{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:37:36Z","timestamp":1785418656622,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,8]]},"group-title":"Neuroscience","reference-count":99,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"https:\/\/ror.org\/02a3w7r50","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CHOP Research Institute","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["F31 NS122297"],"award-info":[{"award-number":["F31 NS122297"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"award":["T32-HG000046"],"award-info":[{"award-number":["T32-HG000046"]}],"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Huntington\u2019s disease involves progressive corticostriatal dysfunction; however, the timing of region-specific transcriptional changes remains unresolved at cellular resolution. Here, we provide a temporal single-nucleus transcriptomic atlas of striatum and motor cortex from zQ175 knock-in mice at 6 and 18 months. This full-length Huntingtin model enables staging of progressive circuit dysfunction. Striatal projection neurons show extensive early dysregulation with progressive striosomal identity erosion, whereas cortical pyramidal neuron dysfunction was layer-specific and coincided with motor symptom onset. By modeling genotype-dependent effects, we distinguish region- and cell type-specific signatures of core disease mechanisms from age-related changes and compensatory adaptations. Integrating gene co-expression and transcription factor regulatory networks, we predict candidate regulators of stage-specific dysfunction. These findings, validated across human HD and mouse model datasets, reveal temporal dynamics of disease pathogenesis in regionally distinct and interconnected neuronal populations, establishing a framework for understanding cell type-selective vulnerability.<\/jats:p>","DOI":"10.64898\/2026.01.07.698249","type":"posted-content","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T20:55:30Z","timestamp":1767905730000},"source":"Crossref","is-referenced-by-count":0,"title":["Temporal single-cell atlas of full-length Huntington\u2019s disease mouse model defines stage-specific signatures of corticostriatal dysfunction"],"prefix":"10.64898","author":[{"given":"Ashley B.","family":"Robbins","sequence":"first","affiliation":[{"name":"Raymond G. 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