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Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans

Abstract

Neural circuits detect environmental changes and drive behavior. The routes of information flow through dense neural networks are dynamic, but the mechanisms underlying this circuit flexibility are poorly understood. Here, we define a sensory context–dependent and neuropeptide-regulated switch in the composition of a C. elegans salt sensory circuit. The primary salt detectors, ASE sensory neurons, used BLI-4 endoprotease–dependent cleavage to release the insulin-like peptide INS-6 in response to large, but not small, changes in external salt stimuli. Insulins, signaling through the insulin receptor DAF-2, functionally switched the AWC olfactory sensory neuron into an interneuron in the salt circuit. Worms with disrupted insulin signaling had deficits in salt attraction, suggesting that peptidergic signaling potentiates responses to high salt stimuli, which may promote ion homeostasis. Our results indicate that sensory context and neuropeptide signaling modify neural networks and suggest general mechanisms for generating flexible behavioral outputs by modulating neural circuit composition.

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Figure 1: A distributed neural network encodes salt concentration.
Figure 2: AWCON sensory neurons act as interneurons in the salt circuit.
Figure 3: AWCON salt responses require peptidergic neurotransmission from ASEL.
Figure 4: INS-6 signals through DAF-2 and AGE-1 to remodel the ASEL-AWCON salt circuit.

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Acknowledgements

We thank the Caenorhabditis Genetics Center, the National Brain Research Project (Japan), C. Bargmann, P. Sengupta, P. Sternberg and A. Zaslaver for worm strains, M. Ailion for unc-31 cDNA, and Y. Jin, C. Stevens, T. Sejnowski, E.J. Chichilnisky and H. Karten for helpful discussions. We also acknowledge J. Fitzpatrick and J. Kasuboski of the Waitt Advanced Biophotonics Center for providing the resources and training to perform confocal imaging and J. Simon for help with the illustrations. We are grateful to A. Tong, C. Yang and other members of the Chalasani laboratory for critical help, advice and insights. This work was funded by grants from The Searle Scholars Program, March of Dimes, Whitehall Foundation, Rita Allen Foundation and US National Institutes of Health grant R01MH096881-01A1 (S.H.C.). S.G.L. holds a graduate research fellowship from the NSF.

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S.G.L. conceived and conducted the experiments, interpreted the data, and wrote the paper. S.H.C. conceived the experiments, interpreted the data and wrote the paper.

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Correspondence to Sreekanth H Chalasani.

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Integrated supplementary information

Supplementary Figure 1 Heat maps show individual ASEL and AWCON sensory neuron and AIA interneuron responses to salt.

(a) ASE and AWC chemosensory neurons in the head of C. elegans. (b) Heat maps of ratio change in fluorescence to total fluorescence for ASEL and AWCON responses to +50 mM NaCl show consistent calcium transients in response to onset of salt stimulus. (c) Heat maps of ASEL and AWCON responses to +10 mM NaCl show consistent calcium transients from ASEL and no responses from AWCON. (d) Heat maps of ratio change in fluorescence to total fluorescence for AIA responses to +50 mM NaCl in wild-type and AWC-ablated animals. Wild-type responses to the onset of +50 mM NaCl are reliably larger than AWC-ablated responses. (e) Heat maps of wild-type and AWC-ablated AIA responses to +10 mM NaCl show similar small responses to the increase in salt. (b–e) One row in heat map corresponds to one neuron. Dark or light gray shading and black lines at 10 and 130 s indicate the duration of a +50 mM or +10 mM NaCl stimulus.

Supplementary Figure 2 Sensory neuron responses to NaCl.

(a) ASEL wild-type calcium responses to increasing concentrations of NaCl (+10, 20, 30 and 50 mM) increase in magnitude. (b) AWCON wild-type neurons switch from a nonresponsive state when stimulated with 10 mM NaCl to responding with increasing magnitude calcium transients to 20, 30 and 50 mM NaCl stimuli. (c) ASE right (ASER) neurons do not respond to the addition of a +50 mM NaCl stimulus; however, they display large calcium transients upon stimulus removal, which is effectively a 50 mM decrease in salt concentration. (d) AWCOFF neurons show large calcium transients in response to a 50 mM increase in NaCl, similar to AWCON (shown in Fig. 1c). (e) ASER neurons respond do not respond to the addition of a +10 mM NaCl stimulus; however, they display small calcium transients upon stimulus removal. (f) AWCOFF neurons do not respond to +10 mM NaCl. (g) AWCON does not respond to +100 mM sucrose. AWCON is not a generalized osmolarity sensor since 100 mM sucrose is an equivalent osmolarity change to 50 mM NaCl. (h) The amphid sensory neurons ASK, AWB and ASH do not respond to +50 mM NaCl. AWB neurons show small increases in fluorescence upon the removal of the salt stimulus. (a–h) Numbers on bars indicate number of neurons imaged. Dark and light gray shading indicates 2 min +50 mM or +10 mM NaCl stimulus, respectively, beginning at t = 10 s. Yellow box indicates the 10 s after stimulus addition, for which the fluorescence is averaged in the bar graphs. Light color shading around curves and bar graph error bars indicate s.e.m.

Source data

Supplementary Figure 3 AWC has a specific role in high salt chemotaxis.

(a) Schematic showing genetic regulators of peptidergic (CADPS homolog/UNC-31) and amino acid or small molecule (Munc13 homolog/UNC-13) synaptic neurotransmission from ASEL. BLI-4 and EGL-3 are proprotein convertase enzymes that proteolytically process neuropeptides to generate mature peptides. (b) Schematic diagram of salt chemotaxis assay. (c) Low 250 mM NaCl point source salt chemotaxis does not differ between wild-type and the AWC cell fate mutants nsy-1 (which has two AWCON neurons and no AWCOFF neurons) and nsy-5 (which has two AWCOFF neurons and no AWCON neurons) (i). High 750 mM NaCl point source chemotaxis is defective in both nsy-1 and nsy-5 mutants, suggesting non-redundant roles for both AWCON and AWCOFF neurons in high salt behavior (ii). (d) Low salt (250 mM NaCl point source) chemotaxis does not differ between wild-type and the neurotransmission defective ASEL::unc-31 RNAi, bli-4, ASEL::bli-4 RNAi, AWCON::bli-4 RNAi, and egl-3 worms. These results support the specific recruitment of AWC under high but not low salt conditions and indicate that these mutants are capable of normal salt chemotaxis under conditions when AWC is not recruited. (e) High salt (750 mM NaCl point source) chemotaxis of wild-type worms compared to AWCON::bli-4 RNAi, egl-3, and ins-6; ASI-specific ins-6 rescue. ASI-specific expression of ins-6 is not sufficient to rescue the high salt chemotaxis deficit of this mutant. (f) Low salt (250 mM NaCl point source) chemotaxis does not differ between wild-type, ins-6 mutants, ASEL-specific rescue of ins-6 with or without two arginine to serine point mutations in the BLI-4 cleavage motif (*RASS), and ASI-specific ins-6 rescue. (c–f) Number in each bar indicates number of assay plates. *Significantly different from wild-type (P < 0.05, two-tailed t-test with Bonferroni correction).

Source data

Supplementary Figure 4 osm-6 cilia control experiments support a role for AWC as an interneuron in the salt circuit.

(a) Confocal images of AWCON neuron (i) and cilia (ii–iv) morphology in wild-type (i,ii), osm-6 mutants (iii) and osm-6; ASEL::osm-6 rescue (iv). The elaborate bilateral ciliary structure (indicated by the white arrows) in wild-type AWCON neurons is lost in osm-6 mutants (iii) and is not rescued in osm-6; ASEL::osm-6 (iv). (b) ASEL responses to +50 mM NaCl in wild-type and osm-6 mutants. ASEL responses to salt are abolished in osm-6 cilia mutants. Yellow box indicates the 10 s after stimulus addition, for which the fluorescence is averaged in the bar graph. Light color shading around curves and bar graph error bars indicate s.e.m. *Significantly different from wild-type (P < 0.05, two-tailed t-test). (c) Heat maps of ratio change in fluorescence to total fluorescence for AWCON responses to +50 mM NaCl in wild-type, osm-6 mutants, osm-6; ASEL::osm-6, and osm-6; AWC::osm-6. One row in heat map corresponds to one neuron. Dark gray shading and black lines at 10 and 130 s indicate the duration of the +50 mM NaCl stimulus.

Source data

Supplementary Figure 5 Mutant AWC and ASEL calcium responses to +50 mM NaCl.

(a) AWCOFF neuron responses to +50 mM NaCl are similar in unc-13 and unc-31 neurotransmission mutants compared to wild-type, suggesting that this neuron (unlike AWCON) may be a direct and intrinsic salt detector. (b) AWCON responses to +50 mM NaCl are unaffected by mutations in the proprotein convertases kpc-1 and aex-5. AWCON::bli-4 RNAi has no effect on AWCON salt responses, indicating that bli-4 does not act in this neuron. (c) AWCON ins-6 insulin-like peptide mutant responses to +50 mM NaCl are not fully rescued by ASI expression of an ins-6 genomic DNA construct. (d) ASEL responses to +50 mM NaCl are not significantly different in unc-13, unc-31 or ins-6 mutants compared to wild-type. (e) ASEL responses to +50 mM NaCl do not differ significantly in bli-4, daf-2 or age-1 mutants compared to wild-type. (a–e) Yellow box indicates the 10 s after stimulus addition, for which the fluorescence is averaged in the bar graphs. Light color shading around curves and bar graph error bars indicate s.e.m. *Significantly different from wild-type (P < 0.05, two-tailed t-test with Bonferroni correction). n.s., not significant.

Source data

Supplementary Figure 6 Salt neural circuit model.

Proposed model for (a) ASEL encoding +10 mM NaCl and (b) AWCON recruitment to encode +50 mM NaCl by BLI-4, UNC-31, INS-6, DAF-2 and AGE-1 dependent signaling to mediate behavioral attraction.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1-6 and Supplementary Tables 1 & 2 (PDF 7612 kb)

AWCON neuron calcium response to +50 mM NaCl

The movie shows a large increase in the calcium signal the AWCON cell body upon the addition of a +50 mM NaCl stimulus at t = 10 s. The salt stimulus is removed at t = 2 min and 10 s. Images are pseudo-color coded with violet indicating low fluorescence and red and white indicating high fluorescence or increased calcium concentration. The movie is sped up three times. (MPG 4050 kb)

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Leinwand, S., Chalasani, S. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat Neurosci 16, 1461–1467 (2013). https://doi.org/10.1038/nn.3511

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