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. 2019 Apr 2;116(14):7107-7112.
doi: 10.1073/pnas.1819261116. Epub 2019 Mar 14.

Reciprocal modulation of 5-HT and octopamine regulates pumping via feedforward and feedback circuits in C. elegans

Hui Liu  1 , Li-Wei Qin  1 , Rong Li  1 , Ce Zhang  1 , Umar Al-Sheikh  1 , Zheng-Xing Wu  2
Affiliations

Reciprocal modulation of 5-HT and octopamine regulates pumping via feedforward and feedback circuits in C. elegans

Hui Liu et al. Proc Natl Acad Sci U S A. .

Erratum in

Abstract

Feeding is vital for animal survival and is tightly regulated by the endocrine and nervous systems. To study the mechanisms of humoral regulation of feeding behavior, we investigated serotonin (5-HT) and octopamine (OA) signaling in Caenorhabditis elegans, which uses pharyngeal pumping to ingest bacteria into the gut. We reveal that a cross-modulation mechanism between 5-HT and OA, which convey feeding and fasting signals, respectively, mainly functions in regulating the pumping and secretion of both neuromodulators via ADF/RIC/SIA feedforward neurocircuit (consisting of ADF, RIC, and SIA neurons) and ADF/RIC/AWB/ADF feedback neurocircuit (consisting of ADF, RIC, AWB, and ADF neurons) under conditions of food supply and food deprivation, respectively. Food supply stimulates food-sensing ADFs to release more 5-HT, which augments pumping via inhibiting OA secretion by RIC interneurons and, thus, alleviates pumping suppression by OA-activated SIA interneurons/motoneurons. In contrast, nutrient deprivation stimulates RICs to secrete OA, which suppresses pumping via activating SIAs and maintains basal pumping and 5-HT production activity through excitation of ADFs relayed by AWB sensory neurons. Notably, the feedforward and feedback circuits employ distinct modalities of neurosignal integration, namely, disinhibition and disexcitation, respectively.

Keywords: C. elegans; disexcitation; octopamine; pharyngeal pumping; serotonin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
ADFs augment pharyngeal pumping possibly via two neuronal circuits. (A) Pumping rates in worms of different genotypes as indicated treated with or without the indicated chemicals. (B) Curves (Left) and average peak intensities (Right) of the somal Ca2+ transients in RIC interneurons in the indicated worms under the administration of OP50 supernatant. (C) Pumping rates in worms of different genotypes as indicated. (D) Curves (Left) and average peak intensities (Right) of the somal Ca2+ transients in AWBs in the indicated worms under the administration of OP50 supernatant. Statistical significance is indicated as follows: ns, not significant, *P < 0.05, **P < 0.01, and ****P < 0.0001 in comparison with the value for WT worms or as indicated.
Fig. 2.
Fig. 2.
Top-down feedback circuit consisting of RIC, AWB, and ADF neurons. (A–K) Curves (Left) and average peak intensities (Right) of the food cue-evoked somal Ca2+ signals in AWBs (A and B) and ADFs (C–K) in worms of the indicated genotypes treated with or without chemicals as indicated. (L) Pumping rates in the indicated worms treated with or without exogenous 5-HT (4 μM). Statistical significance is indicated as follows: ns, not significant, *P < 0.05, **P < 0.01, and ****P < 0.0001 in comparison with the value for WT worms or as indicated.
Fig. 3.
Fig. 3.
Identification of the neurotransmission modalities between neurons in the ADF-RIC-AWB-ADF feedback circuit. (A) Curves (Left) and average peak intensities (Right) of the somal Ca2+ signals in ADFs in WT worms under the administration of various concentrations (in OD) of E. coli OP50. (B–D) Curves (B and C) and average peak intensities (D) of the somal Ca2+ signals in the indicated worms in RICs under different concentrations of E. coli OP50. (E–J) Curves (Left) and Hill plots (Right) of the somal Ca2+ signals (peak values in the first 10 s of the on or off responses as indicated by the frame) in neurons in the indicated worms treated with the indicated chemicals at various concentrations. All data are expressed as the mean ± SEM as indicated by solid traces or bars ± gray shading or error bars. The number of tested worms for each genotype is indicated.
Fig. 4.
Fig. 4.
Roles of the feedback circuit in the regulation of pharyngeal pumping and ADF activity. (A and B) Pumping rates (A) and percent decreases in pumping rates (B) in worms of the indicated genotypes cultured in solutions with various E. coli OP50 concentrations. (C) Pumping rates in the indicated worms under well-fed conditions and after 8 h of food deprivation. (D and E) Curves (D) and average peak intensities (E, WT data from Fig. 3A) of the somal Ca2+ signals in ADFs in the indicated worms under various concentrations of E. coli OP50. (F) Fluorescence intensity of GFP in ADFs driven by the tph-1 promoter in the indicated worms. Statistical significance is indicated as follows: ns, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 compared with the value for WT N2 (A) or mgIs42 worms (D), as indicated (B), or within a feeding condition (C).
Fig. 5.
Fig. 5.
Model of the neural circuits that regulate pumping and 5-HT production in food-sensing ADFs under conditions of food supply and food deprivation. In a well-fed state, increased 5-HT release from ADFs augments disinhibitory activity in the feedforward circuit to enhance pumping via suppression of OA secretion in RIC interneurons that results in reduced activity in SIA neurons. In a fasting state, reduced disexcitation in the feedback circuit maintains basal 5-HT production in ADFs, and reduced disinhibition in the feedforward circuit mediates pumping inhibition due to food deprivation signals conveyed by OA.
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