{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:47:30Z","timestamp":1785422850755,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,11]]},"group-title":"Neuroscience","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R21NS135762"],"award-info":[{"award-number":["R21NS135762"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1NS114128-01A1S1"],"award-info":[{"award-number":["RF1NS114128-01A1S1"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["G24KJ0033"],"award-info":[{"award-number":["G24KJ0033"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["G25K18771"],"award-info":[{"award-number":["G25K18771"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The\n                  <jats:italic>C9orf72<\/jats:italic>\n                  hexanucleotide repeat expansion is the most prevalent genetic cause of ALS\/FTD. Here, we used\n                  <jats:italic>Drosophila<\/jats:italic>\n                  models expressing toxic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS\/FTD. We found that circadian rhythmicity and period length were disrupted in a repeat number-, dosage-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly restored circadian function under select conditions. These results implicate reduced neuronal activity in C9orf72-ALS\/FTD circadian deficits, underscoring the importance of precisely tuned, circuit- and stage-specific interventions.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        C9orf72 dipeptide and nucleotide repeats disrupt circadian rhythms in\n                        <jats:italic>Drosophila<\/jats:italic>\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Circadian dysfunction with reduced PDF and neurites emerges before neuron loss<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Increased neuronal activity rescues mild circadian dysfunction<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Activity-based rescue is effective across ages and models when precisely tuned<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.07.669085","type":"posted-content","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T14:55:22Z","timestamp":1754924122000},"source":"Crossref","is-referenced-by-count":0,"title":["Increased neuronal activity restores circadian function in\n                  <i>Drosophila<\/i>\n                  models of C9orf72-ALS\/FTD"],"prefix":"10.64898","author":[{"given":"Sho","family":"Inami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Jenny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oghenerukevwe","family":"Akpoghiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara I.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra K.","family":"Strich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Tonoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Trotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron 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