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Thalamostriatal (T-S) synapses are critical for CF, and we previously identified Heat Shock Factor 1 (HSF1) as a regulator of T-S density in HD. However, how HSF1 regulates T-S synapses and whether it modulates cognitive flexibility (CF) remained unclear. Here, we combined HSF1 ChIP-seq, transcriptomics, synapto-proteomics, targeted genetic manipulations and behavioral analyses to study how HSF1 regulates T-S synapses and CF. We found HSF1 directly controls a transcriptional program governing postsynaptic architecture and actin cytoskeletal dynamics, which are disrupted in aging and HD. Loss of HSF1 drives selective destabilization of actin patches at T-S shaft synapses and impaired CF decline. Our results underscore a novel function for HSF1 in the regulation of striatal neural circuits with essential implications in the neurobiology of cognitive flexibility.<\/jats:p>","DOI":"10.64898\/2026.08.03.742053","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T09:20:38Z","timestamp":1786094438000},"source":"Crossref","is-referenced-by-count":0,"title":["HSF1 controls transcriptional programs that establish thalamostriatal shaft synaptic architecture and preserve cognitive flexibility"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-6097","authenticated-orcid":false,"given":"Nicholas B","family":"Rozema","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4839-7783","authenticated-orcid":false,"given":"Nicole","family":"Zarate","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3421-7000","authenticated-orcid":false,"given":"Rachel","family":"Mansky","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9080-163X","authenticated-orcid":false,"given":"Persephone","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinsey","family":"Gerlach","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2584-5765","authenticated-orcid":false,"given":"Aishwarya","family":"Bhowmik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3764-7329","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Minnesota Supercomputing Institute, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-0067","authenticated-orcid":false,"given":"Arif","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2291-1617","authenticated-orcid":false,"given":"Steven M","family":"Graves","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1136-5462","authenticated-orcid":false,"given":"Rocio","family":"Gomez-Pastor","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical School, University of Minnesota, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080903550946000_2026.08.03.742053v1.1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1555115"},{"key":"2026080903550946000_2026.08.03.742053v1.2","doi-asserted-by":"crossref","unstructured":"Riddle, D. 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