Local synaptic inputs support opposing, network-specific odor representations in a widely projecting modulatory neuron

Thank you for submitting your article "Local synaptic inputs support opposing, network-specific odor representations in a widely projecting modulatory neuron" for consideration by eLife. Your article has been reviewed by three peer reviewers, including Mani Ramaswami as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by a Reviewing Editor and Ronald Calabrese as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Baranidharan Raman (Reviewer #3).

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Summary:

This study investigates how the contralaterally-projecting serotonin-immunoreactive deuterocerebral neuron (CSDn) functions in olfactory processing across two brain areas: the antennal lobe (AL), the first olfactory neuropil, and the downstream lateral horn (LH), which is involved in innate olfactory behavior. By employing 2-photon calcium imaging the author show that the CSDn processes in the antennal lobe are hyperpolarized during most odorant exposure, whereas the CSDn processes in the downstream lateral horn are depolarized during the same epochs. Interestingly, the AL responses seem to be uniform and independent of the odor applied, while the LH responses show some degree of odor-specificity. By correlating the odor-evoked activities of the CSDn in the LH to responses of PNs, the authors demonstrate that these patterns are highly correlated and that PNs most likely provide the synaptic input onto the CSDn in the LH. GRASP experiments between both neuronal populations yield a positive signal and provide further support for a direct synaptic connection between certain PNs and the CSDn. Moreover, by using a dataset derived from whole brain EM reconstructions, the authors show that the CSDn receives input from about 17 glomeruli from the AL.

Using an experimentally-constrained, multi-compartmental model that captures the passive properties of the serotonergic neuron to analyze whether the neurites in the AL and LH function as independent compartments within the CSDn, the authors show that transmission of electrical signals in this neuron is asymmetric. While hyperpolarization from the antennal lobe spreads to the somatic and LH segments, propagation of electrical signals from LH compartment to the AL/somatic segments is impeded. Using laser ablation to isolate CSDn processes in LH, they test a prediction from the model. Odor-evoked CSDn responses in LH are enhanced following severing of connection between the AL and LH (as negative contributions from the hyperpolarized processes in the AL are removed).

In summary, this study demonstrates that the CSDn shows distinct odor response properties in different brain regions. Odor-independent inhibition in the AL is likely mediated by multiglomerular inhibitory local interneurons and odor-specific excitation in the LH mediated by projection neurons. It also shows that inhibition from the AL propagates to probably suppress olfactory responses at the LH level.

Showing how different olfactory circuits may locally and differentially engage or disengage serotonergic modulation of stimulus-evoked responses, the findings of this study are very interesting and constitute an important advance on the authors previous paper in eLife. However, it could be improved and enhanced in the following ways.

Essential revisions:

1) It would be valuable to identify the synaptic partners of the CSDn in the LH to elucidate which responses are being suppressed at the LH level. The authors could use their EM reconstruction dataset to follow-up the neuronal circuitry within (and beyond) the LH.

2) It would also be interesting to know whether PNs and the CSDn have any synaptic contacts at the AL level and if so, what that means for the CSDn responses in the LH. These data may already be available from the GRASP experiments.