Mating activates neuroendocrine pathways signaling hunger in Drosophila females

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    After mating, animals show a repertoire of behavioural changes. In flies, this includes an increase in egg-laying, salt, and food (particularly protein) consumption, and a concomitant decrease in sexual receptivity. This valuable study compellingly shows that flies also have an increased sugar appetite and they identify the central brain circuitry that controls this increase in the mated condition.

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Mated females reallocate resources to offspring production, causing changes in nutritional requirements and challenges to energy homeostasis. Although observed in most species, the neural and endocrine mechanisms that regulate the nutritional needs of mated females are not well understood. Here, we investigate the neural circuitry that regulates sugar appetite in mated Drosophila melanogaster females. During copulation, a male-derived sex peptide is transferred to females, silencing the mating status circuit to elicit many postmating behavioral changes 1-3 . We find that increased sucrose consumption is a postmated female behavior and show that it is mediated by the mating status circuit. We discovered that sexually dimorphic insulin receptor (Lgr3) neurons integrate mating status and nutritional state signals to adjust sucrose consumption. Lgr3+ cells receive inhibitory input from the mating status circuit via female specific pCd-2 neurons. In mated females, the inhibition of Lgr3 cells from pCd-2 is attenuated, transforming the mated signal into a long-term hunger signal that promotes sugar intake. Our results thus demonstrate that the mating circuit alters nutrient sensing centers in females to promote sugar consumption, providing a mechanism to increase intake in anticipation of the energetic costs associated with reproduction.

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  1. eLife assessment

    After mating, animals show a repertoire of behavioural changes. In flies, this includes an increase in egg-laying, salt, and food (particularly protein) consumption, and a concomitant decrease in sexual receptivity. This valuable study compellingly shows that flies also have an increased sugar appetite and they identify the central brain circuitry that controls this increase in the mated condition.

  2. Reviewer #1 (Public Review):

    Animals respond to their environment in a state-dependent manner. One of the best examples of this is the dramatic changes in behaviours in the female after mating. In flies, this includes an overall increase in food consumption, a well-documented increase in protein appetite, increased salt appetite, increased egglaying behaviour, and reduced sexual receptivity.

    In this study, the authors argue that sugar is a macronutrient that should be essential to support the increased metabolic needs of the fly and the lipid demand of the eggs. They isolate sugar (instead of providing it in a choice assay) and document that indeed mated flies have an increased appetite for sugars.

    They then go on to demonstrate that this increase is not need-based, but is anticipatory in nature and that it is not changes in sensitivity of the sugar-sensing neurons, but central brain circuitry that drives this behvioural change. Finally, they work out the circuitry demonstrating that it diverges from the well-described three-layer mating circuit (SPSN>SAG>pC1) that is active in virgins but inhibited by sex-peptide in mated females. They use EM datasets to identify the pCd2>Lgr3+ neurons as downstream of pC1 and develop genetic tools to monitor and manipulate neuronal activity in these neurons to show that the Lgr3+ neurons are active in the mated state because they receive inhibitory inputs from the pCd2s.

    As LG3 neurons are known to be activated by the DILPs, which mediate satiety, their model proposes the state of mating (as signalled by central brain circuitry) is essentially a state of additional hunger.

  3. Reviewer #2 (Public Review):

    This manuscript by Laturney et al. has found a previously uncharacterized neural link between female mating status and upregulation of sugar intake in the common fruit fly, Drosophila melanogaster. Although mated female flies have been known to increase both yeast and salt intake compared to virgin females, changes in sugar intake have not been previously described. Using quantitative monitoring of food intake, functional calcium imaging, connectome tracing, and neuronal manipulations, authors convincingly demonstrated that the Sex Peptide sensory neurons (SPSN) and their downstream neural circuit control the activity of female-specific Lgr3 neurons in a mating-dependent manner. In virgin females, the SPSN circuit (including its output pCd-2 neurons) is active, which is predicted to inhibit hunger-promoting Lgr3 neurons. After mating, the SPSN circuit becomes silent, which should disinhibit Lgr3 neurons. Indeed, they found that optogenetic silencing of pC2-d neurons promoted sucrose consumption. The newly characterized pCd-2 neurons are sexually dimorphic, consistent with their role in female-specific post-mating modulation of sucrose consumption.

    Aside from the novelty of the mating-dependent changes in sugar intake, an exciting discovery of the current study is that separate circuits control different aspects of post-mating behavioral changes (increased egg-laying, mating rejection, increased sugar consumption). This finding illustrates a general neural mechanism by which a single "internal state" exerts its influences on multiple behaviors via branches of circuits from a hub for the given state (pC1 for the female mating status), which is a powerful mechanistic model for other internal states.

    The high-quality data based on elegant yet rigorous experiments deserve praise as a textbook example. They presented multiple independent lines of evidence to demonstrate the function of each component of the SPSN circuit over the sucrose consumption Lgr3 neurons, which convincingly proves that the pCd-2a/b neurons transmit information of mating status to a hunger-controlling hub. Experiments have been exceptionally rigorous. Genetic manipulations were performed with multiple controls. They used multiple split GAL4 lines to target specific classes of neurons to eliminate the neuronal off-target effect. They also used multiple types of feeding assays to clarify the feeding phenotype induced by mating. Overall, the scientific rigor of this work sets a standard for researchers in the field to follow.

    That the activity levels of pCd-2 neurons and their downstream Lgr3 neurons are indeed influenced by mating has not been directly tested. Since multiple previous publications consistently demonstrated that the SPSN-SAG-pC1 axis is suppressed by the Sex Peptide, the authors' conclusion that pCd-2 neurons are suppressed after mating (for example, see line 319) is very likely correct. However, what the authors showed was that silencing of the SPSN circuit "can" increase sucrose consumption in virgin females. To what extent mating suppresses pCd-2 neurons (and disinhibits Lgr3 neurons) remains uncharacterized. The inhibition exerted by the Sex Peptide is likely partial, which might not be precisely recapitulated by the optogenetic silencing. Mated female flies show an increased preference for protein and salt. The authors' finding that they also increase sugar consumption after mating indicates that mating causes a substantial change in female feeding patterns. The current work elevates the value of Drosophila as a neurogenetic model to understand how the nervous system achieves the complex tasks of nutritional homeostasis after mating, which dramatically alters the energy allocation in many species (including mammals). Data presented in this work will advance our understanding of how females coordinate feeding priorities in a face of changing nutritional demands after mating, which is one of the fundamental questions in neuroscience.

  4. Reviewer #3 (Public Review):

    Mating changes an animal's behavior. In Drosophila, mated females have higher energy needs, suggesting that their consumption of caloric foods may be altered. While previous studies have examined post-mating changes in the consumption of specific nutrients such as salt and protein, it was not known whether the intake of sugar, their primary energy source, is also changed. This study describes a post-mating increase in sugar intake and identifies the neural circuit that mediates this change. By using precise genetic manipulations, behavioral assays, and new connectome datasets, the authors provide high-quality data to support their claims.

    This study reveals several new insights into the regulation of behavior after mating: 1) Female flies increase sugar intake after mating, and this is an "anticipatory" change rather than a homeostatic change resulting from energy depletion. 2) The post-mating change in sugar intake is mediated by the sex peptide circuit, SPSNs-SAG-pC1, which is known to regulate other post-mating changes. 3) The authors identify a new downstream target of pC1, the pCd-2 neurons, which regulate feeding. pCd-2 neurons do not affect egg-laying, and neurons downstream of pC1 that regulate egg-laying or receptivity after mating do not affect sugar intake. Thus, the SPSN-SAG-pC1 circuit that regulates post-mating behaviors diverges downstream of pC1 into multiple branches regulating different behaviors. 4) The authors identify cells downstream of pCd-2, median bundle cells expressing Lgr3, the receptor for Dilp8. These cells are inhibited by pCd-2, suggesting that they are active in mated females, and promote sugar consumption. Because previous studies showed that Dilp8 and Lgr3 are expressed more highly in fed flies and suppress feeding, the present study suggests that Lgr3+ cells integrate hunger and mating signals to regulate feeding. This is an interesting circuit motif that could extend to mammals. In future studies, it will be interesting to test how hunger and mating signals are integrated within these cells (e.g. do they function redundantly, additively, etc).