Tachykinin-like NLP-58 signaling through TKR-1 modulates thermotaxis behavior in Caenorhabditis elegans

Neurokinin B (NKB) signaling plays a central role in mammalian thermoregulatory dysfunction associated with menopause, yet the underlying neural mechanisms remain incompletely understood. Here, we establish Caenorhabditis elegans thermotaxis as a genetically tractable system for investigating conserved tachykinin signaling. We demonstrate that overexpression of nlp-58 , the C. elegans ortholog of mammalian NKB, induces abnormal thermotaxis behavior without impairing the temperature response of the thermosensory neurons. NLP-58 is expressed in multiple neurons, including the AIY interneurons, a central integrative node of the thermosensory circuit. AIY-specific overexpression of nlp-58 is sufficient to reproduce the thermotaxis defect, identifying AIY as an important site of NLP-58-dependent behavioral modulation. Genetic analyses further demonstrated that the thermotaxis behavior is mediated primarily through the tachykinin receptor TKR-1, the homolog of mammalian tachykinin 3 receptor (NK3R), acting in ASG and/or ASJ sensory neurons. We also identified a genetic interaction between dhs-4 , a lipid metabolic enzyme gene, and nlp-58 , suggesting that lipid metabolic pathway modulate tachykinin-dependent thermotaxis behavior. Furthermore, endogenous NLP-58/TKR-1 signaling contributed to the age-dependent decline in thermotaxis behavior. Finally, treatment with fezolinetant, a selective NK3R antagonist used clinically for menopausal vasomotor symptoms, partially improved the thermotaxis defect caused by nlp-58 overexpression. Together, our findings identify the NLP-58/TKR-1 signaling pathway as a modulatory component of thermotaxis behavior and provide a framework for investigating conserved principles of tachykinin-dependent circuit modulation.