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  1. Author Response:

    Reviewer #1 (Public Review):

    The paper has a number of strengths: The basic question of whether individual ORNs drive behavior is an important one, and the authors test ~90% of the different ORN classes which is very extensive. The presentation of the data is beautiful and well-conceived. And the paper is extremely readable. The core observation that only 10/45 tested ORNs can drive locomotor behavior on their own is an important result, as it addresses some labelled-line ideas that have been prevalent in the field.

    There are a few results which are rather unexpected, and one may wonder whether they are somewhat unique to the behavioral apparatus the authors use:

    The absence of an influence of wind on odor responses may not be general (i.e. the authors show it doesn't change single-ORN-elicited behavior, that is likely not true with odor-guided behavior where wind direction is an important cue for the animals to localize the odor source). It is possible that the narrow corridors in the assay used here promotes locomotor behavior in flies (as opposed to in an open arena where flies locomote much less, and may need wind stimulation to promote movement).

    We thank the Reviewer for raising this issue. We agree that experimental results should be interpreted in view of the natural condition. Please note that Bell and Wilson used narrow 50 × 5 × 1.2-mm chambers, similar in size to the 50 × 4 × 3 mm chambers used in the WALISAR assay. Since both widths are narrow, we consider that this minor difference alone cannot easily account for the discrepancy between the two studies. There are other parameters that we consider more likely to account for this, for example, the use of blind flies.

    Action taken: We have added a sentence on this to the new Limitations section in the Discussion, and added a row to Supplementary File 2 - Sheet 3.

    The counter-intuitive effect of starvation on behavior driven by food-sensing ORNs may reflect the fact the optogenetic ORN stimulation is very strong, as the authors discuss. This result can only be interpreted if the spike rates elicited with their optogenetic stimulation were known.

    This result echoes previous results showing that the relationship between hunger and ORN responses can be complicated (Root et al., 2011). We request that electrophysiology is not required for publication.

    Action taken: We have added a row to the Supplementary Table 4 showing that no electrophysiology was done, and have added a sentence about this to the new Limitations section in the Discussion.

    Knowing where in the dynamic range of ORN firing the optogenetic stimulation lies will also be important for interpreting the pairwise interactions between ORNs. For example summation may be more apparent when lower ORN firing rates are being combined. While analyzing ORN pairs, it would also be more informative to examine each pair individually across a range of stimulation intensities, since some pairs may summate and others may max pool etc.

    Individual pairs were examined in Figure 5. Our systematic analyses contradict the earlier published conclusions, suggesting a greater range of combination rules, consistent with complex interactions. Also, these analyses found shifts in weightings suggesting that, rather than fixed, the combination rules are dynamic.

    Action taken: We request that doing further combination analyses are not made a requirement of publication.

    Also in Fig 5G-I the authors analyze all ORN pairs together to look for summation etc. It is more informative to examine each pair individually across a range of stimulation intensities, since some pairs may summate and others may max pool etc. So this data, currently in SuppFig8. should be moved to the main text.

    Action taken: We have moved that Supplementary Figure to the main text.

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  2. Evaluation Summary:

    Olfactory coding is still an open question in neuroscience. Therefore, this paper is of potential interest to a broad audience of neuroscientists. It undertakes a thorough investigation of how olfactory sensory neurons drive avoidance or attraction in flies and also addresses how combinations of active ORNs can become behaviorally meaningful. It has great potential value for clarifying how animals map sensory input to valence.

    (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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  3. Reviewer #1 (Public Review):

    The paper has a number of strengths: The basic question of whether individual ORNs drive behavior is an important one, and the authors test ~90% of the different ORN classes which is very extensive. The presentation of the data is beautiful and well-conceived. And the paper is extremely readable. The core observation that only 10/45 tested ORNs can drive locomotor behavior on their own is an important result, as it addresses some labelled-line ideas that have been prevalent in the field.

    There are a few results which are rather unexpected, and one may wonder whether they are somewhat unique to the behavioral apparatus the authors use:

    The absence of an influence of wind on odor responses may not be general (i.e. the authors show it doesn't change single-ORN-elicited behavior, that is likely not true with odor-guided behavior where wind direction is an important cue for the animals to localize the odor source). It is possible that the narrow corridors in the assay used here promotes locomotor behavior in flies (as opposed to in an open arena where flies locomote much less, and may need wind stimulation to promote movement).

    The counter-intuitive effect of starvation on behavior driven by food-sensing ORNs may reflect the fact the optogenetic ORN stimulation is very strong, as the authors discuss. This result can only be interpreted if the spike rates elicited with their optogenetic stimulation were known.

    Knowing where in the dynamic range of ORN firing the optogenetic stimulation lies will also be important for interpreting the pairwise interactions between ORNs. For example summation may be more apparent when lower ORN firing rates are being combined. While analyzing ORN pairs, it would also be more informative to examine each pair individually across a range of stimulation intensities, since some pairs may summate and others may max pool etc.

    Also in Fig 5G-I the authors analyze all ORN pairs together to look for summation etc. It is more informative to examine each pair individually across a range of stimulation intensities, since some pairs may summate and others may max pool etc. So this data, currently in SuppFig8. should be moved to the main text.

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  4. Reviewer #2 (Public Review):

    In this manuscript, Tumkaya et al mapped the effects of optogenetically activating olfactory sensory neuron types on place preferences in adult flies, used as an index of odor valence. The authors include an impressive number of experimental and control flies tested, and analyzed their data with sophisticated statistical methods. However, I struggled to judge whether the authors achieved their aims, for two main reasons. First, too little information is given on the behavior. It is not clear that reducing the behavior to one number, wTSALE, adequately captures the relevant range of behavioral variation, so the mostly neutral effects reported here may simply reflect an insufficiently sensitive assay. Second, the statistical methods, however innovative they may be, are not in common usage and will be unfamiliar to most readers (including this one). To be understood, these methods should be clearly explained and logically justified over simpler and more intuitive options. Deeper explanation and perhaps simplification would be well worth the effort, given the impact these findings could have on the field.

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  5. Reviewer #3 (Public Review):

    In the current manuscript, Tumkaya et al., set to examine two questions:

    1. What proportion of primary olfactory sensory neurons can individually drive avoidance or attraction?
    2. What are the rules that govern behavioral responses to receptor combinations?

    To this end, they optogenetically activated single ORN classes and examined the behavioral output. They found that only a fifth of ORN-types drove avoidance or attraction. They also found that wind and hunger had no effect on single-ORN class behavioral responses. Finally, they examined several pooling rules that failed to predict behavior. They conclude that the majority of primary olfactory sensory neurons have neutral behavioral effects individually, but participate in broad, odor-elicited ensembles with potent behavioral effects arising from complex interactions.

    The amount of work presented in this manuscript is truly impressive and the authors should be commended for their efforts.

    The conclusion that the majority of olfactory receptor neurons do not individually drive avoidance or attraction is not unsurprising, however, it addresses the still open question of labelled lines in olfaction, and is thus of importance. Some additional experiments will more thoroughly address the second conclusion that receptor combinations are more complex than using either summation or pooling strategies.

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