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  1. Evaluation Summary:

    This manuscript will be of interest to scientists working on learning and memory and synaptic plasticity. It provides a useful overview of different forms of plasticity taking place in the learning and memory center of the fly, the mushroom body. The study mostly uses an acetylcholine sensor to image activity, which is novel and helps to tie together previous studies reporting memory-induced changes in calcium transients. In particular, the study highlights the compartmentalised plasticity along Kenyon cell axon terminals, the main cell type of the mushroom body. The current version of the manuscript could be improved by including some key issues: (1) behavioral experiments for the Cac knock-down experiments, (2) specific controls for some of the imaging experiments, (3) consideration of the role of dopaminergic neurons and (4) acknowledgment of the complexity of the mushroom body circuit and the literature that has addressed this previously.

    (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.The reviewers remained anonymous to the authors.)

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  2. Reviewer #3 (Public Review):

    This study shows learning-induced compartmentalized plasticity in Kenyon cells (KCs) of the mushroom body gamma lobe using a genetically encoded acetylcholine sensor. The authors made several major discoveries that the plasticity is bidirectional and depends on memory valence. Interestingly, the compartments along the axon terminals of the KCs undergo spatial 'gradient' of plasticity. Knock-down of the genes that differentially regulate intracellular calcium induced distinct effects on learning-induced plasticity. These results explain, at least partly, that learning-induced plasticity at KC-MBON synapses takes place on the presynaptic side. The experiments and analysis are overall thorough, and conclusions are generally supported by the results. In the following, I list some flaws to be addressed that concern necessary controls, more careful interpretation of the statistics and results, and the choice of the cac RNAi strain.

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  3. Reviewer #2 (Public Review):

    Stahl et al. investigate presynaptic Kenyon cell plasticity in the context of appetitive and aversive memories, using a genetically-encoded acetylcholine receptor-based sensor as primary read-out (instead of calcium indicators used in several previous studies). Therefore, the authors investigate one step downstream of the classically conducted calcium (or cAMP, etc.) imaging experiments - the level of neurotransmitter release. Likewise, this is one step upstream of the other widely-used readout of the postsynaptic MBON activity (or dopaminergic neurons). The authors investigate contributions of CS+ and/or CS- plasticity throughout the compartments of the gamma lobe. All in all, this manuscript confirms several previous studies that investigated individual compartment plasticity (often plasticity is measured at the level of the MBONs and therefore in single compartments), and taken together with other recent publications, this study can be seen as a valuable compendium (as it addresses appetitive and aversive short-term memory protocols in the context of several compartments). As the authors address an important step between presynaptic and postsynaptic calcium transients, their work actually confirms that conclusions deduced from changed calcium transients correlate to neurotransmitter release, as expected. This study also addresses differential effects on the CS+ and the CS-, which is important, as previous studies often concentrated (partially for technical reasons) on either the CS+ specifically, or the relative changes of CS+ to CS- only. The authors further investigate the role of the active zone-localized voltage gated calcium channel cacophony in memory-related plasticity - this part needs to be strengthened by additional controls.

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  4. Reviewer #1 (Public Review):

    The paper aims to understand if and how axonal compartmentalization functions in the MB 𝝲 lobe in the context of olfactory learning. Further the authors focus on these process and find distinct molecular mechanisms underlying appetitive and aversive learning (cac and IP3). Lastly the authors focus on how this compartmentalization influences the downstream MBON function.

    The paper is written well and straightforward in its approach and implications. The neuroanatomy, experimental details are clearly presented and I would rate this paper very high on a readability scale. The imaging and behavioral approaches are appropriate for the research question and address the limitations from a technical perspective. Results are presented well, but authors don't dwell on the results much before transitioning into another part of the question they seek to ask. This undermines the complexity of the MB circuits and an effort should be made to address dynamics of other lobes that underlie these behaviors. One issue is that even though the experiments work well together in supporting the results they fail to incorporate more complex dynamics of other lobes or consider the EM connectivity which might complicate the simplistic interpretations. The role of dopamine in this compartmental logic has not been directly addressed which potentially plays into this circuit.

    This is impactful work as it addresses the pre-synaptic dynamics of MB with a focus on ACh release across compartments and how they differ between two forms of learning. The use of Grab Ach is a big highlight of the paper as this question could not have been asked without this tool. The authors also address the regulation of Ca2+ responses in the compartments that result in altered responses in valence-coding MBONs. Its also interesting to see the switch in 𝝲2 and 𝝲3 dynamics between appetitive and aversive learning. Lastly the match of Ca2+ responses in MBONs with the Ach compartmentalization highlights the behavioral relevance of axonal compartmentalization.

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