of neuronal number and type of LNs as well as the preference for the input and output partners of each LN type. (2) They introduced "layer" as a quantitative parameter to describe how many synapses away on average a particular neuron or neuron type is from the sensory world. A few interesting new discoveries from this analysis include that on average, multi-glomerular antennal lobe projection neurons (PNs) are further away from the sensory world than uniglomerular PNs; inhibitory lateral horn neurons are closer to the sensory world than excitatory lateral horn neurons. (3) By leveraging previous analyses they performed on another EM volume (FAFB) and comparing n = 3 (bilateral FAFB, unilateral hemibrain) samples, they analyzed stereotypy and variability of neurons and connections, something rarely done in serial EM reconstruction studies but is very important.
Overall, the text is clearly written, figures well illustrated, and quantitative analysis expertly performed. I have no doubt that this work will have long-lasting values for anyone who study the fly olfactory system, and for the connectomics field in general.
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Reviewer #1 (Public Review):
The manuscript presents a very nice and very detailed approach to illustrate the anatomical hierarchies and also some differences of signal transmission in the olfactory vs. thermosensory-/hygrosensory systems.
The authors first provide a complete description of the Drosophila olfactory system, from first, second and third-order neurons in the lateral horn. Using a generally applicable analysis methods, they extract information flow and layered organisation between olfactory input and descending interneurons. Among the results is the interesting finding that downstream of the mushroom body and lateral horn, output neurons converge to presumably regulate behavior. In an additional set of analyses, Schlegel et al. describe and quantify inter- vs. intraindividual stereotypy of neurons and motifs. They actually …
Reviewer #1 (Public Review):
The manuscript presents a very nice and very detailed approach to illustrate the anatomical hierarchies and also some differences of signal transmission in the olfactory vs. thermosensory-/hygrosensory systems.
The authors first provide a complete description of the Drosophila olfactory system, from first, second and third-order neurons in the lateral horn. Using a generally applicable analysis methods, they extract information flow and layered organisation between olfactory input and descending interneurons. Among the results is the interesting finding that downstream of the mushroom body and lateral horn, output neurons converge to presumably regulate behavior. In an additional set of analyses, Schlegel et al. describe and quantify inter- vs. intraindividual stereotypy of neurons and motifs. They actually compare neurons from three hemispheres of two brains and show an astounding degree of similarity across brains. This is somewhat reassuring and helpful to the field of Drosophila connectomics.
While the many details and data make the manuscript a somewhat strenuous read, and the sheer flood of data could be a bit overwhelming, the data and findings are impressive and important.
The work is very complementary to the data presented by Li et al. on the mushroom body.
The structure and the step-by-step approach to showing increasingly complex circuitry and by defining different layers of the circuitry is very helpful for the reader to get an impression of the complexity of this brain.
Of significant importance and of use for the community are, in addition to the data, the described methods tools for data analysis.
Using this type of analysis, the authors test hypotheses and prevailing assumptions in the field. For instance, they find that in early layers of the olfactory system neurons tend to connect to the next higher layer, whereas neurons in higher layers interconnect or even connect back to earlier layers. This is a very interesting finding that might have important implications regarding top-down feedback and recurrent loops in olfactory processing.
Analysis of connectivity in the antennal lobe suggests that the system is highly lateralized. This finding also has important implications and helps to explain why flies might be able to discern left from right odor sources.
The manuscript shows many examples of what other scientists/readers of the manuscript could extract from the raw anatomical data. This will be very useful for the community beyond the data that is actually already shown in the manuscript.
The authors also compare their findings to the connectome/motifs identified for the larval olfactory system. There are many similarities as expected.
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Evaluation Summary:
This study is a tour-de-force that makes a major contribution to the field. It provides a wealth of information about connectivity in the Drosophila olfactory system, identifying a variety of novel features of its neural organization. The study provides a careful analysis of the practically important and biologically interesting question of stereotypy among animals which previous connectomic studies of the fly brain lacked. A variety of interesting hypotheses are generated. Finally, it establishes a paradigm for the analysis other neural systems.
(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 #2 agreed to share their name with the authors.)
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