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Glia-derived neurons are required for sex-specific learning in C. elegans

Abstract

Sex differences in behaviour extend to cognitive-like processes such as learning, but the underlying dimorphisms in neural circuit development and organization that generate these behavioural differences are largely unknown. Here we define at the single-cell level—from development, through neural circuit connectivity, to function—the neural basis of a sex-specific learning in the nematode Caenorhabditis elegans. We show that sexual conditioning, a form of associative learning, requires a pair of male-specific interneurons whose progenitors are fully differentiated glia. These neurons are generated during sexual maturation and incorporated into pre-exisiting sex-shared circuits to couple chemotactic responses to reproductive priorities. Our findings reveal a general role for glia as neural progenitors across metazoan taxa and demonstrate that the addition of sex-specific neuron types to brain circuits during sexual maturation is an important mechanism for the generation of sexually dimorphic plasticity in learning.

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Figure 1: The MCMs are newly identified male-specific neurons.
Figure 2: MCM connectivity.
Figure 3: The MCMs are required for male-specific associative learning.
Figure 4: MCM ablation does not affect other male-specific behaviours.
Figure 5: The MCMs originate from a male-specific cell division of the AMso glial cells.
Figure 6: The male AMso cells are fully differentiated glia before and after the division that generates the MCM neuron.

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Acknowledgements

We would like to acknowledge M. Barr, in whose laboratory A.B. discovered the MCMs; WormAtlas for illustrations (reproduced with permission); T. Jarrell for contributions to the EM reconstruction; and W. Letton for the generation of strains and preliminary ablation studies. We thank M. Boxem, D. Portman, H. Baylis, L. Bianchi and R. Garcia for strains and reagents; M. Zhen, O. Hobert, I. Carrera, N. Stefanakis and S. Shaham, for unpublished reagents. Purified ascarosides were a gift from F. Schroeder to the Barr laboratory. Additional strains were obtained from the CGC, which is funded by NIH grant P40 OD010440. We thank L. Cochella, I. Carrera, S. Jarriault, and several of our close colleagues in CDB and NPP at University College London for discussions and comments on the manuscript; C. Barnes for advice on statistical analysis. This work was supported by a Master it! Scholarship Scheme (Malta and EU) to M.S., by NIH grant OD010943 to D.H.H., by Marie Curie CIG grant 618779 to R.J.P. and by a grant from The G. Harold and Leila Y. Mathers Charitable Foundation to S.W.E.; S.J.C. is supported by NIH grant 5T32GM007491; R.J.P. is a Wellcome Trust Research Career Development Fellow 095722/Z/11/Z; A.B. is supported by the Wellcome Trust Institutional Strategic Support Fund 097815/Z/11/A.

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Authors and Affiliations

Authors

Contributions

M.S., T.F., R.J.P. and A.B. conceived and performed the development and behaviour experiments. S.J.C., K.C.Q.N., S.W.E. and D.H.H. performed the ultrastructural analysis of the MCMs. S.J.C. and S.W.E. reconstructed the connectivity of the MCMs from serial EM sections. R.J.P. and A.B. co-wrote the manuscript and discussed it with all the authors.

Corresponding authors

Correspondence to Richard J. Poole or Arantza Barrios.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 The MCMs are newly identified male-specific neurons.

a, WormAtlas-style diagram depicting the morphology and position of one of the bilateral pair of MCM neurons in the head of a male worm and its projection within the nerve ring and along the ventral cord. b, Volumetric reconstruction of the MCML cell body and projection based on tracing of serial EM sections. c, Co-expression of transgenes for neuronal markers in the rab-3-positive cells identified as MCMs (indicated with dashed red circles). All photographs are lateral views of animals oriented anterior to the left and dorsal to the top except for ric-19, which are dorsal views. Transgenes are listed in Extended Data Table 1. pdf-1 (neuropeptide pigment dispersing factor); snb-1 (synaptobrevin); ida-1 (tyrosine phosphatse-like receptor, orthologue of mammalian phogrin); ric-19 (rab-2 effector); nca-1 (NALCN Na+ channel subunit); ccb-1 (voltage-gated Ca2+ channel subunit); unc-36 (voltage-gated Ca2+ channel subunit); inx-3 (gap junction innexin). D, dorsal; L, left; R, right; V, ventral. d, Diagram of the neurons that directly connect to and from the MCMs. Triangles, sensory neurons; octagons, interneurons and unidentified neurons. The thickness of the arrows is proportional to the anatomical strength of the connections (Extended Data Table 2).

Extended Data Figure 2 The MCMs are not required for other male-specific behaviours.

a, Response of intact and MCM-ablated males (inIs179(ida-1::gfp);him-8(e1489) and otIs356(rab-3::rfp)him-5(e1490)) to dilutions of ascaroside pheromones (Ascr). Graphs represent Tukey box plots of logarithmic transformations of the data; n, number of independent events (that is, entry in scoring region). t-test with Bonferroni correction was used for statistical analysis. ***P < 0.001; **P < 0.01; *P < 0.05; n.s., no statistically significant difference (P ≥ 0.05). b, Response efficiency to mate contact of intact, MCM-ablated and pdf-1(tm1996) mutant males measured as the proportion of responses out of total contacts with an hermaphrodite. Intact and MCM-ablated animals were inIs179(ida-1::gfp);him-8(e1489). Wild-type animals were him-5(e1490). A response indicates that the male placed its tail ventral down on the mate’s body and backed along it to make a turn. c, d, Proportion of good turns (c) and location of vulva efficiency (d) of intact and MCM-ablated males (inIs179(ida-1::gfp);him-8(e1489) and otIs356(rab-3::rfp)him-5(e1490)). e, Fertility (measured as proportion of cross-progeny) of intact and MCM-ablated males (otIs356(rab-3::rfp)him-5(e1490)). For be, n, number of individual animals tested. Error bars indicate s.e.m. Mann–Whitney U-test was used for statistical analysis. *P < 0.05; n.s., no statistically significant difference (P ≥ 0.05). f, Mate-searching behaviour, measured as PL values (probability of leaving food per hour) in the absence or presence of mates, of intact and MCM-ablated males (otIs356(rab-3::rfp)him-5(e1490)). n, number of individual animals tested. Two independent population assays were performed on different days. Maximum likelihood statistical analysis was used to compare PL values. Error bars indicate s.e.m. ***P <0.001; n.s., no statistically significant difference (P ≥ 0.05).

Extended Data Figure 3 The MCMs arise from a division of the AMso glial cell.

All photographs are lateral views of animals oriented anterior to the left and dorsal to the top. a, Fluorescent photographs showing the two cells expressing rnr-1::gfp co-labelled with the glial marker ptr-10::rfp and the neuronal marker rab-3::rfp in the head of males at the early and late L4 stages. The AMso and MCM cell bodies are indicated with dashed lines. b, Fluorescent images of the AMso cell body and its projection at two time points during cell division. Photos are overexposed for visualization of the projection, indicated by arrows. The chromosomes are labelled with a histone::rfp transgene, and the AMso cell body is indicated by dashed lines.

Extended Data Figure 4 AMso plasticity is regulated by AMso genetic sex.

a, Diagram of the AMso and MCM lineage. b, c, Proportion of individuals with MCMs in control animals and animals expressing sex-reversing transgenes in AMso. b, AMso masculinization with grl-2::fem-3::SL2::mCherry transgenes (oleEx18 and oleEx24). c, AMso feminization with grl-2::tra-2IC::SL2::mCherry transgenes (oleEx19 and oleEx23) and ztf-16::tra-2IC::SL2::mCherry transgene oleEx22. MCM cell fate was identified with ida-1::gfp or rab-3::yfp reporter transgenes. In the head, the grl-2 promoter drives expression in AMso and the excretory duct and pore cells, and the ztf-16 glial enhancer drives expression in the AMso and amphid sheath glia. # indicates an independent transgenic array line for each manipulation. χ2 test was used for statistical analysis; ***P < 0.001; n.s., no statistical significant difference (P ≥ 0.05); n = number of animals scored.

Extended Data Figure 5 The MCMs lose molecular and structural characteristics of glia after birth.

a, Proportion of MCMs with presence of the glial marker ptr-10::myrRfp or the neuronal marker ida-1::gfp at different stages after MCM birth. b, Electron micrograph of a cross-section of an adult male head showing the MCM and AMso cell body ultrastructure. Neighbouring tissues are colour coded following WormAtlas (http://www.wormatlas.org/colorcode.htm). Purple (pharynx), muscle (green), hypodermis (light cream), AMso (amphid socket, pink). The dendrites of the amphid neurons (amphid bundle) are not colored.

Extended Data Table 1 Reporter transgenes for neuronal markers tested for MCM expression
Extended Data Table 2 MCM connectivity
Extended Data Table 3 Cell ablations of candidate MCM progenitors
Extended Data Table 4 Mosaic analysis of sex-transformation arrays, scoring the presence of MCMs
Extended Data Table 5 Reporter transgenes for glial/AMso markers

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Sammut, M., Cook, S., Nguyen, K. et al. Glia-derived neurons are required for sex-specific learning in C. elegans. Nature 526, 385–390 (2015). https://doi.org/10.1038/nature15700

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