Infections have been identified as possible risk factors for aging-related neurodegenerative diseases, but it remains unclear whether infection-related immune molecules have a causative role in neurodegeneration during aging. Here, we reveal an unexpected role of an epidermally expressed antimicrobial peptide, NLP-29 (neuropeptide-like protein 29), in triggering aging-associated dendrite degeneration in C. elegans. The age-dependent increase of nlp-29 expression is regulated by the epidermal tir-1/SARM-pmk-1/p38 MAPK innate immunity pathway. We further identify an orphan G protein-coupled receptor NPR-12 (neuropeptide receptor 12) acting in neurons as a receptor for NLP-29 and demonstrate that the autophagic machinery is involved cell autonomously downstream of NPR-12 to transduce degeneration signals. Finally, we show that fungal infections cause dendrite degeneration using a similar mechanism as in aging, through NLP-29, NPR-12, and autophagy. Our findings reveal an important causative role of antimicrobial peptides, their neuronal receptors, and the autophagy pathway in aging- and infection-associated dendrite degeneration.

Prairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (Oxtr) is critical for the display of social monogamy in these animals. We used CRISPR mutagenesis to generate three different Oxtr-null mutant prairie vole lines. Oxtr mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex, even when assayed using different experimental setups. Mothers lacking Oxtr delivered viable pups, and parents displayed care for their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that social attachment, parturition, and parental behavior can occur in the absence of Oxtr signaling in prairie voles.