Neuromedin U signaling regulates memory retrieval of learned salt avoidance in aC. elegansgustatory circuit

Abstract

<jats:title>Abstract</jats:title><jats:p>Learning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of memory retrieval in <jats:italic>C. elegans</jats:italic> gustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the expression of learned salt avoidance. Aversive learning depends on the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the immediate retrieval, but not the acquisition, of learned salt avoidance. CAPA-1 subsequently signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to eventually modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other memory and decision-making circuits.</jats:p><jats:sec><jats:title>Graphical Abstract</jats:title><jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="683888v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

System-wide mapping of neuropeptide-GPCR interactions inC. elegans

“…Functional studies validated several neuropeptide-GPCR pairs discovered in vitro and, guided by receptor interactions, characterized novel roles of neuropeptides in the regulation of food searching, nociceptive responses, locomotory arousal, aversive learning and other behaviors 72,73,[86][87][88][89] . Here, we present the complete resource of neuropeptide-GPCR interactions (Figures S2-S7); neuropeptide-receptor couples that were validated and reported in functional studies are listed in Table 1.…”

“…In most cases, the C. elegans receptor was activated by a peptide that was a previously recognized ortholog of the neuropeptide ligands of related GPCRs 42,95,96 . Consistent with previous reports, our biochemical data supports the conservation of ligand-receptor couples related to vasopressin/oxytocin (NTC-1/NTR-1), tachykinin (NLP-58/TKR-1), GnRH (NLP-47/GNRR-1), cholecystokinin (NLP-12/CKR-1/CKR-2), neuromedin U (CAPA-1/NMUR-1/NMUR-2), NPY (FLP-34/NPR-11), thyrotropin-releasing hormone (TRH-1/TRHR-1), luqin (LURY-1/NPR-22), pigment dispersing factor (PDF-1/PDF-2/PDFR-1), and myoinhibitory peptide (MIP-1/SPRR-2) signaling systems in C. elegans 5,6,52,57,60,61,72,73,87,90,[98][99][100][101] . In addition, we deorphanized four novel C. elegans peptide GPCRs related to neuropeptide FF/SIFamide (NPR-35), tachykinin (TKR-2), NPY (NPR-12), and myoinhibitory peptide (SPRR-1) receptors (Data S9).…”

“…In addition, its genome encodes around 150 predicted peptide GPCRs 47,71 . Many of these neuropeptide systems are shared between nematodes and other animals, including humans, and have conserved functions 6,42,72,73 .…”