Review for "The wiring diagram of a glomerular olfactory system"

Completed on 5 Feb 2016 by Leslie Vosshall . Sourced from http://biorxiv.org/content/early/2016/01/25/037721.

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I presented this paper to the Vosshall Lab Olfaction and Behavior Journal Club on 2/3/2016. Here is my synthesis of our discussion.

This is an important, foundational paper that provides for the first time a global view of all 'players' in the compact olfactory system of the Drosophila melanogaster larva. Because this animal has an early olfactory processing system that is superficially similar to that of vertebrates, lessons learned here will be broadly applicable to studies in other animals. This is a connectomics study that uses comprehensive transmission electron microscopy analysis to develop a parts list and a wiring diagram of the entire larval antennal lobe. The paper builds on earlier work that described the cell types and functional connectivity of the circuit based on light microscopy, but that missed many cell types. The strength here is that through the work of multiple labs, we have a complete inventory of incoming olfactory sensory neurons (OSNs), the odorant receptors they express, and the chemical ligands that activate these receptors and OSNs. The major surprises are the fascinating connectivity of multi-glomerular projection neurons, cells that have mostly been ignored by the field; and the beautiful wiring of local interneurons (LNs). It’s clear that much of the sophisticated processing of this system is achieved by LNs that reciprocally inhibit each other, and talk to incoming sensory afferents as well as projection neurons. It would not have been possible to access these cells without the kind of painstaking reconstructions afforded by connectomics. The work sets the field on a course to understand how this connectivity develops, and how the circuit computes odor information to make decisions according to the salience of the stimulus received.

We had the following comments and queries, in no particular order of priority:

1. It would be extremely helpful to have 3-dimensional models of the reconstructed antennal lobe so that the relationship of cell types and synapses can be seen more clearly. Obviously in a PDF only a 2-D flattened z-stack is possible. Even depth coding would help the reader grasp the relationships here. Perhaps you will host this on a server so that readers can “play” with adding and removing cells to see how it all fits together?

2. The non-expert will not understand how you mapped odorant receptor-specific OSNs onto the antennal lobe. Having Supplementary Figure 1, which was based on the Masuda-Nakagawa work of 2009 integrated earlier in the presentation would help the reader understand the logic of assembling the map. Also you misspelled her name in the text.

3. The discovery of the Keystone LN is important. This was our favorite neuron—it will be exciting to see in future functional work how it acts as a hub for routing information by inhibition. It would be helpful to have your thoughts about Keystone and possible homologues in other systems. How do you think it relates to the hub neuron that Cori Bargmann has described in C. elegans? Are there circuit motifs like this in mammalian CNS?

4. The distinction between “picky” and “choosy” LNs was lost on us. Maybe that can be explained more clearly, or names that are less interchangeable can be devised?

5. Neuromodulation is clearly important here, and we wondered why dopamine was not included in the analysis. Perhaps there are no dopamine neurons in the vicinity, or markers were not suitable for mapping onto EM stacks.

6. We wondered how feasible it would be to develop a theoretical neural circuit model based on the connectomics to predict the behavior of the larva given a known odor activating a known OSN.

7. Supplementary Figure 8 is interesting, but perhaps an orthogonal non sequitur in this connectomics paper.