{"doi":"10.48496/m467-t235","title":"The Neuropeptide Regulation of Host-Seeking Behavior in Aedes Aegypti Mosquitoes","abstract":"Aedes aegypti mosquitoes are the principal vectors for several human diseases including Dengue Fever, which causes ~400 million cases and ~24,000 deaths per year (Bhatt et al., 2013; WHO, 2002). Novel strategies to combat mosquito-borne diseases are needed for A. aegypti and other mosquitoes such as the malaria vector Anopheles gambiae. Our goal was to discover new ways to interfere with the ability of a mosquito to locate a human host for a blood meal. Currently, the mechanistic basis of host-seeking and its regulation remain incompletely understood. Although it is known that mosquitoes require human odor cues to locate a human host, the critical odor components and associated olfactory receptors have not been identified (Klowden, 1995; Takken and Knols, 1999). Previous work showed that mosquito host-seeking behavior is inhibited by a hemolymph-borne humoral factor for three days following a blood meal. Subsequent studies identified Head Peptide-I as a candidate neuropeptide modulating this suppression in host-seeking behavior. This conclusion was strengthened by the observation that Head Peptide-I injection into non-blood-fed females triggered the inhibition of host-seeking. The mechanism by which this important peptide alters mosquito behavior and the receptor through which it signals are unknown (Brown et al., 1994). We used a cell-based calcium-imaging screen to identify the G-protein coupled receptor NPY-Like Receptor-1 (NPYLR1) as a candidate Head Peptide-I receptor. We found that multiple NPYLR1 agonists, including the feeding-related Short-Neuropeptide-3 (sNPF3), are capable of inhibiting host-seeking behavior when injected into non-blood-fed females. To investigate whether NPYLR1 is required for Head Peptide-I inhibition, we pioneered targeted mutagenesis with zinc-finger nucleases to create multiple NPYLR1 null-mutant mosquito lines. We predicted that these mutants would no longer show inhibition of host-seeking behavior after a blood meal. While we can say with certainty that NPYLR1 is a receptor for Head Peptide-I, we found no behavioral effects for NPYLR1 mutants in locomotion, egg-laying, sugar feeding, blood feeding, or host-seeking behavior. Our results suggest that NPYLR1 is not required in vivo for Head Peptide-I action and that a redundant signaling mechanism for behavioral inhibition exists. Future work will determine the necessity of Head Peptide-I during host-seeking inhibition and attempt to identify additional Head Peptide-I and sNPF receptors. This research will clarify the mechanism of Head Peptide-I inhibition and could form the basis for novel strategies to control mosquito host-seeking behavior.","journal":"Digital Commons - RU (Rockefeller University)","year":2025,"id":559792,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1462022,"name":"Jeff Liesch","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:39.010633Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}