Drosulfakinin signaling modulates female sexual receptivity in Drosophila
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Evaluation Summary:
The manuscript by Wang and colleagues expands our understanding of the neural circuit mechanisms underpinning innate sexual behaviors in Drosophila. It exploits an arsenal of sophisticated tools to demonstrate that the neuropeptide Drosulfakinin (DSK) modulates female sexual receptivity via 71G01-neurons > Dsk-m-neurons > CCKLR-17D3 receptor expressing neurons. The study also introduces new transgenic tools that will be valuable for the community and will be of interest to neuroscientists exploring neuropeptide function and female sexual behavior.
(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 #1 agreed to share their name with the authors.)
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Abstract
Female sexual behavior as an innate behavior is of prominent biological importance for survival and reproduction. However, molecular and circuit mechanisms underlying female sexual behavior is not well understood. Here, we identify the Cholecystokinin-like peptide Drosulfakinin (DSK) to promote female sexual behavior in Drosophila . Loss of DSK function reduces female receptivity while overexpressing DSK enhances female receptivity. We identify two pairs of Dsk -expressing neurons in the central brain to promote female receptivity. We find that the DSK peptide acts through one of its receptors, CCKLR-17D3, to modulate female receptivity. Manipulation of CCKLR-17D3 and its expressing neurons alters female receptivity. We further reveal that the two pairs of Dsk -expressing neurons receive input signal from pC1 neurons that integrate sex-related cues and mating status. These results demonstrate how a neuropeptide pathway interacts with a central neural node in the female sex circuitry to modulate sexual receptivity.
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Evaluation Summary:
The manuscript by Wang and colleagues expands our understanding of the neural circuit mechanisms underpinning innate sexual behaviors in Drosophila. It exploits an arsenal of sophisticated tools to demonstrate that the neuropeptide Drosulfakinin (DSK) modulates female sexual receptivity via 71G01-neurons > Dsk-m-neurons > CCKLR-17D3 receptor expressing neurons. The study also introduces new transgenic tools that will be valuable for the community and will be of interest to neuroscientists exploring neuropeptide function and female sexual behavior.
(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 #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this manuscript, the authors investigate the circuit and molecular basis of sexual receptivity in Drosophila. They focus on the role of the neuropeptide Drosulfakinin (Dsk) in this process. By genetically manipulating the peptide and its receptor, the authors demonstrate that Dsk, via its receptor, CCKLR-17D3, modulates sexual receptivity in female flies. In terms of circuitry, they use a combination of intersectional genetics, trans-synaptic labelling, electrophysiology, and circuit dissection to show that the neurons within the R71G01-Gal4 expression domain modulate this receptivity via the Dsk-m neurons. The data in this study are clear and generally well presented.
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Reviewer #2 (Public Review):
Innate drives in animals are integrated with external environmental cues to modify behavioral outputs. The manuscript by Wang et al. investigated the role of neuropeptide Drosulfakinin (Dsk) in promoting female sexual receptivity. Using a neurogenetic approach the authors demonstrate that Dsk gene product as well as neuronal activity is required for female copulation rate. Genetic approaches were used to identify R71G10-GAL4 neurons as downstream to Dsk neurons and electrophysiology was used to show functional connection between the two populations. A medial subset of Dsk neurons was identified to modulate female copulation rate. It was further shown that female mating is modulated by its receptor CCKLR-17D3.
While the findings reported seem interesting for a broad neuroscience audience, the advance made …
Reviewer #2 (Public Review):
Innate drives in animals are integrated with external environmental cues to modify behavioral outputs. The manuscript by Wang et al. investigated the role of neuropeptide Drosulfakinin (Dsk) in promoting female sexual receptivity. Using a neurogenetic approach the authors demonstrate that Dsk gene product as well as neuronal activity is required for female copulation rate. Genetic approaches were used to identify R71G10-GAL4 neurons as downstream to Dsk neurons and electrophysiology was used to show functional connection between the two populations. A medial subset of Dsk neurons was identified to modulate female copulation rate. It was further shown that female mating is modulated by its receptor CCKLR-17D3.
While the findings reported seem interesting for a broad neuroscience audience, the advance made appears incremental. Several of the claims in the manuscript will require further experiments to support the conclusions drawn. The manuscript adds further data to recent findings reporting Dsk function in Drosophila, however, several of these earlier studies were either omitted altogether or not appropriately cited in the manuscript, some of these include- Nichols and Lim, 1996, Cell Tissue Res; Soderberg, et al. 2012, Front. Endocrinology; Williams et al., 2014, Asahina et al., 2014, Cell; Genetics; Wu et al. 2019, Nat. Comm.; Agrawal et al. 2020, JEB.
One of the major concerns about the study comes from omission of using appropriate tools to dissect Dsk function. The Dsk-GAL4 and Dsk antibodies reported in this manuscript and an earlier study from the same lab (Wu et al., eLife, 2020) do not cover all the Dsk neurons. Earlier studies have shown that the neurons from pars intercerebralis region contain Dsk producing neurons and these Dsk neurons are crucial for regulating hunger and aggressive behaviors. Therefore, it will be important to identify what is the role of these Dsk producing neurons in regulating female mating behaviors by using these earlier published drivers. This will be important given the conclusions drawn are for involvement of Dsk and Dsk neurons overall, which were further sub-divided to elucidate the role of Dsk-M neurons.
Several of the genetic tools used in this study were published from these authors earlier, however these are not referred to appropriately in the main text which leads to confusion as to which tools are created in the current study vs. earlier study.
Copulation rate and latency was used as a proxy for overall female sexual behavior, and it is extended further in the discussion section and even speculated that Dsk neurons might integrate various sensory stimuli including courtship song and pheromonal cues. However, to conclude the effects of Dsk signaling on female sexual behavior it would be more appropriate to look at other behavioral parameters during mating through video analysis and provide rigorous statistical analysis.
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Reviewer #3 (Public Review):
The authors present an extensive set of experiments, spanning from behavior, trans-synaptic mapping to electrophysiology, to show that the Drosulfakinin (DSK) signaling pathway regulates sexual receptivity in Drosophila. They report that DSK neurons act downstream of 71G01-Gal4 neurons to promote female sexual receptivity. The authors describe a subset of DSK neurons in the brain as essential mediators of this behavior. They further identify the receptor through which DSK exerts its function, paving the way to investigate the downstream circuitry involved in female sexual receptivity. More generally, this work, combined with a previous report by another group focused on male courtship, suggests that the DSK circuitry modulates sex-specific behaviors essential for reproductive success in Drosophila.
Overall, …
Reviewer #3 (Public Review):
The authors present an extensive set of experiments, spanning from behavior, trans-synaptic mapping to electrophysiology, to show that the Drosulfakinin (DSK) signaling pathway regulates sexual receptivity in Drosophila. They report that DSK neurons act downstream of 71G01-Gal4 neurons to promote female sexual receptivity. The authors describe a subset of DSK neurons in the brain as essential mediators of this behavior. They further identify the receptor through which DSK exerts its function, paving the way to investigate the downstream circuitry involved in female sexual receptivity. More generally, this work, combined with a previous report by another group focused on male courtship, suggests that the DSK circuitry modulates sex-specific behaviors essential for reproductive success in Drosophila.
Overall, Wang et al., address an interesting question and provide insights into the neural circuit mechanisms of female sexual behaviors in flies. In addition, the study introduces new transgenic tools that will be of interest to the scientific community. The authors use alternative approaches to validate their main findings, which strengthen the study. However, there are a few issues regarding data analysis and presentation that require attention.
It is not clear whether the authors have used proper statistical tests. The authors should assess the nature of the data and use rigorous statistical analyses. Also, they should clearly report what tests are used to analyze the data and what comparisons are made in each data set.
I believe a substantial improvement in the writing style would help readers fully judge and appreciate the findings of this study. The authors could enrich the Introduction by adding information about the courtship ritual in flies and explaining its relevance for mate selection. Moreover, they could describe how female flies signal sexual receptivity and accept a male for copulation. This would help them highlight the importance of their work and make it more attractive for non-specialist readers. In addition, more elaboration on the rationale of the experiments, details of the techniques used in the study, and a better description of the results would help readers better grasp the findings and implications of this study. Finally, the findings of the study could be better discussed in the context of what it is known regarding female sexual receptivity and other key neural players. The authors could speculate how DSK neurons control sexual receptivity. They could elaborate on the interesting finding that the same peptidergic pathway shapes key male and female behaviors during courtship. How do the findings in the female compare to what it's known in the male?
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