Ancient neuromodulation by vasopressin/oxytocin-related peptides

Abstract

Neuropeptidergic signaling is widely adopted by animals for the regulation of physiology and behavior in a rapidly changing environment. The vasopressin/oxytocin neuropeptide family originates from an ancestral peptide precursor in the antecedent of protostomian and deuterostomian animals. In vertebrates, vasopressin and oxytocin have both hormonal effects on peripheral target tissues, such as in the regulation of reproduction and water balance, and neuromodulatory actions in the central nervous system controlling social behavior and cognition. The recent identification of vasopressin/oxytocin-related signaling in C. elegans reveals that this peptidergic system is widespread among nematodes. Genetic analysis of the C. elegans nematocin system denotes vasopressin/oxytocin-like peptides as ancient neuromodulators of neuronal circuits involved in reproductive behavior and associative learning, whereas former invertebrate studies focused on conserved peripheral actions of this peptide family. Nematocin provides neuromodulatory input into the gustatory plasticity circuit as well as into distinct male mating circuits to generate a coherent mating behavior. Molecular interactions are comparable to those underlying vasopressin- and oxytocin-mediated effects in the mammalian brain. Understanding how the vasopressin/oxytocin family fine-tunes neuronal circuits for social behavior, learning and memory poses a major challenge. Functional conservation of these effects in nematodes and most likely in other invertebrates enables the development of future models to help answering this question.

Keywords: C. elegans; learning; nematocin; neuromodulation; neuropeptide; oxytocin; reproductive behavior; vasopressin.

Figure 1. Schematic architecture and sequence alignment of vasopressin/oxytocin-related precursor proteins. Amino acid sequences are aligned for representative precursors (with GenBank accession numbers) from mammals, ecdyzozoans and lophotrochozoans: C. elegans nematocin (AFJ42491.1), human vasopressin (AAA61291.1) and oxytocin (AAA59977.1), Lymnea stagnalis conopressin (AAB35220.1), Tribolium castaneum inotocin (NP_001078831.1) and Eisenia fetida annetocin (CAD20057.2). Identical residues are highlighted in black and similar amino acids in gray. Disulfide bridges in the peptide and neurophysin domain are indicated with red lines and cleavage sites for proprotein convertases in blue. An additional glycopeptide, copeptin, is cleaved from the human vasopressin precursor, but probably not from other depicted sequences. Glycosylation of copeptin occurs at the asterisk-marked residue.

Figure 2. Putative model for nematocin-dependent regulation of gustatory plasticity in C. elegans (based on Hukema et al.). Cells and selected genes implicated in gustatory plasticity are depicted. Genetic evidence supports for genes depicted in white to be active in the same genetic pathway, and effects of asterisk-marked genes were assigned to gene functions in the indicated neuron(s). Chemoattraction to low salt concentrations is primarily mediated by the ASE neurons; while ASH, ADL, ASI and ADF neurons are thought to promote salt avoidance in gustatory plasticity. Integration of attraction and avoidance signals determines the worm’s chemotaxis behavior. In this model, gustatory plasticity following pre-exposure to “low salt” and “no food” cues could result from the sensitization of avoidance-promoting neurons, most likely by an ASE-derived signal and/or the desensitization of attraction-promoting cells. Sensory information is also indirectly received by the nematocin (NTC-1)-producing AVK interneurons and potentially other nematocinergic cells. Nematocin secretion from these neurons activates the NTR-1 receptor in the ASEL neuron among others, which in turn may contribute to the production of the ASE-derived sensitization-signal. In addition, nematocin could act on avoidance-promoting neurons to shift the balance toward salt avoidance.