Sex-specific topology of the nociceptive circuit shapes dimorphic behavior in C. elegans

Vladyslava Pechuk, Yehuda Salzberg, Gal Goldman, Aditi H. Chaubey, R. Aaron Bola, Jonathon R. Hoffman, Morgan L. Endreson, Renee M. Miller, Noah J. Reger, Douglas S. Portman, Denise M. Ferkey, Elad Schneidman, Meital Oren-Suissa

Preprint posted on 15 December 2021

Article now published in Current Biology at

Rewiring a single synaptic connection reprograms a sexually dimorphic behavior in C. elegans.

Selected by Chee Kiang Ewe


Sexual selection often results in sexual dimorphism – the differences in appearance and behavior between males and females of the same species – that promotes reproductive success. For example, in many species of songbirds, the male produces a complex song to attract mating partners, whereas the female does not. However, this sexual display may unwittingly lead to increased exposure to predators and parasites. This “viability cost” is optimized during evolution to ensure the overall fitness of the species in different environments [1,2].

Despite a relatively simple nervous system (302 and 387 neurons in hermaphrodite and male, respectively), the nematode C. elegans exhibits many complex sex-specific behaviors. The recent reconstruction of the connectomes of both male and hermaphrodite worms provides a springboard for understanding the neuronal basis of sexually dimorphic characteristics [3]. It has previously been shown in C. elegans that sex-specific neurons may drive sexually dimorphic behaviors. For example, the distinct pheromone response between sexes can be, in part, attributed to the head CEM sensory neurons present only in males [4]. In other cases, the variation in synaptic wiring patterns among the sex-shared neurons can generate dimorphic outputs. In this fascinating preprint, the authors demonstrated that dimorphic behavioral responses evoked by noxious/painful sensations (known as nociception) in C. elegans is driven by the same set of sex-shared neurons that are differentially wired, providing an important insight into the molecular mechanism underlying sex-specific circuit development.

Figure 1: Hermaphrodite (left) vs. male (right) nociceptive circuit. The distinct connectivity structures give rise to sexually dimorphic behaviors (adapted from figures 2; Pechuk, Goldman, Salzberg, et al. 2021).

Main findings:

  • C. elegans exhibits sexually dimorphic aversive behaviors

To investigate sex-specific aversion response, the authors exposed both males and hermaphrodites to various noxious stimuli, including SDS, glycerol, quinine, and copper. While both sexes avoided noxious stimuli at high concentrations, the authors found that hermaphrodites showed an increased sensitivity at low concentrations.

  • Variation in the connectivity between the sex-shared neurons generates sexually dimorphic behaviors

ASH neurons, the primary nociceptors in C. elegans, relay sensory information through the downstream interneurons that mediate forward (AVB, PVC) and backward (AVA, AVD) movement. Although all the neurons in this circuit are sex-shared, the synaptic wiring patterns are sexually dimorphic. For example, ASH forms chemical synapses with AVA and AVB only in hermaphrodites, not in males (Figure 1).

The authors found that activating ASH neurons (which were modified to contain a light-sensitive ion channel) with LED light triggered sexually dimorphic aversive behaviors; however, sensory transduction in ASH did not appear to exhibit dimorphism as the expression of sensory receptors and their downstream signaling molecules, calcium response, and the synaptic transmission machinery were similar in both sexes. The authors later showed that, in contrast, sex differences in the connectivity in the nociceptive circuit (downstream of ASH input) could account for the distinct behavioral output.

To investigate how the neural network structure might give rise to dimorphic behavior, the authors performed computational simulation and found a small set of biophysical parameters that would trigger an aversive response upon ASH activation in both males and hermaphrodites, as observed experimentally. Importantly, the same parameters were shown to activate dimorphic behaviors in male and hermaphrodite with different circuit structures.

Using calcium imaging, AVA interneurons were found to behave differently in males and hermaphrodites in response to aversive stimuli as the calcium response was stronger and lasted longer in hermaphrodites than in males. Male ASH neurons do not connect to AVA (Figure 1), but feminizing sensory neurons by expressing TRA-2 (driven by osm-5 promotor that is activated in most ciliated sensory neurons), which stabilizes the TRA-1 hermaphroditic identity determinant transcription factor in otherwise male animals [5], causes ectopic formation of ASH-AVA synapses as well as hermaphrodite-like nociceptive response. Remarkably, artificially tethering ASH and AVA by expressing mammalian connexin36-mediated synthetic gap junctions in the two neurons in males promoted glycerol-induced aversive behavior, as observed in wild-type hermaphrodites. Thus, sexually dimorphic ASH-AVA connection gives rise to distinct nociceptive behaviors in males and hermaphrodites.

Curiously, masculinizing the hermaphrodite nervous system showed very little effect on synaptic patterning and behaviors, suggesting that the hermaphrodite nervous system is more robust than that of males, which may have important evolutionary and ecological implications.

  • Rewired males are less efficient at searching for hermaphrodites

To investigate whether the dimorphic nociceptive neuronal circuit controls other behavioral outputs outside of nociception, the authors turned their attention to mate searching and mating behaviors which are also highly sex-specific. The authors activated ASH with light in wild-type and sensory-feminized males and compared their ability to search and contact the hermaphrodites while receiving optogenetic nociceptive stimulations. It was found that sensory-feminized males are less efficient at reaching the hermaphrodites, suggesting that the altered circuitry topology that allows males to readily avoid noxious stimuli impairs mating behaviors. Hence, the sexually dimorphic nociceptive circuit is likely the consequence of sexual selection that promotes male mating success.

What I liked about this preprint:

Using a network model, the authors predicted how sex-specific synapses generate dimorphic behaviors and confirmed their findings through a series of elegant molecular analyses. The finding that sexually dimorphic behavioral response can be tuned by rewiring a single synaptic connection is particularly striking!

Questions to the authors:

How do you think the nociceptive circuit might interact with the mating circuit?

Can sensory-feminized males still respond to mate-finding pheromone cues from the hermaphrodites?


  1. Okada K, Katsuki M, Sharma MD, Kiyose K, Seko T, Okada Y, et al. Natural selection increases female fitness by reversing the exaggeration of a male sexually selected trait. Nature Communications 2021 12:1. 2021;12: 1–10. doi:10.1038/s41467-021-23804-7
  2. Møller AP, Nielsen JT, Garamszegi LZ. Song post exposure, song features, and predation risk. Behavioral Ecology. 2006;17: 155–163. doi:10.1093/BEHECO/ARJ010
  3. Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al. Whole-animal connectomes of both Caenorhabditis elegans sexes. Nature. 2019;571: 63–71. doi:10.1038/s41586-019-1352-7
  4. Narayan A, Venkatachalam V, Durak O, Reilly DK, Bose N, Schroeder FC, et al. Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America. 2016;113: E1392–E1401. doi:10.1073/PNAS.1600786113/-/DCSUPPLEMENTAL
  5. Mowrey WR, Bennett JR, Portman DS. Distributed Effects of Biological Sex Define Sex-Typical Motor Behavior in Caenorhabditis elegans. The Journal of Neuroscience. 2014;34: 1579. doi:10.1523/JNEUROSCI.4352-13.2014


Tags: circuit topology, neuroscience, sexual dimorphism

Posted on: 23 December 2021


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Author's response

Meital Oren-Suissa shared

How do you think the nociceptive circuit might interact with the mating circuit?

We hypothesize that the interneuron level integrates attractive and repulsive cues, and the stronger input “wins” and triggers the appropriate behavior. In the feminized males the integration of the sensory inputs is tuned to prefer the aversive ones more than in wild-type males, because of their rewired ASH-AVA connection. Thus, in the decision-making process between avoidance and attraction to mates, the feminized males prefer the avoidance behavior.

Can sensory-feminized males still respond to mate-finding pheromone cues from the hermaphrodites?

Yes, they can. We tested a control group of feminized males without ATR (the essential co-factor of the light-sensitive channel), and this group showed the same high attraction levels as wild-type males. Thus, our results suggest that the sensory-feminized males have wild-type pheromone sensing.

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