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Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine-coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and\n                    <jats:italic>gar-3<\/jats:italic>\n                    mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.\n                  <\/jats:p>","DOI":"10.7554\/elife.107726","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T14:30:59Z","timestamp":1756218659000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.107726","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptional responses to chronic oxidative stress require cholinergic activation of G-protein-coupled receptor signaling"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7243-1422","authenticated-orcid":true,"given":"Kasturi","family":"Biswas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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